case study for heart failure

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• Arq Bras Cardiol
• v.105(4); 2015 Oct

Case 4 – A 79-Year-Old Man with Congestive Heart Failure Due to Restrictive Cardiomyopathy

Sumaia mustafa.

1 Instituto do Coração (InCor) HC-FMUSP, São Paulo, SP – Brasil

Alice Tatsuko Yamada

Fabio mitsuo lima.

2 Grupo Fleury Medicina e Saúde, São Paulo, SP – Brasil

Valdemir Melechco Carvalho

Vera demarchi aiello, jussara bianchi castelli.

JAP, a 79-year-old male and retired metalworker, born in Várzea Alegre (Ceará, Brazil) and residing in São Paulo was admitted to the hospital in October 2013 due to decompensated heart failure.

The patient was referred 1 year before to InCor with a history of progressive dyspnea triggered by less than ordinary activities, lower-extremity edema, and abdominal enlargement. He sought medical care due to the abdominal enlargement, which was diagnosed as an ascites. He denied chest pain, hospitalization due to myocardial infarction or stroke, hypertension, dyslipidemia, and diabetes.

The patient was a previous smoker and had stopped smoking at the age of 37 years. He was also an alcoholic and reported drinking alcohol for the last time 1 year before.

He was referred to InCor for treatment of heart failure.

An echocardiogram revealed an increased thickness in the septum (17 mm) and free left ventricular wall (15 mm), and a left ventricular ejection fraction of 26%.

The patient reported daily use of enalapril 10 mg, spironolactone 25 mg, furosemide 80 mg, omeprazole 40 mg, and ferrous sulfate (40 mg Fe) three tablets.

On March 12, 2013, his physical examination showed a weight of 55 kg, height of 1.75 m, body mass index (BMI) of 18 kg/m 2 , heart rate of 60 bpm, blood pressure of 90 X 50 mm Hg, and the presence of a hepatojugular reflux. There were no signs of jugular venous hypertension, and the pulmonary and cardiac auscultations were normal. He had ascites, and his liver was palpable 5 cm below the right costal margin. Peripheral pulses were palpable, and a ++/4+ edema was observed.

An ECG (February 23, 2012) had shown a sinus rhythm, heart rate of 52 bpm, PR interval of 192 ms, QRS duration of 106 ms, indirect signs of right atrial overload (wide variability in QRS amplitude between V1 and V2), and left atrial overload (prolonged and notched P waves), low QRS voltage in the frontal plane with an indeterminate axis, an electrically inactive area in the anteroseptal region and secondary changes in ventricular repolarization ( Figure 1 ).

ECG: sinus bradycardia, low-voltage QRS complexes in the frontal plane, indirect signs of right atrial overload (small QRS complexes in V1 and wide QRS complexes in V2), left atrial overload, electrically inactive area in the anteroseptal region.

A chest x-ray showed cardiomegaly.

Laboratory tests performed on April 20, 2012, had shown the following results: hemoglobin 13.1 g/dL, hematocrit 40%, mean corpuscular volume (MCV) 87 fL, leukocytes 9,230/mm 3 (banded neutrophils 1%, segmented neutrophils 35%, eosinophils 20%, basophils 1%, lymphocytes 33%, and monocytes 10%), platelets 222,000 /mm 3 , cholesterol 207 mg/dL, HDL-cholesterol 54 mg/dL, LDL-cholesterol 138 mg/dL, triglycerides 77 mg/dL, creatine phosphokinase (CPK) 77 U/L, blood glucose 88 mg/dL, urea 80 mg/dL, creatinine 1.2 mg/dL (glomerular filtration rate ≥ 60 mL/min/1.73 m 2 ), sodium 131 mEq/L, potassium 6.3 mEq/L, aspartate aminotransferase (AST) 22 U/L, alanine aminotransferase (ALT) 34 U/L, uric acid 6.3 mg/dL, TSH 1.24 µUI/mL, free T4 1.36 ng/dL, prostate-specific antigen (PSA) 1.24 ng/mL. On urinalysis, urine specific gravity was 1.007, pH 5.5, the sediment was normal, and there were no abnormal elements.

A new echocardiographic assessment on April 20, 2012, had shown an aortic diameter of 32 mm, left atrium of 52 mm, septal and posterior left ventricular wall thickness of 15 mm, diastolic/systolic left ventricular diameters of 46/40 mm, and left ventricular ejection fraction of 28%. Both ventricles had diffuse and marked hypokinesia. The valves were normal and the pulmonary artery systolic pressure was estimated at 32 mmHg ( Figure 2 ).

Echocardiogram - a) Four-chamber view: marked enlargement of the left and right atria; b) parasternal long-axis view: enlarged left atrium, left ventricular wall thickening, normal cavity.

A 24-hour electrocardiographic (Holter) monitoring on April 19, 2012, showed a baseline sinus rhythm with a lowest rate of 46 bpm and greatest rate of 97 bpm; 48 isolated, polymorphic, and paired ventricular extrasystoles; 137 atrial extrasystoles; and an episode of atrial tachycardia over three beats with a frequency of 98 bpm. There were no atrioventricular or intraventricular blocks interfering with the conduction of the stimulus.

The patient was transferred from the pacemaker clinic to the general cardiopathy clinic.

During a clinic appointment on January 22, 2013, the patient was asymptomatic and reported the use of enalapril 10 mg, spironolactone 25 mg, furosemide 60 mg, and carvedilol 12.5 mg. His physical examination was normal.

The main diagnostic hypotheses were hypertrophic or restrictive cardiomyopathy.

A testicular ultrasound (September 09, 2013) was normal, except for cystic formations in the right inguinal canal. An abdominal ultrasonography (September 10, 2013) showed substantial ascites and hepatic cysts with internal septations, and no signs of portal hypertension.

After presenting an increase in dyspnea with the development of paroxysmal nocturnal dyspnea, worsening ascites and lower-extremity edema, and paresthesia on hands and feet, the patient was admitted to the hospital.

On physical examination (October 19, 2013) he was oriented and eupneic, with a heart rate of 69 bpm, blood pressure of 80 X 60 mmHg, a normal pulmonary auscultation, cardiac auscultation with arrhythmia and no murmurs, substantial ascites, and edema and hyperemia of the lower extremities.

A chest x-ray (October 21, 2013) showed cardiomegaly and interstitial lung infiltrates; the lateral incidence showed the right ventricle markedly enlarged ( Figures 3 and ​ and4 4 ).

Chest x-ray (October 21, 2013), posteroanterior (PA) view: pulmonary interstitial infiltrates and cardiomegaly.

Chest x-ray (October 21, 2013) in lateral view: right ventricle markedly enlarged.

On ECG, the patient presented atrial flutter with variable atrioventricular block, indirect signs of right atrial overload (Peñaloza-Tranchesi sign), heart rate of 61 bpm, low QRS voltage in the frontal plane, intraventricular conduction impairment, left ventricular overload, and secondary changes in ventricular repolarization ( Figure 5 ).

ECG: Atrial flutter, impaired intraventricular conduction, left ventricular overload.

Laboratory tests on October 19, 2013, showed the following results: hemoglobin 13.5 g/dL, hematocrit 42%, leukocytes 7,230/mm 3 (neutrophils 66%, eosinophils 12%, lymphocytes 13%, monocytes 9%), platelets 232,000 /mm 3 , urea 193 mg/dL, creatinine 2.03 m/dL (glomerular filtration rate of 34 mL/min/1,73 m 2 ), sodium 133 mEq/L, potassium 3.9 mEq/L, C-reactive protein (CRP) 18.1 mg/L, vitamin B12 360 pg/mL, folic acid 8.35 ng/mL, total bilirubin 0.75 mg/dL, direct bilirubin 0.37 mg/dL, AST 24 U/L, ALT 16 U/L, gamma-glutamyl transferase (gamma GT) 241 U/L, alkaline phosphatase 166 U/L, iron 71 µg/dL, ferritin 62.9 ng/mL, prothrombin time (PT, INR) 0.95, activated partial thromboplastin time (aPTT, rel) 0.95, ionic calcium 1.09 mmol/L, chloride 89 mEq/L, and arterial lactate 15 mg/dL. Urinalysis showed urine specific gravity of 1.020, pH 5.5, proteinuria 0.25 g/L, epithelial cells 4,000/mL, leukocytes 2,000/mL, erythrocytes 3,000/mL, and hyaline casts 27,250/mL.

Another echocardiogram performed on October 21, 2013, showed a left atrial diameter of 56 mm, septal thickness of 18 mm, posterior wall thickness of 13 mm, left ventricle (diastole/systole) with 46/40 mm, left ventricular ejection fraction of 28%, pulmonary artery systolic pressure estimated at 45 mmHg, marked left ventricular and moderate right ventricular dysfunction, and moderate tricuspid insufficiency.

An ultrasound of the kidneys and urinary tract (October 24, 2013) showed that the left kidney measured 9.6 cm, and the right kidney measured 9 cm and had simple cortical cysts.

Serum protein electrophoresis was normal, and a urinary electrophoresis did not detect proteins. Measurement of serum beta 2-microglobulin was 7 mg/mL (limit for individuals above the age of 60 years = 2.6 mg/mL).

A biopsy of the cheek mucosa (October 23, 2013) showed deposits of amyloid substance in the deep chorion and in the adjacent adipose tissue.

Stool microscopy (October 25, 2013) was positive for Blastocystis hominis and Entamoeba coli .

A paracentesis drained 3,500 mL of a yellowish fluid with normal cellularity.

During hospitalization, the patient received daily intravenous furosemide 60 mg, carvedilol 25 mg, hydrochlorothiazide 100 mg, hydralazine 75 mg, isosorbide 80 mg, aspirin 100 mg, spironolactone 25 mg, and enoxaparin 40 mg. The patient also received oxacillin 2 g/day for 7 days initially, and later vancomycin, meropenem and teicoplanin, and piperacillin/tazobactam.

A new chest x-ray (November 08, 2013) showed cardiomegaly and an interstitial pulmonary infiltrate suggestive of pulmonary congestion ( Figure 6 ).

Chest x-ray (November 08, 2013): pulmonary interstitial infiltrates suggestive of pulmonary congestion and cardiomegaly.

During a new paracentesis (November 11, 2013), the aspirated fluid was bloody, and the patient presented hypotension and decreased consciousness, progressing to cardiac arrest with pulseless electrical activity, which was reverted. This was followed by ventricular tachycardia, cardioverted with 200 J.

New tests (November 11, 2013 - morning) showed the following results: hemoglobin 11.9 g/dL, hematocrit 36%, leukocytes 7,780/mm 3 (neutrophils 83%, eosinophils 2%, lymphocytes 9%, and monocytes 6%), platelets 188,000 /mm 3 , urea 301 mg/dL, creatinine 4.14 mg/dL, sodium 125 mEq/L, potassium 4.4 mEq/L, CRP 97.06 mg/L. On venous blood gas analysis, pH was 7.33, bicarbonate 19.9 mmol/L, and base excess (-) 5.4 mmol/L. Additional tests performed on the same day (November 11, 2013 – 5:44 pm) showed hemoglobin of 6.3 g/dL, sodium of 123 mEq/L, potassium of 5.4 mEq/L, venous lactate of 93 mg/dL, PT (INR) of 3.2 and aPTT (rel) of 1.98.

Later during the day, the patient progressed with shock refractory to high doses of dobutamine (20 µg/kg/min ) and norepinephrine (1.2 µg/kg/min), followed by cardiac arrest with pulseless electrical activity that recovered but was followed by a new irreversible cardiac arrest with pulseless electrical activity during intra-aortic balloon placement (November 11, 2013 – 6:30 pm).

Clinical Aspects

The patient JAB, a 79-year-old previous smoker and alcoholic man residing in São Paulo, attended an outpatient clinic at InCor due to heart failure which worsened progressively since 2012, requiring hospitalization for treatment.

Heart failure is a systemic and complex clinical syndrome, defined as a cardiac dysfunction that causes the blood supply to be insufficient to meet tissular metabolic demands, in the presence of a normal venous return, or which only meets the demands with high filling pressure 1 .

Prevalence studies estimate that 23 million individuals worldwide have heart failure and that 2 million new cases are diagnosed annually. According to DATASUS information, Brazil has about 2 million individuals with heart failure and 240,000 new cases diagnosed annually 2 .

The main causes of heart failure are hypertension, coronary artery disease, Chagas disease, cardiomyopathies, endocrinopathies, toxins, and drugs, among others 1 . The cardinal manifestations of heart failure are dyspnea and fatigue, and may include exercise intolerance, fluid retention, and pulmonary and systemic congestion 3 . The patient in this case presented with progressive dyspnea triggered by less than ordinary activities, lower-extremity edema, and ascites, which characterized him as class III according to the New York Heart Association (NYHA) classification.

On complementary tests, the echocardiogram showed marked left ventricular hypertrophy with some degree of asymmetry, and reduced ejection fraction. Cardiac hypertrophy is often associated with hypertension or hypertrophic cardiomyopathy, but both present with normal or increased ECG voltage. Therefore, the findings of ventricular hypertrophy associated with decreased ECG voltage in the absence of pericardial effusion are exclusive of infiltrative cardiomyopathies, a group of cardiac disorders within the restrictive cardiomyopathies 4 .

Restrictive cardiomyopathy may occur with a wide variety of systemic diseases. Some restrictive cardiomyopathies are rare in clinical practice and may present initially with heart failure. This type of cardiomyopathy is characterized by filling restriction, with reduced diastolic volume in one or both ventricles, normal or close to normal systolic function, and ventricular wall thickening. It may be idiopathic or associated with other diseases, such as amyloidosis, endomyocardial disease with or without eosinophilia, sarcoidosis, and hemochromatosis, among others 5 . In this case, the presence of amyloid deposits in the cheek mucosa biopsy indicated a diagnosis of amyloidosis, and the increase in serum beta-2 microglobulin reflected a worse prognosis 5 .

Amyloidosis is characterized by deposits of amyloid protein in different organs and tissues. These deposits may be responsible for different types of clinical presentation, with a spectrum that ranges from lack of symptoms to sequential organic dysfunction culminating with death 6 .

Cardiac amyloidosis is caused by amyloid deposits around cardiac fibers, and can be identified by a left ventricular wall thickening exceeding 12 mm in the absence of hypertension with at least one of the following characteristics: conduction disorder and low voltage complexes on the ECG, restrictive cardiomyopathy, low cardiac output, isolate atrial involvement (as commonly seen in elderly individuals) or diffuse involvement affecting the ventricles. In the latter situation, it can cause heart failure with a poor prognosis 4 , 7 .

Our patient, who was not hypertensive, presented low voltage complexes on the ECG, which were more prominent in the frontal plane, an electrically inactive area in the anteroseptal region, and diffuse changes in ventricular repolarization. This pattern can be found in some diseases in addition to infiltrative cardiomyopathies, such as decompensated hypothyroidism, pericardial effusion, chronic obstructive pulmonary disease, and obesity. Other electrocardiographic information, such as the pattern of infarction, can be found with or without obstructive coronary atherosclerotic disease by deposition of substances in the microcirculation and small intramyocardial arteries 8 .

Amyloidosis may be classified as primary, secondary, or hereditary. Primary amyloidosis, in which AL is the primarily involved protein, may be further subdivided into idiopathic (localized forms) or associated with multiple myeloma or other plasma cell dyscrasias (systemic forms) 9 .

Multiple myeloma is a neoplastic disorder of plasma cells that affects individuals with an average age of 70 years at diagnosis. Some characteristics of the patient in this case could suggest multiple myeloma: age, male gender, renal failure, and cylindruria. However, other important clinical parameters were absent, such as hypercalcemia, anemia, and bone disease. Also, the Bence-Jones protein, which is present in up to 75% of the cases, was not detected on urinary electrophoresis 10 .

The secondary type of amyloidosis results from deposits of AA protein and frequently arises as a complication of infectious or inflammatory processes, such as rheumatoid arthritis (the most common cause), tuberculosis, systemic lupus erythematosus, inflammatory bowel disease, syphilis, or even neoplastic diseases. Pro-inflammatory cytokines, which are present in these disorders, stimulate the hepatic production of serum A amyloid 11 .

Finally, the hereditary type of the disease has an autosomal dominant transmission and may involve several types of amyloid proteins, such as the AA protein in some groups of patients with familial Mediterranean fever, and the ATTR protein (derived from the transthyretin or prealbumin) in familial amyloid polyneuropathy 12 .

As for the treatment, measures to control symptoms related to diastolic heart failure, such as volume control, should be implemented. Diuretics and vasodilators should be administered with caution since the cardiac output in these patients is greatly dependent on increased venous pressures. Specific treatment should be directed to the etiology of the amyloidosis 13 .

After an evaluation in the clinic on January, 2013, the patient received medications that are proven to modify the rates of hospitalization and mortality in heart failure with reduced ejection fraction (beta-blockers, angiotensin-converting enzyme inhibitors, aldosterone antagonist), and symptom-relieving agents (diuretics) 14 . The patient was receiving enalapril 10 mg, spironolactone 25 mg, furosemide 60 mg, and carvedilol 12.5 mg.

After 8 months, due to the decompensated heart failure and hypotension, the patient returned to the emergency room and required hospitalization. The use of conventional therapy for heart failure often worsens the progression of amyloidosis. Therefore, cardiac amyloidosis should be suspected when the patient’s clinical condition worsens in response to conventional treatment, particularly in individuals older than 50 years. The therapy is exclusively symptomatic and should not include digitalis, beta-blockers, angiotensin-converting enzyme inhibitors, or calcium channel antagonists, since some studies have shown an increased sensitivity to these drugs which can lead to hypotension and intensification of conduction disorders 15 .

Therefore, the decompensation of the patient’s heart failure with deterioration of the ascites culminated in two paracenteses, with the last paracentesis probably accompanied by a puncture accident due to the appearance of bloody fluid, decrease in red blood count, and hypovolemic shock associated with cardiogenic shock, culminating in a mixed refractory shock and cardiac arrest with pulseless electrical activity (Dr. Sumaia Mustafa, Dr. Alice Tatsuko Yamada).

Diagnostic hypotheses:

• Heart failure due to restrictive cardiomyopathy (probably cardiac amyloidosis associated with multiple myeloma);
• Decompensated heart failure;
• Cause of death: mixed shock (hypovolemic + cardiogenic) with cardiac arrest with pulseless electrical activity (Dr. Sumaia Mustafa, Dr. Alice Tatsuko Yamada) .

The heart weighed 680 g and was increased in volume due to moderate cavity dilation and wall thickening in all four chambers ( Figure 7 ). The myocardium had an increased consistency. The endocardium of the atria, in particular, was finely granular and brown-yellowish in appearance. There were no significant changes in the valves, and the coronary arteries were armed without significant obstruction of their lumen.

Gross Section of the heart base showing biatrial enlargement and thickening of the cardiac walls. Note the granular aspect of the right atrial endocardium (area demarcated with an ellipse).

Histological examination of the myocardium showed extracellular deposits of amorphous and eosinophilic material promoting atrophy of the contractile cells. These deposits stained positive with Congo red when observed under polarized light ( Figures 8 and ​ and9). 9 ). This same material was present in the interstitium of the cheek mucosa evaluated by biopsy ( Figure 10 ) according to data from the clinical history. Deposits were also observed in the tunica media of muscular arteries in both lungs ( Figure 11 ) and in the renal hilum.

Photomicrography of the ventricular myocardium showing atrophic cardiomyocytes due to deposits of amorphous eosinophilic material in the interstitium. Hematoxylin and eosin staining (20x objective magnification).

Photomicrography of myocardial tissue obtained under polarized light. Note the greenish material that corresponds to amyloid substance stained by Congo red (5x objective magnification).

Biopsy of the cheek mucosa performed approximately 1 month before death. Note that the mucosal chorion reacts positively to Congo red (photomicrography obtained under conventional microscopy with a 10x objective magnification).

Photomicrography of a peripheral muscular pulmonary artery showing areas of positivity for deposits of amyloid in the arterial wall (Congo red staining photographed under conventional microscopy, 5x objective magnification).

Bone marrow histological examination showed hypercellularity of moderate degree for the patient's age, and no signs of monoclonal proliferation. Immunohistochemical reactions for immunoglobulin kappa and lambda light chains were inconclusive, and CD138 labeling showed no proliferation of plasma cells.

Autopsy findings included a 4-cm hepatic cyst in the right lobe lined with flat cells without atypia, and retention cysts in the right kidney. The right adrenal weighed 44 g and was increased in volume and completely calcified. The histological examination showed only calcification and was inconclusive for the possibility of prior malignancy.

There was a voluminous serosanguinous ascites and a serous pericardial effusion. We found no visceral or abdominal vessel injury resulting from the paracentesis and the amount of bloody material in the ascitic fluid was small.

Histologically, there were signs of congestive heart failure in the lungs and liver (Dr. Vera Demarchi Aiello) .

Diagnoses: Cardiovascular amyloidosis;

Congestive heart failure;

Calcified nodule in the right adrenal gland (Dr. Vera Demarchi Aiello).

Mass spectrometry

Mass spectrometry gathers all qualities to establish an unequivocal diagnosis of amyloidosis since it has a high sensitivity and ability to identify the proteins through sequencing 16 . Therefore, we adopted an approach based on shotgun proteomics to identify the amyloid deposits in the sample.

Sections of heart tissue containing amyloid deposits (confirmed by staining with Congo red) fixed in formalin and embedded in paraffin were dissected and the proteins were then extracted with Liquid Tissue® MS Protein Prep Kit (Expression Pathology) according to the manufacturer's protocol. After digestion with trypsin, the resulting peptides were analyzed by high-resolution liquid chromatography-mass spectrometry using the mass spectrometer Q-Exactive (Thermo Fisher Scientific). The acquisitions of spectral data were carried out using the DDA (date dependent analysis) mode with a selection of the 10 most abundant ions for sequencing by HCD (Higher-energy collisional dissociation). The data were processed with the software MaxQuant. The proteomic analysis was performed in triplicate.

The processed data generated lists of proteins representing the protein content of the sample. In total, 25 possible amyloid proteins were investigated in these lists in order to determine the identity of the deposited substance. There were 15 peptides belonging to transthyretin that together covered 76.2% of the full sequence of the protein.

To confirm the result, we also evaluated the abundance of different peptides present in the sample. Among the 25 most abundant peptides, three belonged to transthyretin (ALGISPFHEHAEVVFTANDSGPR, TSESGELHGLTTEEEFVEGIYK, and GSPAINVAVHVFR). The others were assigned to actin, myosin, desmin, and myoglobin, confirming the identity of the amyloid protein (Dr. Fabio Mitsuo Lima and Dr. Valdemir Melechco Carvalho- Fleury Group).

Cardiovascular amyloidosis due to deposition of transthyretin (Dr. Vera Demarchi Aiello, Dr. Jussara Bianchi Castelli, Dr. Fabio Mitsuo Lima and Dr. Valdemir Melechco Carvalho) .

This case demonstrates how important it is in amyloidosis to investigate the deposited substance. Amyloidosis is a generic name to describe a group of diseases characterized by extracellular deposits of different substances in different organs. These substances are fibrillar proteins that become insoluble with changes in their spatial conformation. More than 20 types of proteins have been described in these deposits 16 . From an anatomopathological perspective, the deposits can be characterized by immunohistochemical reactions, but with some restrictions as described below. The cardiovascular system is most often affected by the AL protein (deposits of light-chain immunoglobulin), senile, and familial forms 17 , 18 .

The pathologist may identify neoplastic proliferation of plasmocytes producing the deposited immunoglobulins by bone marrow examination labeled for these cells. In tissue preparations, the pathologist may demonstrate by immunohistochemistry if the deposited substance is one of these immunoglobulins. Some authors recommend a biopsy of other organs before the endomyocardial biopsy to confirm the diagnosis and identify the type of amyloid 19 . In this case, immunohistochemical labeling was not helpful in establishing the diagnosis, because it was inconclusive to the type of protein deposited.

Although there are reports in the literature of identification of transthyretin in tissues by immunohistochemical reactions, this was not possible in this case. However, with mass spectrometry analysis, we identified that the deposited protein was transthyretin, which is usually present in senile and familial forms of amyloidosis. In this patient, the familial form was less likely due to the exclusive involvement of heart and blood vessels. However, only a genetic research and evaluation of other members of the family could exclude it completely.

Another point that deserves discussion in this case is the laboratory report of high levels of immunoglobulin E. We could assume that this referred to the deposited protein, but the diagnostic methods performed to complement the autopsy revealed that this was not the case.

Dr. Vera Demarchi Aiello and Dr. Jussara Bianchi Castelli (Pathology Laboratory, InCor, FMUSP).

Heart Failure; Cardiomyopathy, Restrictive; Ascites; Cardiomegaly; Heart Arrest.

Editor da Seção: Alfredo José Mansur ( rb.psu.rocni@rusnamja )

Editores Associados: Desidério Favarato ( rb.psu.rocni@otaravaflcd )

Vera Demarchi Aiello ( rb.psu.rocni@arevpna )

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Chapter 5:  10 Real Cases on Acute Heart Failure Syndrome: Diagnosis, Management, and Follow-Up

Swathi Roy; Gayathri Kamalakkannan

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Case 1: Diagnosis and Management of New-Onset Heart Failure With Reduced Ejection Fraction

A 54-year-old woman presented to the telemetry floor with shortness of breath (SOB) for 4 months that progressed to an extent that she was unable to perform daily activities. She also used 3 pillows to sleep and often woke up from sleep due to difficulty catching her breath. Her medical history included hypertension, dyslipidemia, diabetes mellitus, and history of triple bypass surgery 4 years ago. Her current home medications included aspirin, atorvastatin, amlodipine, and metformin. No significant social or family history was noted. Her vital signs were stable. Physical examination showed bilateral diffuse crackles in lungs, elevated jugular venous pressure, and 2+ pitting lower extremity edema. ECG showed normal sinus rhythm with left ventricular hypertrophy. Chest x-ray showed vascular congestion. Laboratory results showed a pro-B-type natriuretic peptide (pro-BNP) level of 874 pg/mL and troponin level of 0.22 ng/mL. Thyroid panel was normal. An echocardiogram demonstrated systolic dysfunction, mild mitral regurgitation, a dilated left atrium, and an ejection fraction (EF) of 33%. How would you manage this case?

In this case, a patient with known history of coronary artery disease presented with worsening of shortness of breath with lower extremity edema and jugular venous distension along with crackles in the lung. The sign and symptoms along with labs and imaging findings point to diagnosis of heart failure with reduced EF (HFrEF). She should be treated with diuretics and guideline-directed medical therapy for congestive heart failure (CHF). Telemetry monitoring for arrythmia should be performed, especially with structural heart disease. Electrolyte and urine output monitoring should be continued.

In the initial evaluation of patients who present with signs and symptoms of heart failure, pro-BNP level measurement may be used as both a diagnostic and prognostic tool. Based on left ventricular EF (LVEF), heart failure is classified into heart failure with preserved EF (HFpEF) if LVEF is >50%, HFrEF if LVEF is <40%, and heart failure with mid-range EF (HFmEF) if LVEF is 40% to 50%. All patients with symptomatic heart failure should be started on an angiotensin-converting enzyme (ACE) inhibitor (or angiotensin receptor blocker if ACE inhibitor is not tolerated) and β-blocker, as appropriate. In addition, in patients with New York Heart Association functional classes II through IV, an aldosterone antagonist should be prescribed. In African American patients, hydralazine and nitrates should be added. Recent recommendations also recommend starting an angiotensin receptor-neprilysin inhibitor (ARNI) in patients who are symptomatic on ACE inhibitors.

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This case study involves a 76 year old female named Mary Lou Poppins, who presented to the ED accompanied by her son. She called her son after having symptoms of shortness of breath and confusion. Her past medical history includes hypertension, hyperlipidemia, coronary artery disease, and she was an everyday smoker for 30 years. She reports her home medications are lisinopril, simvastatin, and baby aspirin. Her current lifestyle includes: being a widow of six years, she lives alone, she walks her dog everyday, she drives to her knitting group three days a week, she makes dinner for her grandchildren once a week, she attempts to eat healthy but admits to consuming salty and high fat foods, and she insists on being very independent.

Mary Lou Poppins initial vitals in the emergency department includes a blood pressure of 138/70, heart rate of 108. respiratory rate of 26, temperature 98.9 degrees fahrenheit, and oxygen saturation of 84%. Her initial assessment included alert and oriented to person and place, dyspnea, inspiratory crackles in bilateral lungs, and a cough with pink frothy sputum. Her labs and diagnostics resulted in a BNP of 740 pg/ml, an echocardiogram showing an ejection fraction of 35%, an ECG that read sinus tachycardia, and a chest x-ray that confirmed pulmonary edema.

The Emergency Department physician diagnosed Mary Lou Poppins with left-sided heart failure. The orders included: supplemental oxygen titrated to keep saturation >93%, furosemide IV, enoxaparin subq, and metoprolol PO. Nursing Interventions included: monitoring oxygen saturation, adjusting oxygen route and dosage according to orders, assessing mentation and confusion, obtaining IV access, reassessing vitals, administering medications, and keeping the head of the bed elevated greater than 45 degrees. She was admitted to the telemetry unit for further stabilization, fluid balance monitoring, and oxygen monitoring.

On day one of hospital admission, Mary Lou Poppins required 4L of oxygen via nasal cannula in order to maintain the goal saturation of >93%. Upon assessment, it was determined that she was oriented to person and place. Auscultation of the lungs revealed bilateral crackles throughout, requiring collaboration with respiratory therapy once in the morning, and once in the afternoon. Physical therapy worked with the patient, but she was only able to ambulate for 100 feet. During ambulation, the patient had a decrease of oxygen saturation and dyspnea, requiring her oxygen to be increased to 6L. At the end of the day, strict intake and output monitoring showed an intake of 1200 mL of fluids, with an urinary output of 2L.

On day two of admission, Mary Lou began demonstrating signs of improvement. She only required 2 L of oxygen via nasal cannula with diminished crackles heard upon auscultation. Morning weight showed a weight loss of 1.3 lbs and the patient was oriented to person, place, and sequence of events. During physical therapy, she was able to ambulate 300 feet without required increased oxygen support. Daily fluid intake was 1400 mL with a urinary output of 1900 mL.

On the third and final day of admission, Mary Lou was AOx4 and did not require any type of oxygen support. When physical therapy arrived, the patient was able to ambulate 500 feet, which was close to her pre-hospital status. When the doctor arrived, the patient informed him that she felt so much better and felt confident going home. The doctor placed orders for discharge.

Upon discharge and throughout the patient’s hospital stay, Mary Lou Poppins was educated regarding the disease process of heart failure; symptoms to monitor for and report to her doctor; the importance of daily monitoring of weight, blood pressure, and heart rate; and the importance of adhering to a diet and exercise regime. Education was also provided regarding her medications and the importance of strictly adhering to them in order to prevent exacerbations of heart failure. Smoking cessation was also included in her plan of care. The patient received an informational packet regarding her treatment plan, symptoms to monitor for, and when to call her physician. Upon discharge, the patient was instructed to schedule a follow up appointment with her cardiologist for continued management of her care.

The patient was put in contact with a home health agency to help manage her care. The home health nurse will help to reinforce the information provided to the patient, assess the patient’s home and modify it to meet her physical limitations, and help to create a plan to meet daily dietary and exercise requirements. Regular follow-up appointments were stressed to Mary Lou Poppins in order to assess the progression of her disease. It will be important to monitor her lab values to also assess her disease progression and for any potential side effects associated with her medications. Repeat echocardiograms will be necessary to monitor her ejection fraction; if it does not improve with the treatment plan, an implanted cardiac defibrillator may be necessary to prevent cardiac death.

Open-Ended Questions

• What were the clinical manifestations that Mary Lou Poppins presented with in the ED that suggested the new onset of CHF?
• What factors most likely contributed to the onset of CHF?
• What patient education should Mary Lou Poppins receive on discharge in regards to managing her CHF?

Nursing Case Studies by and for Student Nurses Copyright © by jaimehannans is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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• Advances in management...

Advances in management of heart failure

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• Peer review
• Paul Heidenreich , professor of medicine 1 2 ,
• Alexander Sandhu , assistant professor of medicine 1 2
• 1 Department of Medicine, Stanford University School of Medicine, Palo Alto, CA 94306, USA
• 2 VA Palo Alto Health Care System, Palo Alto, CA, USA
• Correspondence to: P Heidenreich heiden{at}stanford.edu

Heart failure is increasing in prevalence in many countries with aging populations. Fortunately, remarkable scientific advances have been made in the past few years that have led to new treatments and improved prognosis for patients with heart failure. This review examines these changes with a focus on the diagnosis and medical management of heart failure. The changes include the increase to four foundational drug classes (pillars of therapy) now recommended for patients with heart failure and reduced left ventricular ejection fraction, use of sodium-glucose cotransporter-2 inhibitors for those with a higher ejection fraction, and the importance of rapid initiation of life prolonging therapies once a diagnosis of heart failure has been made. Device management and other non-drug management have also evolved with the publication of new clinical trials. The review emphasizes evidence published since the recent heart failure guidelines of the European Society of Cardiology and American College of Cardiology/American Heart Association/Heart Failure Society of America in 2021 and 2022. Additional studies are needed to determine how best to implement these new interventions in clinical practice.

Introduction

Heart failure is a common and growing health and economic burden for many of the world’s communities. This growth is pronounced in societies with aging populations. Advances in heart failure care have been dramatic over recent years, including new drugs, devices, and diagnostic care strategies. Clinical guidelines published within the past few years have included many of these changes, but even these recent guidelines are already out of date in their recommendations for treatment and diagnosis. In light of this rapidly changing scientific evidence base, we provide an up-to-date review of the most important aspects of heart failure care.

Sources and selection criteria

We searched PubMed and the Cochrane Database of Systematic reviews for articles published between January 2015 and 7 July 2023 to identify new randomized controlled trials (RCTs) and large cohort studies of treatments and diagnostic strategies for heart failure. We also identified epidemiologic studies published from 2020 to 2023. We included older studies to provide context. We focused on studies not included in the recent European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) guidelines from 2021 and 2022. 1 2 We prioritized RCTs over observational data when reviewing interventions. We did not consider case reports or case series in our review.

Epidemiology

The Global Burden of Disease Study estimated that 57 million people were living with heart failure in 2019. 3 4 Although this number has been increasing in countries with aging populations, the age standardized rate has fallen from 7.7 per 1000 in 2010 to 7.1 per 1000 in 2019. 3 4 The change over time in the age adjusted prevalence from 2009 to 2019 (an average 0.3% decline per year during this period) has not been linear, with rates initially falling but then increasing by 0.6% per year between 2016 and 2019. 3 4 The reason for this change in prevalence is unclear and requires further investigation. An increase in hospital admissions for heart failure has been noted for young adults (age 18-45) in the US, with rates increasing from 1.8 per 10 000 in 2013 to 2.5 per 10 000 in 2018. 5

Large differences in prevalence are noted across global regions for both men and women ( fig 1 ). 3 4 The region with the highest prevalence of heart failure includes the high income countries of North America, and the lowest prevalence was in central Asia. An estimated 3% of the US population will have heart failure by 2030. 6 The largest declines in age adjusted rates were noted in high income countries of North America and Australasia regions.

Country specific, age adjusted prevalence of heart failure from 1990 to 2019 in men (top) and women (bottom). Estimates are from the Global Burden of Disease Study 3 4

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Survival following a diagnosis of heart failure is poor and is highly influenced by age. In the UK, survival approaches 80% at five years for people aged 45-64 but is closer to 20% at five years for those aged ≥85. 7 Fortunately, survival rates have improved since 2000, particularly among younger patients. 7

Although overall survival is an important outcome, it reflects the combined effects of all the patient’s conditions. The incremental impact of heart failure on survival is difficult to discern, as most patients with heart failure have multiple comorbidities. Years of life lost due to heart failure can be estimated by examining survival relative to actuarial estimates of life expectancy. Data from the UK have shown that heart failure is associated with a 2.4-fold greater loss of time alive than observed in the age and sex matched general population over 10 years. 8 Length of life lost with heart failure varies from five months (women) to one year (men) for people with no comorbidities and from three years (women) to 4.5 years (men) for those with three or more comorbidities. 8

The impact of covid-19 on the incidence of heart failure is uncertain but may be substantial. Studies from the US Veterans Affairs healthcare system have suggested that covid-19 is associated with an increased risk of cardiovascular events including death, myocardial infarction, and stroke. 9 10

Prevention, screening, and identification of heart failure

Heart failure can be largely prevented or delayed with optimal control of risk factors. 11 12 Uncontrolled hypertension remains the most common risk factor for incident heart failure. 13 14 Optimal blood pressure control is associated with a 40% reduction in heart failure events, 15 and multiple therapies for comorbid conditions reduce the risk of progression to heart failure including sodium-glucose cotransporter-2 (SGLT2) inhibitors, which reduce the risk of incident heart failure in patients with diabetes mellitus. 16 17 18 Among patients with chronic kidney disease, both SGLT2 inhibitors and finerenone (in those with diabetes) reduce the risk of incident heart failure. 19 20

Several clinical risk models can identify patients at high risk for progression to heart failure. 21 22 23 24 Concentrations of natriuretic peptide (B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP)) are also elevated among patients at high risk of incident heart failure or asymptomatic systolic dysfunction. 25 26 27 In the STOP-HF (St Vincent’s Screening to Prevent Heart Failure) study, patients with a cardiovascular risk factor were screened using BNP. Patients with elevated concentrations had echocardiography and collaborative cardiology and primary care management. This led to a reduction in subsequent left ventricular systolic dysfunction and emergency hospital admissions for cardiovascular reasons. 28 Similar results were confirmed in a trial among patients with diabetes mellitus. 29 Since these trials, additional treatment options are now available to prevent incident heart failure among people at high risk. 1 2 Expanding natriuretic peptide screening could lead to earlier diagnosis and treatment, substantially reducing the morbidity of heart failure.

Given that heart failure is a progressive condition with high early morbidity, prompt recognition is critical. In the UK, more than 80% of first diagnoses of heart failure are made in the hospital, and more than 40% of these patients have symptoms that should promote earlier assessment. 30 Women were noted to take six times longer to receive a diagnosis of heart failure and were twice as likely to be misdiagnosed. 31 Similar patterns of delayed diagnosis of heart failure have been noted in the US and Canada. 32 33 34 Minimizing the morbidity of heart failure requires increased awareness among patients and primary care clinicians, as well as additional strategies to facilitate disease recognition.

The diagnosis of heart failure requires the presence of symptoms consistent with cardiac dysfunction along with evidence of either significantly reduced left ventricular systolic function (≤40%) or increased filling pressures. This is now incorporated into the recently published universal definition of heart failure. 35 Heart failure is categorized into three groups based on the left ventricular ejection fraction (LVEF): heart failure with reduced ejection fraction (HFrEF) if the LVEF is ≤40%; heart failure with mildly reduced ejection fraction (HFmrEF) if the LVEF is 41-49%, and heart failure with preserved ejection fraction (HFpEF) if the LVEF is ≥50%. Patients with LVEF >40% require additional evidence of increased filling pressures (at rest or with exercise) to establish a diagnosis of heart failure.

Diagnosis of HFpEF

The diagnosis of HFpEF is particularly challenging, as determining increased filling pressure can be difficult. Most definitions of HFpEF exclude patients with heart failure symptoms due to valve disease, arrhythmia, pericardial constraint, or high cardiac output. Although invasive testing with cardiac catheterization is the gold standard for determining elevated left ventricular filling pressures, the diagnosis can be made non-invasively. Unfortunately, no single non-invasive test result has both a high sensitivity and a high specificity ( fig 2 ).

Test characteristics for common non-invasive tests of increased left ventricular filling pressure. No single test threshold has both sensitivity and specificity above 70%. 10 E/e’=early diastolic mitral inflow velocity to early diastolic mitral annulus velocity; GLS=global longitudinal strain; LA=left atrium; NT-proBNP=N-terminal pro B-type natriuretic peptide

Accordingly, clinical scores have been created using the results from multiple tests to diagnose HFpEF. These include H2FPEF (Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension (pulmonary artery systolic pressure >35 mm Hg), Elder age >60, elevated Filling pressures, E/e’ >9) 36 and HFA-PEFF (Heart Failure Association—Pre-test assessment; Echocardiography and natriuretic peptide score; Functional testing; Final etiology). 37 A recent evaluation found that these two scores have similar prognostic value, although 28% of patients had discordant findings (HFpEF diagnosed by only one of the algorithms). 38

Perhaps as important as making the diagnosis of heart failure is determining whether the patient will benefit from therapy for HFpEF. Thus, clinicians can use the enrollment criteria from clinical trials showing benefit to make a diagnosis of HFpEF. The two clinical trials of SGLT2 inhibitors that showed benefit for patients with HFpEF used the following enrollment criteria: New York Heart Association (NYHA) II-IV symptoms, treatment with a diuretic, an NT-BNP >300 pg/mL if sinus rhythm (>600 or >900 pg/mL if atrial fibrillation), and evidence of structural heart disease (left atrial enlargement, left ventricular hypertrophy), in the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, or a recent hospital admission for heart failure. 39 40

Determining the cause of heart failure

Determining the underlying cause of heart failure symptoms is an important second step after making a diagnosis, as some conditions have specific treatments. 1 2 Additional testing beyond echocardiography is often needed, and although routine screening with cardiac magnetic resonance (CMR) imaging is not clearly beneficial, 41 selected use of CMR often provides useful information. The patterns of late gadolinium enhancement and certain T1 and T2 techniques may suggest a diagnosis of non-compaction, myocarditis, or Chagas disease, as well as infiltrative cardiomyopathies including amyloidosis, iron overload, sarcoidosis, and Fabry disease. 1 2 Patients with dilated cardiomyopathy and those with significant hypertrophy on echocardiography may be most likely to benefit from CMR.

Four medication pillars of HFrEF therapy

For patients with heart failure and a reduced left ventricular ejection fraction to ≤40% (HFrEF), four classes of drugs are now known to improve survival. 1 2 These are renin-angiotensin system inhibitors including angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) or angiotensin receptor/neprilysin inhibitors (ARNI); β blockers; mineralocorticoid receptor antagonists (MRAs); and SGLT2 inhibitors ( table 1 ; fig 3 ). Using the relative risk reduction from the clinical trials, it has been estimated that the combination of the four pillars of HFrEF therapy will lead to a 73% relative risk reduction in mortality and a number needed to treat of four to prevent a death compared with no treatment. 42

Life prolonging medications for heart failure with reduced left ventricular ejection fraction 42

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Schematic of treatment for heart failure with reduced ejection fraction. ARNI=angiotensin receptor/neprilysin inhibitor therapy; BP=blood pressure; CRT=cardiac resynchronization therapy; EF=ejection fraction; HF=heart failure; ICD=implantable cardiac defibrillator; LBBB=left bundle branch block; MRA=mineralocorticoid receptor antagonist; NYHA=New York Heart Association; PA=pulmonary artery; SGLT2i=sodium glucose linked cotransporter 2 inhibitor; TEER=transcatheter edge-to-edge repair

The combination of an ARB and a neprilysin inhibitor is now recommended as one of the pillars of HFrEF therapy. The PARADIGM-HF (Prospective Comparison of ARN Inhibitors with ACE Inhibitors to Determine Impact on Global Mortality and Morbidity in HF) trial randomized 8442 patients with HFrEF. It found a 20% reduction in cardiovascular death or admission to hospital for heart failure with sacubitril and valsartan compared with enalapril (hazard ratio 0.80, 95% confidence interval 0.73 to 0.87). 43 Sacubitril/valsartan was also associated with a significant reduction in symptoms, as measured by the Kansas City Cardiomyopathy Clinical Summary Score (hazard ratio 1.64, 0.63 to 2.65). 43 A second RCT was conducted in patients admitted to hospital with heart failure (PIONEER-HF58: Comparison of Sacubitril-Valsartan vs Enalapril on Effect of N-Terminal Pro–Brain Natriuretic Peptide [NT-proBNP] in Patients Stabilized From an Acute HF Episode). 44 This trial in 881 patients showed a reduction in NT-proBNP concentrations (ratio of change 0.71, 95% confidence interval 0.63 to 0.81) for patients starting sacubitril/valsartan during hospital admission compared with those treated with enalapril. Safety was also demonstrated, with no significant differences in worsening renal function, hyperkalemia, and symptomatic hypotension. The 2022 US Heart Failure Guideline now recommends ARNI as the first line agent with ACE inhibitor or ARB alone for patients unable to take ARNI. 2 Use of ARNI along with an ACE inhibitor is contraindicated.

No benefit with ARNI was observed for patients with advanced heart failure defined as NYHA class IV symptoms or patients taking chronic inotropic therapy. 45 The LIFE (LCZ696 in Advanced HF) study randomized 335 patients with advanced heart failure and found that after 24 weeks of treatment, changes in NT-proBNP were not clearly different between patients treated with sacubitril/valsartan and those treated with valsartan alone (ratio of change 0.95, 0.84 to 1.08).

SGLT2 inhibitors

This new class of drugs (sodium-glucose cotransporter-2 inhibitors) was originally designed to improve glycemic regulation in diabetes but was found to also improve cardiac outcomes, including the prevention of heart failure. Subsequent trials in patients with reduced LVEF have consistently shown a significant reduction in hospital admissions due to heart failure, with several also showing a reduction in cardiovascular mortality. 46 Accordingly, this class (for example, dapagliflozin and empagliflozin) is now one of the four pillars of HFrEF therapy.

Sotagliflozin is a combined SGLT1 and SGLT2 inhibitor, and whether it should be placed in the same class as purer SGLT2 inhibitors is unclear. In a study in 1222 patients with diabetes and recent hospital admission for heart failure, initiation of sotagliflozin before or shortly after discharge reduced death from cardiovascular causes and hospital admissions and urgent visits for heart failure compared with placebo (hazard ratio 0.67, 0.52 to 0.84). 47 A second study randomized 10 584 patients with diabetes and renal dysfunction, 20% of whom had heart failure, to sotagliflozin or placebo. The combined endpoint of cardiovascular death, hospital admission for heart failure, and urgent visits for heart failure was reduced by sotagliflozin, with similar effects for patients with and without heart failure (hazard ratio 0.74, 0.63 to 0.88). 48 The 2021 ESC guideline has grouped sotagliflozin with the SGLT2 inhibitors in its recommendations for patients with heart failure and diabetes. 1 The drug was only recently approved in the US and thus was not eligible for inclusion in the ACC/AHA/HFSA 2022 guideline. 2

Importance of rapid initiation of therapy

The importance of rapid initiation of life prolonging heart failure medication is now recognized owing to results from the Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies (STRONG-HF) trial. 49 This multicenter study with 1078 patients from 87 hospitals in 14 countries examined rapid up-titration of guideline directed medication after an admission for acute heart failure. The intervention group had their medications up-titrated to 100% of recommended doses within two weeks of discharge. The primary endpoint of 180 day readmission to hospital due to heart failure or all cause death was reduced by an absolute percentage of 8.1% (95% confidence interval 2.9% to 13.2%) with rapid titration. We note that the STRONG-HF trial was conducted before SGLT2 inhibitors became standard of care for HFrEF therapy.

Further evidence of the benefit of rapid initiation comes from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. 50 Among 4744 patients in this trial, the time to clinical benefit was surprisingly fast with a significant reduction in cardiovascular death or worsening heart failure observed by 28 days after randomization to dapagliflozin compared with placebo (hazard ratio 0.51, 95% confidence interval 0.28 to 0.94). 50 Similarly, in 1222 patients treated with sotagliflozin compared with placebo, 47 the time to a sustained and significant reduction in the primary endpoint was 27 days (hazard ratio 9.62, 0.39 to 0.99). However, the time to benefit was twice as long for patients with heart failure and preserved ejection fraction. 51

Although the goal is to initiate all four drug classes in a timely manner, the optimal order and timing of initiation remains controversial. Investigators have modeled the potential benefit of different strategies based on how quickly benefits were observed in clinical trials. 52 They found that a strategy of starting with SGLT2 inhibitors and MRAs should lead to the greatest improvement in outcome. Other authors advocate for a more rapid approach, starting all four drugs at low doses together. 53 Starting drugs rapidly in combination may be the quickest way to reach recommended doses, although it also may increase the risk of temporary side effects (for example, hypotension or elevated creatinine). Side effects may lead clinicians and patients to assume a permanent drug intolerance and reduce the chances that the patient is ultimately treated with all four recommended classes. The patient’s condition may indicate the appropriate drug to use first. For example, an SGLT2 inhibitor or MRA may be the appropriate first drug in those with borderline low blood pressure. Additional studies are needed to determine which initiation strategy leads to the optimal sustained use of recommended treatments. Strategies for implementation of guideline directed medical therapy have been recently reviewed. 54

Although diuretics are a mainstay of treatment for patients with signs or symptoms of congestion, they have not been shown to improve mortality. 2 55 The efficacies of two loop diuretics were compared in the TRANSFORM-HF trial of 2859 patients who were randomized to furosemide or torsemide. 56 The primary outcome of all cause death was similar for the two loop diuretics (hazard ratio with torsemide treatment 1.02, 0.89 to 1.18).

Recently, the efficacy of intravenous acetazolamide in addition to intravenous loop diuretics was examined in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial. 57 Among 519 patients with heart failure, greater decongestion was seen in the group randomized to acetazolamide (successful decongestion within three days: 42.2% v 30.5%; P<0.001). In the Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC) trial, 239 patients were randomized to a thiazide diuretic or placebo in addition to a loop diuretic. 58 The addition of the thiazide significantly increased decongestion but with an increase in serum creatinine. Together, the ADVOR and CLOROTIC trials suggest that add-on diuretic therapy can improve decongestion compared with loop diuretics alone, although long term safety is uncertain. 57 58

Treatment of patients with improved ejection fraction

LVEF will improve from below 40% to above 40% during follow-up in about 15% of patients. 59 Some will even have a normalization of their LVEF (>50%). Although this improvement may imply recovery, a randomized trial of 51 patients with predominantly familial/idiopathic dilated cardiomyopathy found that discontinuing medication in those with apparent recovery of left ventricular function (LVEF >50%, NT-proBNP <250 ng/L, normalized left ventricular volume) led to relapses of heart failure in 46% (95% confidence interval 29% to 67%) at six months compared with 0% in those continuing medication (P=0.0001). 60 Accordingly, the ACC/AHA/HFSA guideline was revised in 2022 to use the term “improved” instead of “recovered” when the LVEF increases from ≤40% to >40%. 2

Continued HFrEF treatments are recommended for patients whose LVEF improves, although whether dose escalation or additional medications are beneficial once symptoms have resolved and LVEF has improved remains uncertain. In rare cases, withdrawal of therapy will succeed without relapse of heart failure. These patients with truly recovered LVEF include those whose cardiomyopathy is the result of a toxin, tachycardia, or other insult that has been eliminated. Unfortunately, being certain of the cause of cardiomyopathy is often difficult, and any attempt at withdrawal should be gradual with close follow-up and should be done only in selected cases in which heart failure has a specific and reversible cause.

Treatment of HFmrEF and HFpEF

As noted above, an LVEF of 41-49% is mildly reduced (HFmrEF) whereas patients with an LVEF ≥50% are considered to have preserved ejection fraction (HFpEF). These labels apply only to patients who have not previously had an LVEF ≤40% (these are referred to as heart failure with improved ejection fraction). SGLT2 inhibitors are recommended as the first line medication for patients with mildly reduced or preserved LVEF on the basis of the two trials that enrolled many patients with an LVEF >40%. 39 40

Of the other treatments for HFrEF, ARNI, ACE inhibitors, ARBs, and MRAs are second line therapies as the evidence for benefit is much weaker than for patients with HFrEF. Accordingly, MRAs and ACE inhibitors/ARBs/ARNI have a class 2B recommendation for HFmrEF and HFpEF in guidelines for patients with mildly reduced or preserved LVEF. 2

Of note, β blockers are not recommended for patients with HFpEF (2B recommendation for HFmrEF). 2 Lack of benefit for HFpEF was noted in a meta-analysis of randomized trials of β blockers, which reported a non-significant trend toward increased cardiovascular and all cause mortality in patients with preserved LVEF and sinus rhythm (hazard ratio 1.70, 0.78 to 4.10). 61

LVEF and benefit of medical therapy

LVEF can be difficult to quantify with echocardiography, but it has been routinely used to determine eligibility for clinical trials in heart failure. Given the growing evidence for treatment benefit in patients with higher LVEF levels, some authors have questioned the continued use of the LVEF to classify patients with heart failure. Multiple drug therapies have been tested across the ejection fraction spectrum: β blockers, ACE inhibitors/ARBs, ARNI, MRAs, and SGLT2 inhibitors. Traditionally, trials have stratified patients on the basis of LVEF ≤40% or >40%. However, most therapies have shown a benefit at higher thresholds than the traditional cutoff of reduced LVEF at 40%. For β blockers, a reduction in cardiovascular mortality was observed with LVEF <50%. 61 For MRA therapy, a larger treatment benefit is more likely for patients with LVEF 41-49% than with LVEF ≥50%. 62 The treatment benefit of sacubitril/valsartan was observed with LVEF <60%. 63 For SGLT2 inhibitor therapy, the relative treatment effect was similar across the LVEF spectrum. 64 Overall, these results suggest that the LVEF thresholds for systolic dysfunction used in treatment trials may benefit from reclassification but that LVEF will remain important for determining optimal management.

The association of LVEF with the benefit of early initiation and titration was evaluated in a sub-study of the STRONG-HF trial. 65 This study showed the consistency of the rapid implementation of guideline based medical therapy across the entire spectrum of LVEF after an admission for heart failure.

Other drug treatments

Several additional medications can be used to improve outcomes among patients with HFrEF. This section discusses several of these therapies: hydralazine/isosorbide dinitrate therapy, ivabradine, vericiguat, intravenous iron, and glucagon-like peptide-1 receptor agonists. We discuss their evidence and contemporary role.

Hydralazine/isosorbide dinitrate therapy

The combination of hydralazine and isosorbide dinitrate is a guideline recommended therapy for self-identified Black patients with HFrEF with NYHA class III or IV heart failure despite treatment with optimal medical therapy as described above. 1 2 The combination therapy causes both arterial and venous vasodilation in addition to nitrous oxide augmentation that may have remodeling benefits. 66 A-HeFT (African-American Heart Failure Trial) randomized 1050 self-identified Black patients to hydralazine/isosorbide dinitrate therapy versus placebo. Patients receiving hydralazine/isosorbide dinitrate therapy had a 43% relative reduction in death over a mean follow-up of 10 months (10.2% v 6.2%; P=0.02). 67 However, rates of treatment and adherence to hydralazine/isosorbide dinitrate therapy are low. 68 69 This may be due to multiple factors, including the difficulty of adhering to a three times daily medication and concerns about a race based indication. Additionally, the effectiveness of combined hydralazine and isosorbide nitrate therapy among non-Black patients remains unclear. 65 Although hydralazine/isosorbide dinitrate therapy remains an important tool for reducing morbidity among Black patients with HFrEF, we believe that it should remain a second line therapy for patients with persistent HFrEF after optimization of the four pillars described above ( fig 4 ).

Updates in heart failure since the 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America and 2021 European Society of Cardiology heart failure guidelines. 1 2 Of note, angiotensin receptor/neprilysin inhibitor (ARNI) may not be beneficial in patients with a left ventricular ejection fraction >60%. 63 CV=cardiovascular; HF=heart failure; HFmrEF=heart failure with mildly reduced ejection fraction; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction; HRQOL=health related quality of life; PA=pulmonary artery; SGLT2=sodium-glucose cotransporter-2

Ivabradine inhibits the channel responsible for the cardiac pacemaker current, I(f ), in the sinus node. 70 In SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial), among 6558 patients with HFrEF with sinus rhythm and a heart rate ≥70 bpm, ivabradine led to an 18% relative reduction (hazard ratio 0.82, 0.75 to 0.90) compared with placebo in the composite outcome of cardiovascular death and hospital admission for heart failure. 71 However, only 26% of patients were taking a target dose of β blocker therapy. Given the substantial benefit of β blocker therapy, patients with HFrEF should first have their β blocker dose optimized before initiation of ivabradine therapy.

Vericiguat is a novel heart failure medication that stimulates soluble guanylate cyclase and up-titrates the nitric oxide signaling pathway promoting vasodilation and reduced cardiac remodeling. In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, 5050 patients with HFrEF with recent hospital admission or intravenous diuretic treated with vericiguat versus placebo had a 10% relative reduction (hazard ratio, 0.83 to 0.98) in the risk of cardiovascular death or hospital admission for heart failure. 72 However, patients in the highest quarter of natriuretic peptide concentrations were less likely to benefit from vericiguat compared with placebo. 73 Although vericiguat was effective among a high risk HFrEF cohort, the smaller magnitude of benefit has rendered it a second line therapy for patients at high risk following optimization of the four pillars described above.

Intravenous iron infusion

Multiple studies have shown that iron deficiency and anemia are associated with increased mortality and decreased exertional capacity. 74 75 Several trials have shown that intravenous iron reduces the risk of hospital admission for heart failure and improves patient reported health status among patients with HFrEF. 76 77 78 79 80 Unfortunately, these effects have not been reproduced with oral iron administration. 81 These findings emphasize the importance of screening for iron deficiency and intravenous repletion; hospital admissions for heart failure are an ideal opportunity for screening and intervention.

Glucagon-like peptide-1 receptor agonists

Similarly to SGLT2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP1RA) were initially developed to improve glycemic control among patients with diabetes mellitus. In a meta-analysis of eight trials with cardiovascular outcomes evaluating GLP1RA among patients with type 2 diabetes mellitus, GLP1RA reduced the risk of cardiovascular death (hazard ratio 0.87, 0.80 to 0.94) and hospital admission for heart failure (0.89, 0.82 to 0.98). 82 However, the prevalence of heart failure at baseline was between only 9% and 24% across these trials. 83

GLP1RA were subsequently shown to be potent therapies for weight loss among obese patients without diabetes mellitus. 84 85 In the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial, semaglutide versus placebo was found to significantly reduce the composite outcome of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke among patients with existing atherosclerotic cardiovascular disease who were overweight or obese but without diabetes mellitus. Among enrolled patients, 24% had chronic heart failure at baseline.

Given the high prevalence of both diabetes mellitus and obesity among patients with heart failure, the potential benefits of GLP1RA warrant optimism. The Effect of Semaglutide 2.4 mg Once Weekly on Function and Symptoms in Subjects with Obesity-related Heart Failure with Preserved Ejection Fraction (STEP-HFpEF) trial evaluated the effect of semaglutide versus placebo on patient reported health status among 529 non-diabetic patients with ejection fraction ≥45%, obesity, and evidence of impaired health status (Kansas City Cardiomyopathy Questionnaire (KCCQ) score of <90) at baseline. Participants treated with semaglutide had on average a 7.8 (95% confidence interval 4.8 to 10.9) greater increase in their KCCQ score than patients treated with placebo, in addition to a significant 20.3 m larger improvement in their six minute walk distance.

Concern persists regarding the use of GLP1RA among patients with HFrEF. In a pooled analysis of two GLP1RA trials including patients with HFrEF, treatment with GLP1RA increased hospital admissions for heart failure. 86 Existing data support the use of GLP1RA among patients with obesity and HFpEF, but additional data on the safety and efficacy among patients with HFrEF is needed.

Devices and invasive therapies

Pulmonary artery pressure monitoring.

The CardioMEMS device is an ambulatory pulmonary artery pressure monitor. Ambulatory pulmonary artery pressure monitoring can be used to guide adjustment of medication (for example, loop diuretics) and monitor for signs of decompensation. In the initial CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association (NYHA) Class III Heart Failure Patients) trial, the CardioMEMS device reduced hospital admissions for heart failure and improved patient reported health status among 550 patients with heart failure irrespective of LVEF and a previous admission for heart failure (hazard ratio 0.72, 0.60 to 0.85). 87 Although the GUIDE-HF (hemodynamic-GUIDEed management of Heart Failure) trial failed to show a reduction in hospital admissions for heart failure (1022 patients; hazard ratio 0.88, 0.74 to 1.05), the subsequent MONITOR-HH (remote hemodynamic monitoring of pulmonary artery pressures in patients with chronic heart failure) trial found an improvement in patient reported health status and a reduction in admissions for heart failure with pulmonary artery pressure monitoring (348 patients; improvement in KCCQ overall summary score of 7.1 (95% confidence interval 1.5 to 12.8). 88 89 A meta-analysis of the three trials estimated a 30% reduction in hospital admissions for heart failure with pulmonary artery pressure monitoring (hazard ratio 0.70, 0.58 to 0.86). 90 When considering implementation of pulmonary artery pressure monitoring, it is critical to remember that the effectiveness of any remote monitoring interventions is dependent on the downstream responses to abnormal readings. Maximizing the effectiveness of hemodynamic monitoring requires establishment of workflows to promote active monitoring and appropriate interventions for abnormal hemodynamics.

Implantable cardiac defibrillators and cardiac resynchronization therapy

Implantable cardiac defibrillators (ICDs) and cardiac resynchronization therapy (CRT) remain mainstays of HFrEF therapy. 1 2 Although multiple trials have illustrated the survival benefit with ICD therapy for patients with HFrEF, the more recent DANISH (Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure) trial did not find a significant reduction in all cause mortality among 556 patients with non-ischemic cardiomyopathy (hazard ratio 0.87, 0.68 to 1.12). 91 However, patients under the age of 70 did have a survival benefit with ICD therapy. This likely reflects the fact that ICD therapy prevents only sudden cardiac death; as the competing risk of non-cardiovascular death increases (for example, increasing age) or the risk of sudden cardiac death decreases (for example, non-ischemic cardiomyopathy or effective medical therapy), the absolute benefit of ICD therapy decreases. 92 However, despite improvements in medical therapy, sudden cardiac death remains frequent among patients with HFrEF. 93 The shared decision making around ICD implantation should incorporate not only the patient’s preference but also estimates of an individual patient’s expected benefit. 92 94 95

CRT has shown the greatest benefit in patients with a wide QRS (≥150 ms, typically in a left bundle branch block pattern). CRT has traditionally relied on biventricular pacing. Conduction system pacing is a novel approach of pacing the His bundle or left bundle branch. 96 Small studies have suggested that conduction system pacing may be a potential alternative to promoting ventricular synchrony. 97 98 99 100 Ongoing trials are testing whether this strategy leads to similar clinical outcomes to traditional CRT via coronary sinus pacing.

Mitral transcatheter edge-to-edge repair

HFrEF is often accompanied by severe secondary mitral regurgitation (often described as posterior leaflet restriction on the echocardiography report), which is associated with increased risk of mortality and hospital admission. 101 102 Mitral regurgitation often improves with optimal medical therapy and positive ventricular remodeling. 103 For patients with persistent severe mitral regurgitation, repair of the mitral valve via transcatheter edge-to-edge repair (TEER) is a potential therapy. Two trials of mitral valve TEER had discordant results. In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial in 614 patients, mitral TEER led to a 47% reduction in hospital admission for heart failure (hazard ratio 0.53, 0.40 to 0.70) and reduced all cause mortality by 38% (0.62, 0.46 to 0.82). 104 However, the MITRA-FR (Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) trial showed no reduction in mortality or hospital admission for heart failure with mitral valve TEER (304 patients; odds ratio 1.16, 0.73 to 1.84). 105 The discordant results may be due to the degree of mitral regurgitation in relation to the severity of cardiomyopathy. Greater mitral regurgitation in relation to the degree of left ventricular dilation (disproportionate mitral regurgitation) may be more likely to benefit from mitral valve repair. 106 In addition, MITRA-FR did not require optimization of guideline based medical therapy before the procedure.

Revascularization

Coronary artery bypass grafting (CABG) for patients with severe coronary artery disease has been shown to improve outcomes compared with medical therapy, 107 but the early studies showing benefit typically did not include patients with significantly reduced ejection fraction. In addition, medical therapy has advanced substantially since these trials were conducted. In response to these concerns, the Surgical Treatment for Ischemic Heart Failure (STICH) trial randomized 1212 patients with an ejection fraction ≤35% and coronary artery disease amenable to CABG or medical therapy. 108 The primary outcome of all cause mortality was not significantly lower with CABG (hazard ratio 0.86, 0.72 to 1.04). However, the secondary outcome of death from any cardiovascular cause or hospital admission with heart failure showed a benefit with CABG (hazard ratio 0.74, 0.64 to 0.85), and current guidelines recommend bypass grafting if severe disease suitable for bypass is present and the LVEF is <35% 2

The potential benefit of revascularization with percutaneous coronary intervention was recently evaluated in the Revascularization for Ischemic Ventricular Dysfunction (REVIVED) trial. 109 This study found that among 700 patients with extensive coronary artery disease amenable to percutaneous coronary intervention and viable myocardium, the intervention did not improve mortality or hospital admission compared with usual care (hazard ratio 0.99, 0.78 to 1.27). This study is consistent with previous randomized evaluations suggesting that using viability to target revascularization does not improve outcome. 110

Treatment of advanced heart failure

Heart failure can be a progressive condition despite optimal therapy, and appropriate timing of referral to heart failure specialists is important. 111 The I-NEED-HELP acronym provides potential triggers for that referral. 112

Clinical outcomes with left ventricular assist device (LVAD) therapy have continued to improve over time. An improvement in post-implantation survival to more than 50% at five years has been seen, in addition to a reduction in rates of stroke and gastrointestinal bleeding. 113 After recall of the Heartware LVAD, the HeartMate 3 centrifugal flow left ventricular assist device is the only available durable LVAD. In the MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial, the HeartMate 3 had lower rates of reoperation, pump thrombosis, stroke, and gastrointestinal bleeding than the HeartMate 2 axial flow pump. 114

Heart transplant remains the cornerstone of therapy for patients with stage D heart failure. The median survival after heart transplant now exceeds 12 years. 115 The ability to effectively transplant hearts from hepatitis C positive donors and following circulatory arrest has increased the potential donor pool. 116 117 Improvements in donor preservation have also allowed sharing of potential donors across greater distances. 118

Non-drug, non-device therapies

Sodium and fluid restriction.

Restricting dietary sodium intake is commonly recommended to reduce symptoms of heart failure. However, limited data are available to support such restriction. The SODIUM-HF (Study of Dietary Intervention under 100 mmol in Heart Failure) trial randomized 806 patients to a low sodium diet of less than 1500 mg/day or usual care. It found similar rates of cardiovascular hospital admission, cardiovascular emergency department visit, or all cause death (hazard ratio 0.89, 0.63 to 1.26). 119 Of note, patients with a low sodium diet had higher patient reported health status. The US cardiovascular disease guidelines continue to recommend dietary sodium restriction among patients with and without heart failure. 2 120 However, potential concerns include that excessive sodium restriction may contribute to poor nutrition or may exacerbate deleterious neurohormonal activation. 121 Although moderating sodium intake may be reasonable, focusing on optimization of therapies shown to improve outcomes should be prioritized.

Fluid restriction in heart failure has also been tested in several randomized trials. A meta-analysis of six trials found that liberal fluid consumption did not increase readmssions due to heart failure or all cause mortality. 122 Accordingly, heart failure guidelines now state that the benefit of fluid restriction is uncertain or note the gap in evidence for its effectiveness. 1 2

Cardiac rehabilitation

Cardiac rehabilitation has generally been reserved for patients with heart failure with reduced LVEF or those who undergo cardiovascular surgery (for example, CABG). The REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial found that dedicated rehabilitation improved physical functioning for older patients admitted to hospital with heart failure regardless of LVEF. 123 A participant level meta-analysis of 13 randomized trials in 3990 participants found (at 12 months of follow-up; most patients had HFrEF) an improvement in six minute walk distance (mean 21.0 (95% confidence interval 1.57 to 40.4) m) and Minnesota Living With Heart Failure score (mean improvement 5.9, 1.0 to 10.9). 124 Additional trials are under way to evaluate the benefit of rehabilitation strategies for patients with HFpEF.

Measuring patient reported outcomes in heart failure

Without treatment, heart failure not only substantially increases the risk of mortality but also impairs quality of life. 125 Improving health related quality of life is an important goal of heart failure treatment. Multiple therapies have been shown to significantly improve quality of life on the basis of patient reported health status ( table 2 ). 87 134 140 141 142 143 144 145 The two most commonly used measures of patient reported health status in treatment trials have been the KCCQ and the Minnesota Living with Heart Failure Questionnaire. 146 147

Heart failure therapies with evidence of improvement in patient reported heart failure health status

Although patient reported health status has been commonly measured in clinical trials, it is rarely used in clinical practice. However, multiple studies have shown that not only is patient reported health status often discordant with the clinician’s assessment but it also has a higher concordance with objective functional testing than does the NYHA classification. 148 149 Patient reported health status is also a strong predictor of hospital admission and death. 150 151 152 153 154 155 Therefore, the call to incorporate routine measurement of patient reported health status into clinical care is increasing. 2 156 157 Theoretically, this could improve clinicians’ understanding of patients’ health status and guide improved shared decision making. Limited data support the potential utility and acceptability of routine assessment of patient reported health status in clinical care, 158 159 160 but no data are available on the clinical impact of such a strategy. Additionally, the challenges of effectively implementing data collection within the electronic health record remain. 161

Inequitable outcomes for health conditions among different groups often exist within societies, and heart failure is no exception. Data from the US suggest race/ethnicity differences in the incidence of and survival with heart failure. 162 163 The cause of disparities in outcome is multifactorial, and these are often driven as much or more by social determinants of health than by differences in patient management. 163 164 A recent analysis from the US found similar use of drug treatments known to prolong survival for patients with heart failure across race and ethnicity groups. 165 Inequitable treatment rates have been observed for device therapies, such as CRT, and therapies for advanced heart failure; these may reflect not only bias but also the critical role of access to care in promoting improved equity. 166 167 168 A focus beyond treatment differences is needed if overall health is to be improved. Improving representation in clinical trials is important to improve our ability to provide appropriate customized care to all patients with heart failure. 169

Several clinical guidelines have been published recently including the ESC (2021) and ACC/AHA/HFSA (2022) guidelines. 1 2 Important differences in guideline recommendations are rare and largely due to differences in the published evidence that occurred between publication. For example, the 2022 ACC/AHA/HFSA guideline includes a 2A recommendation for SGLT2 inhibitors for patients with HFmrEF and HFpEF following the publication of a large clinical trial showing outcome benefit. 2 40 Important studies that were published after these guidelines include a second randomized trial showing benefit of SGLT2 inhibitors in patients with an LVEF >40%, 39 the STRONG-HF trial showing benefit of rapid initiation and titration of medications for those with HFrEF, 49 and a trial showing that pulmonary pressure monitoring using the CardioMEMS device improved outcome. 89 Future guidelines will likely incorporate the trial results into revised recommendations. Figure 4 shows a summary of new evidence published since the 2022 ACC/AHA/HFSA and 2021 ESC heart failure guidelines. 1 2 An update to the 2021 ESC guideline was recently published, 170 and this incorporates new clinical trials of SGLT2 inhibitors, finerenone, and intravenous iron therapy.

Emerging treatments

Continued progress in treatment remains critical given the residual morbidity for patients with heart failure. Omecamtiv mecarbil is a cardiac myosin activator that improves cardiac contractility. In the GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure) trial, 8258 patients with HFrEF who received omecamtiv mecarbil showed an 8% relative reduction (0.92, 0.86 to 0.99) in the risk of cardiovascular death or heart failure event (hospital admission or urgent visit). 171 The benefit was driven by the difference in heart failure events. Multiple secondary analyses have illustrated larger therapeutic benefit among patients with more severe heart failure based on LVEF, systolic blood pressure, NYHA class, or natriuretic peptides. 172 173 174 175 Omecamtiv mecarbil is not available as it was denied approval by the US Food and Drug Administration and is still pursuing approval in Europe.

Several trials will help to clarify the role of existing heart failure therapies. The VICTOR trial is evaluating the efficacy of vericiguat among patients with heart failure who have not had a recent worsening heart failure event (clinicaltrials.gov: NCT05093933 ). The DECISION trial is testing the efficacy and safety of digoxin at low serum concentrations ( NCT03783429 ). Given the controversy of the TOPCAT trial findings, two ongoing trials are evaluating the efficacy of spironolactone among patients with heart failure with LVEF ≥40% ( NCT04727073 ; NCT02901184 ).

Many novel therapies for heart failure are under evaluation in clinical trials. These include multiple trials of finerenone among patients with heart failure across the ejection fraction spectrum ( NCT04435626 ; NCT06033950 ; NCT06024746 ). The SUMMIT trial will evaluate the effect of tirzepatide, another GLP1RA, among patients with HFpEF and obesity ( NCT04847557 ). Other ongoing studies are testing anti-inflammatory therapies among patients with HFmrEF/HFpEF ( NCT05636176 ; NCT04986202 ).

Non-drug care of patients with heart failure also continues to evolve. The CABA-HFPEF trial is testing catheter ablation among patients with heart failure with LVEF ≥40% and atrial fibrillation ( NCT05508256 ). Multiple ongoing trials are evaluating tricuspid valve interventions among patients with severe tricuspid regurgitation.

The management of patients with heart failure has changed markedly in the past several years, with evidence for four life prolonging classes of drugs for patients with reduced LVEF and the benefit of SGLT2 inhibitors for those with mildly reduced and preserved LVEF. Device management and other non-drug management have evolved as results from new clinical trials are published. Identification of appropriate candidates for treatment requires accurate diagnosis, which can be challenging for patients with heart failure and preserved ejection fraction. Additional questions remain—in particular, how best to implement these new treatment recommendations into clinical practice.

Glossary of abbreviations

ACC—American College of Cardiology

ACE—angiotensin converting enzyme

AHA—American Heart Association

ARB—angiotensin receptor blocker

ARNI—angiotensin receptor/neprilysin inhibitor

BNP—B-type natriuretic peptide

CABG—coronary artery bypass grafting

CMR—cardiac magnetic resonance

CRT—cardiac resynchronization therapy

ESC—European Society of Cardiology

GLP1RA—glucagon-like peptide-1 receptor agonists

HFmrEF—heart failure with mildly reduced left ventricular ejection fraction

HFpEF—heart failure with preserved left ventricular ejection fraction

HFrEF—heart failure with reduced left ventricular ejection fraction

HFSA—Heart Failure Society of America

HRQOL—health related quality of life

ICD—implantable cardioverter defibrillator

KCCQ—Kansas City Cardiomyopathy Questionnaire

LVAD—left ventricular assist device

LVEF—left ventricular ejection fraction

MRA—mineralocorticoid receptor antagonists

NYHA—New York Heart Association

RCT—randomized controlled trial

SGLT2—sodium-glucose cotransporter-2

TEER—transcatheter edge-to-edge repair

Questions for future research

Does the order of initiation of medications for heart failure with reduced left ventricular ejection fraction affect the ability to achieve sustained treatment with all four pillars of therapy?

Does the simultaneous initiation of medications increase or decrease the probability of sustained drug treatment?

What are the benefits of medications in addition to sodium-glucose cotransporter-2 inhibitors for patients with heart failure with preserved left ventricular ejection fraction?

Which patients should receive a trial of medication withdrawal if their symptoms resolve and their left ventricular function becomes normal?

How patients were involved in the creation of this manuscript

We obtained input from patient representatives/advocates as this manuscript was prepared. The feedback was helpful in defining the specific topics covered. In particular, the patient representatives/advocates highlighted the importance of including a discussion relating to equity.

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: PH and AS have joint authorship on this paper. PH and AS conceived the paper, did the research, and wrote all drafts including the final version of the paper.

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: PH has received research funding from the VA Health Care System and the American Heart Association and is chair of the 2022 ACC/AHA/HFSA Heart Failure Guideline Writing Committee; AS is a consultant for Lexicon Pharmaceuticals and has received research funding from the American Heart Association, the Gordon and Betty Moore Foundation, Novartis, the National Heart Lung Blood Institute, and Reprieve Cardiovascular.

Provenance and peer review: Commissioned; externally peer reviewed.

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Heart Failure Case Studies

• First Online: 30 March 2023

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• Nicole R. Dellise 3 &
• K. Melissa Smith Hayes 4  

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Heart failure patients presenting to primary care clinics often have multiple, complex comorbidities. Several different disease processes and treatment options may need to be considered simultaneously in the setting of acute on chronic exacerbation of symptoms. This chapter will exemplify complex heart failure patient vignettes and provide practical guidance for the primary care provider, highlighting HF guideline-directed medical therapy.

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Dellise, N.R., Hayes, K.M.S. (2023). Heart Failure Case Studies. In: Hayes, K.M.S., Dellise, N.R. (eds) Managing Heart Failure in Primary Care: A Case Study Approach. Springer, Cham. https://doi.org/10.1007/978-3-031-20193-6_19

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Feature | Advancing Health Equity For Heart Failure Patients: A Case Study for Team-Based Care and Innovation

Cardiology Magazine

Caring for vulnerable populations presents some unique challenges. It also offers immense opportunities for innovation to effect positive change for many lives.

To achieve health care parity, emphasis should be placed on addressing not only the medical needs but also the adverse social determinants of health that often serve as barriers to care.

We describe here the contributions of the Grady Heart Failure Program to decreasing health disparities and addressing the needs of our patients through a comprehensive and multidisciplinary approach.

Grady Health System serves as the safety net hospital for residents of metro Atlanta and its environs, providing care for the underserved in partnership with Emory and Morehouse Schools of Medicine. The geographic area served by Grady comprises predominantly underrepresented minority population groups who call Grady their medical home.

The Grady Heart Failure Program (GHFP) is a unique and innovative multidisciplinary program with an overarching goal of promoting health equity by improving the quality of care and outcomes of vulnerable patients with HF.

Our program provides a broad range of inpatient and outpatient services. Established in March 2011, the Grady Heart Failure Clinic provides comprehensive outpatient care for patients with HF through coordinated systems of care.

The clinic model focuses on four pillars of management:

• optimizing guideline-directed medical therapy (GDMT)
• patient education
• improving process and access to care, and
• addressing social determinants of health (SDOH)

Integrated in this model are facilitating follow-up in the cardiology and primary care clinics, cardiovascular risk factor management, depression screening and a personalized care approach that focuses on patient autonomy/empowerment skills such as adherence to therapy, dietary modifications, physical activity and daily weight self-assessment.

Our multidisciplinary team consists of eight full-time and several part-time advanced practice providers (APPs) in collaboration with cardiologists, a community health worker, nurse care coordinator, pharmacist and quality/process improvement personnel (Table 1).

Core Program Components Addressing Barriers to Health Equity

The core components of the GHFP that address barriers to health equity include a 30-day supply of HF medications at hospital discharge, hospital-based financial assistance, connection to community resources by a dedicated community health worker, rideshare support for patients who lack means of transportation to or from clinic appointments, provision of medically tailored meals post discharge, and mobile health home visits for patients unable to leave their residence due to mobility problems or caregiver responsibilities.

Program Innovation

We have developed several innovative programs specifically tailored to meet the unique needs of our patients and improve quality of care. The routine assessment of SDOH is incorporated into our EMR – a care management tool that has an HF-specific component, completed during the initial consultation by the APP.

With the aid of a community grant to support and expand our partnerships, we created education initiatives for patients and their caregivers that included support to overcome identified barriers to care such as low health literacy, financial strain, lack of insurance and lack of transportation.

Remote blood pressure and weight monitoring using a telehealth program was initiated for patients at high risk for recurrent admissions. Although the initial grant funding has ended, we continue to offer remote patient monitoring, free weight scales and blood pressure monitors, and a 30-day supply of medications to our patients through support from the health system and partnerships with national and community organizations.

We provide rideshare support for patients to attend clinic appointments. Our nurse care coordinator and community health worker also manage other innovative services and partnerships: community partnerships such as Open Hand (prepares and delivers healthy meals to patients), Home Instead (provides in-home care and support with common activities of daily living) and mobile integrated health (MIH) home visits.

The Grady MIH Team conducts home visits to patients identified as high-risk for hospital readmissions within 30 days post discharge. Working in close collaboration with the GHFP team, they assess vital signs, assess home safety, perform medication reconciliation and optimization of HF therapy, and administer appropriate point of care tests and intravenous diuretics if needed. Our partnership with the MIH Team has evolved significantly during the COVID-19 pandemic.

Impact of Our Program on Patients With HF

We perform an average of 140 inpatient and 25 clinical decision unit consults each month. We have completed >1,700 inpatient consults in the past year. The HF clinic consists of nine half-day clinic sessions plus four half-day clinic sessions at a neighborhood health center.

A combined census of approximately 600 patients are seen in clinic each month, with >5,000 patient visits in the past year with a staff of five APPs. Over 6,500 unique patients have received care at the Grady HF clinic since its inception in 2011.

By addressing socioeconomic barriers to care, the program has reduced 30-day readmission rates. For FY 2019, the 30-day all-cause readmission rate dropped to 18.5%, compared with 24.9% at inception, and a 30-day HF-related readmission rate of 10.7%.

The program's goal is to reach 85% of eligible patients within three days of initial discharge. To date, we have surpassed that goal, contacting 94.3% of patients by telephone within three days of hospital discharge and scheduling follow-up clinic visits within seven to 14 days post discharge for more than 97% of our patients.

Awards and Recognition

In recognition of the outstanding service provided by the GHFP, the National Association of Public Hospitals and Health Systems (now America's Essential Hospitals) presented our team with the Gage Award for improving quality in vulnerable populations.

The GHFP actively participates in national quality improvement initiatives such as the Get with the Guidelines and Target-Heart Failure programs of the American Heart Association (AHA). Since 2015, the GHFP has received annual recognition for our participation. We are recipients of the highest form of recognition, "Gold Plus Target-Heart Failure Honor Roll" Award, since 2018. This is an advanced level of recognition that acknowledges hospitals for consistent compliance with quality improvement measures outlined in the AHA secondary prevention guidelines for the treatment of HF patients.

The Centers for Disease Control and Prevention (CDC) recognized the GHFP as a promising program that advances health equity, reduces health disparities and addresses the SDOH related to heart disease. We were selected to participate in a rigorous evaluation process with feedback from experts on how to continually improve our processes and practices. Results from this evaluation showed that our patients had significantly fewer readmissions and reduced length of stay, with estimated net savings to the health system of $899,059 for 348 annual averted readmissions.

These national recognitions and awards are a testament to the dedication and passion of our multidisciplinary team to improve outcomes of the patients we serve.

Adapting HF Care in the Time of COVID-19

The advent of the novel SARS-CoV-2 virus in 2019 has led to significant changes in the delivery of health care. Accordingly, we modified our clinic workflow to deliver continuous and effective care to our patients during this period. Prioritizing the safety of our patients while recognizing the unique needs of our population has been our primary goal.

Despite the challenges we faced, we continue to provide our patients with access to quality HF care safely, thus promoting health equity during this COVID-19 pandemic, a time that has magnified the effects of health disparities.

The Heart Failure Society of America recently issued a statement, providing guidance on virtual visits, emphasizing the need for patient risk stratification, the importance of having a virtual visit workflow and the role of multidisciplinary HF clinicians such as APPs, physicians, pharmacists and licensed social workers. 1

We developed new protocols, which included virtual visits, MIH home visits and remote patient monitoring.

Preliminary comparison of HF clinic visits in the early COVID-19 a seven-week period (March 23-May 9) in 2020 vs. 2019 showed we had only 24 face-to-face visits, vs. 677 in 2019. This reflects a shift from no virtual visits in 2019 to 679 telephone virtual visits and 13 video virtual visits in 2020, along with 122 MIH home visits (vs. none in 2019).

Here are some key changes we made to address disparities during this COVID-19 era:

• Provision of free weight scales and blood pressure monitors to patients prior to hospital discharge or during MIH visits (traditionally given at follow-up clinic visits)
• Access to medications: patients receive their medications from the Grady Pharmacy by mail at no cost
• Access to Care: nurse care coordinator, community health worker and APPs increased communication with our patients through telehealth (decreasing transportation needs)
• MIH Home Visits: in-home follow-up visits for concerns noted during virtual visit. See Figure 2 for more detail.

The success of the Grady Heart Failure Program has truly demonstrated the importance of multidisciplinary team-based care and innovative approaches in managing adverse SDOH and reducing disparities in care for vulnerable patients with HF, as outlined in a recent scientific statement from the AHA on SDOH in this population. 2

Since the Program was established nearly a decade ago, we have achieved consistency in the quality of care despite challenges we face in our safety net health system.

Although the COVID-19 pandemic has highlighted significant disparities in health care and intensified the impact of adverse SDOH, we made swift modifications to our current care delivery process to mitigate its effects and ensure that both medical and nonmedical needs of our HF patients are met.

Our ongoing quest remains achieving health equity for our patients through patient-centered activities.

Our passion to ensure equitable access to high-quality medical care for the underserved gives credibility to the saying, "Atlanta can't live without Grady."

Tweet #CardiologyMag

This article was authored by Modele Ogunniyi, MD, MPH, FACC , associate professor, Emory University School of Medicine and associate medical director, Grady Heart Failure Program; Yetunde Fatade, MD, MPH , PGY 2 Resident, J. Willis Hurst Internal Medicine Residency, Emory University School of Medicine; and Andrea Cafarelli, FNP-BC , advanced practice provider, Faith Works-Fleming, FNP-BC , advanced practice provider, and Diane Wirth, ANP-BC, CACP , manager, all with the Grady Heart Failure Program.

Clinical Topics: Cardiovascular Care Team, COVID-19 Hub, Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: ACC Publications, Cardiology Magazine, Patient Readmission, Patient Discharge, Pharmacists, Caregivers, Medication Reconciliation, Diuretics, COVID-19, Safety-net Providers, House Calls, Community Health Workers, Inpatients, Blood Pressure, Pregnancy, Heart Failure

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Case Study: Acute Heart Failure in a 20-year-old Patient

At Piedmont Heart’s Napa Valley Cardiology Conference, Dr. David Dean presents a challenging case of acute heart failure in a 20-year-old patient. Hear Piedmont’s unusual approach to therapy and tips for success from Dr. Dean, surgical director of Piedmont’s Samsky Advanced Heart Failure Center.

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Case Study: Heart Failure Exacerbation Due to an Often Overlooked Cause

— shows importance of using wide differential when investigating hf.

by Kate Kneisel , Contributing Writer, MedPage Today

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

This month: A noteworthy case study

Why has a 64-year-old man become increasingly short of breath over the past 2 weeks? That's what Sandra K. Rabat, DO, of A.T. Still University School of Osteopathic Medicine in Mesa, Arizona, and colleagues needed to determine, as they reported in Cureus .

The patient's medical history included a diagnosis of congestive heart failure and coronary artery disease in 2014, after stenting of his left anterior descending artery and right coronary artery. He also had high blood pressure and stage III chronic kidney disease (CKD) when he presented to the hospital for assessment after 2 weeks of worsening dyspnea.

The patient told clinicians he became winded even after a few steps, and that at night, he needed to prop himself up on three pillows to improve his breathing. He also had fluid retention in his lower legs, feet, and ankles that lasted all day, and continued to be worsening.

He said he was not aware of anything that might have exacerbated his shortness of breath, and that he did not use oxygen therapy or inhalers at home. He admitted that he was not consistent about taking his prescribed medications – carvedilol, lisinopril, furosemide, atorvastatin, and clopidogrel – and that that he sometimes forgot them entirely.

His family history was significant for premature coronary artery disease and the sudden cardiac death of his grandfather at age 49.

On questioning, he reported feeling that his heart beat was very rapid, but had no other observations. He said he did not use illicit drugs, smoke, or drink alcohol. Social determinants of the patient's health included experiencing homelessness, and he had very little social or family support.

Initial examination found that he was in a hypertensive emergency. His blood pressure was 220/110 mmHg and oxygen saturation was 84% oxygen on room air. Significant lab test findings included a creatinine level that was increased to 2.4 mg/dL from his baseline of 1.7 mg/dL. Troponins were 12,333 pg/ml and brain natriuretic peptide (BNP) was 1,431 pg/ml.

Clinicians noted the complexities of interpreting cardiac troponin levels and BNP in the setting of CKD. However, they said, "the magnitude of elevation of the troponins and BNP was very concerning for another process within the myocardium rather than being a false-positive elevation from CKD alone."

EKG findings included the following:

• Prolonged QTC interval
• Left-axis deviation
• Non-specific ST-T changes
• No ST-segment elevations

Chest x-ray showed that the patient had cardiomegaly with pulmonary edema. Given the high troponin levels and EKG results, the team ruled out ST-segment elevation myocardial infarction (STEMI) as a diagnosis in favor of non-ST-segment elevation myocardial infarction (NSTEMI).

In the emergency department, the patient was started on one dose of clonidine, nasal cannula oxygen, and heparin drip, and later also received hydralazine as needed for systolic blood pressure that exceeded 160 mmHg. In light of his elevated BNP levels and chest x-ray findings, the patient was admitted for acute exacerbation of congestive heart failure. Clinicians started the patient on aggressive diuresis with IV furosemide and accelerated his cardiac workup.

The workup for pulmonary embolus was unremarkable, given the patient's negative venous duplex and V/Q scan, the case authors noted. "Transthoracic echocardiogram revealed significant findings, including an estimated ejection fraction of 10% with moderate mitral regurgitation and moderate tricuspid regurgitation, a dilated right ventricle with severely impaired systolic function, and grade three diastolic dysfunction with restrictive filling."

The team noted that a previous echocardiogram performed about 2 years earlier showed that the patient's estimated ejection fraction had been 60% with preserved left ventricular systolic function. Because of the severity of his left ventricular dysfunction, and dilation of the left ventricle, the patient received a portable external cardiac defibrillator.

An ultrasound of his abdomen revealed bilateral renal atrophy with diffusely increased echogenicity bilaterally, which is indicative of CKD. Because he was in volume overload, clinicians continued his diuresis and closely monitored his creatinine levels.

After interval improvement of his kidney function, the patient underwent cardiac catheterization, which indicated "nonobstructive coronary artery disease and severe pulmonary hypertension."

Right heart hemodynamics revealed a mean pulmonary capillary wedge pressure of 40 mmHg, mean pulmonary artery pressure of 60 mmHg, and mean right atrial (RA) pressure of 32 mmHg, the case authors reported, noting that this ruled out nonischemic cardiomyopathy as a cause of the patient's acute decompensation.

Following the cardiac catheterization, the team discontinued diuretic treatment. The patient was started on dobutamine infusion at 5 mcg/kg/min, and the dose was titrated to achieve a minimum mean arterial pressure of 65 mmHg. He began taking isosorbide mononitrate and hydralazine, and continued with carvedilol.

Diuretic therapy with torsemide was reinstated. Treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor neprilysin inhibitor was contraindicated, due to the patient's medical status: acute kidney injury in the presence of CKD stage III and a glomerular filtration rate of less than 30 ml/min/1.73 m 2 .

Efforts to wean the patient off dobutamine, however, failed when his kidney function worsened to a creatinine level of 2.7 mg/dL, which the authors noted confirmed a need for inotropic support. When his kidney function improved, they started the patient on milrinone infusion with close monitoring, based on evidence of decompensated heart failure with low cardiac output and signs of end-organ hypoperfusion.

The objective was to combine milrinone infusion with standard heart failure therapy, including a beta-blocker, as tolerated. "The benefit of using milrinone over dobutamine in this patient's case is that milrinone, a phosphodiesterase inhibitor, will not antagonize a beta-blocker like dobutamine," the authors explained.

Because dobutamine's action is partly related to beta-1 and beta-2 adrenergic receptors, concomitant beta-blocker therapy would likely reduce the hemodynamic response to treatment, the team speculated. The patient was scheduled for a cardiac MRI, possibly to be followed by endomyocardial biopsy.

This proved to be unnecessary, however, when the test result came back as "positive for Coxsackie B viral antibody immunoglobulin G (IgG), indicating chronic viral infection," Rabat and co-authors said.

"This case highlights how viruses continue to be an underappreciated cause of heart failure. In fact, viral myocarditis is an underdiagnosed cause of acute heart failure and chronic dilated cardiomyopathy," as is iron deficiency anemia , the authors wrote.

Cardiomyopathy – which is associated with muscle or electrical dysfunction of the heart – is defined by the American Heart Association as a heterogeneous group of diseases of the myocardium, usually with inappropriate ventricular hypertrophy or dilatation.

Noting that viral myocarditis is often overlooked due to its varied presentation, Rabat and co-authors urged clinicians not to underestimate the substantial cardiovascular risks associated with a large spectrum of viral infections, some of which can lead to significant deterioration in decompensated patients.

"Coxsackie B virus is one of the most common causes of viral myocarditis and is responsible for 10-20% of all myocarditis and dilated cardiomyopathy cases," the case authors said. Parvovirus B19, adenovirus, Epstein-Barr virus, HIV, and COVID-19 have also been reported to cause myocarditis.

Viral myocarditis may go undiagnosed due to the wide variety of presentations, which can range from dyspnea to more aggressive symptoms suggestive of acute coronary syndrome. One review noted that among more than 3,000 patients with suspected acute or chronic myocarditis, dyspnea was found in 72%, chest pain in 32%, and arrhythmias in 18%.

"Myocarditis generally results from cardiotropic viral infection followed by active inflammatory destruction of the myocardium," the case authors stated. After the initial acute symptoms of viral myocarditis, the viral infection may either clear completely, persist, or "lead to a persistent auto-immune-mediated inflammatory process with long-term symptoms of heart failure."

A persistent viral infection of the myocardium can result in a progressive deterioration of left ventricular ejection fraction (LVEF), which likely explains the current patient's decline in LVEF from 60% to 10% over less than 2 years, Rabat and co-authors noted.

Despite being considered the diagnostic gold standard for acute or chronic inflammatory heart disease, endomyocardial biopsy is used infrequently because of the perception of associated risks and the absence of a widely accepted and sensitive histologic standard.

Endomyocardial biopsies may be complemented with use of liquid biopsy to monitor circulating biomarkers, including microRNAs (miRNAs), which have also demonstrated excellent diagnostic capability, the team noted. In fact, in a recent study , expression levels of miRNAs differentiated between patients with viral myocarditis, inflammatory cardiomyopathy, and healthy donors with a specificity of over 95%.

"However, further studies would be needed to elevate the routine use of miRNA-panel in addition to further guidelines to help optimize the management of this disease," the case authors wrote, noting that current guidelines advise optimal use of heart failure medications to manage symptoms.

Rabat and co-authors noted that the COVID-19 pandemic has brought to light a global sensitivity to viral infections. The pathogenesis of viral myocarditis in heart failure remains poorly understood and represents a significant global public health issue. The team urged clinicians investigating heart failure to maintain a wide index of suspicion and be aware "that even chronic Coxsackie B viral infection can cause an acute presentation of heart failure."

Read previous installments of this series:

Part 1: Heart Failure: A Look at Low Ejection Fraction

Part 2: Exploring Heart Failure With Preserved Ejection Fraction

Part 3: Heart Failure With Reduced Ejection Fraction: Diagnosis and Evaluation

Part 4: Case Study: Lightheadedness, Fatigue in Man With Hypertension

Part 5: Heart Failure With Preserved Ejection Fraction: Diagnosis and Evaluation

Part 6: Heart Failure Medical Management

Part 7: Managing Heart Failure Comorbidities

Kate Kneisel is a freelance medical journalist based in Belleville, Ontario.

Disclosures

The authors reported no conflicts of interest.

Primary Source

Source Reference: Rabat S K, et al "A case report on an underappreciated cause of heart failure: Chronic viral myocarditis" Cureus 2022; DOI: 10.7759/cureus.27253.

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Study shows heart failure, not stroke is the most common complication of atrial fibrillation

by British Medical Journal

The lifetime risk of atrial fibrillation (a heart condition that causes an irregular and often abnormally fast heart rate) has increased from one in four to one in three over the past two decades, finds a study from Denmark in The BMJ today.

And among those with the condition, two in five are likely to develop heart failure over their remaining lifetime and one in five encounter a stroke, with little or no improvement in risk evident over the 20 year study period.

As such, the researchers say stroke and heart failure prevention strategies are needed for people with atrial fibrillation .

Atrial fibrillation is estimated to affect 18 million people in Europe by 2060 and 16 million people in the US by 2050. In the English NHS alone, more new cases of atrial fibrillation are diagnosed each year than the four most common causes of cancer combined, and direct expenditure on atrial fibrillation has reached £2.5 billion.

Once atrial fibrillation develops, patient care has primarily focused on the risk of stroke, but other complications such as heart failure and heart attack have yet to be fully explored.

To address this knowledge gap, researchers analyzed national data for 3.5 million Danish adults with no history of atrial fibrillation at age 45 or older to see whether they developed atrial fibrillation over a 23 year period (2000–22).

All 362,721 individuals with a new diagnosis of atrial fibrillation during this time (46% women and 54% men) but with no complications, were subsequently followed until a diagnosis of heart failure, stroke or heart attack.

Potentially influential factors such as history of high blood pressure, diabetes, high cholesterol, heart failure, chronic lung and kidney disease , family income and educational attainment, were also taken into account.

The results show that the lifetime risk of atrial fibrillation increased from 24% in 2000–10 to 31% in 2011–22. The increase was larger among men and individuals with a history of heart failure, heart attack, stroke, diabetes, and chronic kidney disease.

Among those with atrial fibrillation, the most common complication was heart failure (lifetime risk 41%). This was twice as large as the lifetime risk of any stroke (21%) and four times greater than the lifetime risk of heart attack (12%).

Men showed a higher lifetime risk of complications after atrial fibrillation compared with women for heart failure (44% vs. 33%) and heart attack (12% vs. 10%), while the lifetime risk of stroke after atrial fibrillation was slightly lower in men than women (21% vs. 23%).

Over the 23-year study period, there was virtually no improvement in the lifetime risk of heart failure after atrial fibrillation (43% in 2000–10 vs. 42% in 2011–22) and only slight (4–5%) decreases in the lifetime risks of any stroke, ischemic stroke, and heart attack after atrial fibrillation, which were similar among men and women.

This is an observational study , so no firm conclusions can be drawn about cause and effect, and the authors acknowledge that they may have missed patients with undiagnosed atrial fibrillation. Nor did they have information on ethnicity or lifestyle factors, and say results may not apply to other countries or settings.

But despite these caveats, they conclude, "Our novel quantification of the long term downstream consequences of atrial fibrillation highlights the critical need for treatments to further decrease stroke risk as well as for heart failure prevention strategies among patients with atrial fibrillation."

Interventions to prevent stroke have dominated atrial fibrillation research and guidelines during this study period, but no evidence suggests that these interventions can prevent incident heart failure , say UK researchers in a linked editorial.

They call for alignment of both randomized clinical trials and guidelines "to better reflect the needs of the real-world population with atrial fibrillation" and say this robust observational research "provides novel information that challenges research priorities and guideline design, and raises critical questions for the research and clinical communities about how the growing burden of atrial fibrillation can be stopped."

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Yuli Y Kim, Gentian Lluri, Christiane Haeffele, Tami Daugherty, Richard A Krasuski, John D Serfas, R Andrew de Freitas, Avaliese Porlier, Adam M Lubert, Fred M Wu, Anne Marie Valente, Eric V Krieger, Jonathan Buber, Fred H Rodriguez, Scott Gaignard, Anita Saraf, Morgan Hindes, Michael G Earing, Matthew J Lewis, Marlon S Rosenbaum, Ali N Zaidi, Kali Hopkins, Elisa A Bradley, Ari M Cedars, Jong L Ko, Wayne J Franklin, Abby Frederickson, Salil Ginde, Jasmine Grewal, Annique Nyman, Jungwon Min, Charlotte Schluger, Elizabeth Rand, Benjamin E Rosenthal, Moira Hilscher, Jack Rychik, Maarouf A Hoteit, Hepatocellular carcinoma in survivors after Fontan operation: a case–control study, European Heart Journal , Volume 45, Issue 16, 21 April 2024, Pages 1477–1480, https://doi.org/10.1093/eurheartj/ehad788

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Liver injury is universal in patients who have undergone Fontan palliation for complex congenital heart disease and results in fibrosis and cirrhosis. 1 Fontan-associated liver disease (FALD) can be rarely complicated by hepatocellular carcinoma (HCC), 2–4 risk factors for which are not fully elucidated. We aim to identify clinical characteristics associated with the development of HCC in adult single ventricle patients with Fontan circulation.

This is a multi-centre, retrospective case–control study of Fontan patients ≥ 18 years old across 18 North American centres of the Alliance for Adult Research in Congenital Cardiology between 2005 and 2021 and approved by all research oversight boards. Cases were included based on histologic or imaging-based diagnosis of HCC [computed tomography (CT) or magnetic resonance imaging (MRI) that fulfil Liver Imaging Reporting and Data System® (LI-RADS)-5 criteria, 5 plus alpha-fetoprotein (AFP) > 20 ng/mL or evidence of lesion growth ≥ 50% within 6 months or > 100% in a period of over 6 months on serial imaging studies]. Controls were randomly selected in a 3:1 ratio from the centre in which the case was derived. Inclusion criteria were blood work and abdominal imaging (ultrasound, CT, or MRI) within 18 months of the last clinic visit, the latter without a focal liver lesion or if present, imaging evidence of stable size over at least 24 months. Those without imaging or labs, AFP ≥ 10 ng/dL at any time, or history of hepatitis B or C were excluded.

Clinical characteristics and laboratory values were collected by chart review. AST to Platelet Ratio Index (APRI) and Fibrosis-4 Index (FIB-4) (non-invasive methods that correlate with degree of fibrosis on biopsy in other chronic liver disease states) 6 and Model for End-stage Liver Disease excluding INR (MELD-XI) scores were calculated and collapsed into binary (low/high) variables using cut-offs of < 0.5 and ≥ 0.5, < 1.45 and ≥ 1.45, and < 11 and ≥ 11, respectively. Radiology and liver biopsy reports were reviewed by a board-certified hepatologist. Bivariate and multivariate analyses were performed to examine association between variables and HCC. We included characteristics having a significant association with HCC risk ( P <0.05) in the multivariate logistic regression model after evaluating collinearity and area under the curve (AUC) of the receiver operating characteristic (ROC).

There were 58 HCC cases (43% female and 79% White) and 174 controls ( n = 232). Out of a total of 3251 adult Fontan patients followed across all 18 centres, the estimated prevalence of HCC was 1.8%. Median age of HCC diagnosis was 31 (interquartile range 26–38) years. One-year survival after HCC diagnosis was 81%.

There was no difference between cases and controls regarding age, sex, body mass index, underlying congenital heart defect, age at Fontan operation, or time since Fontan; those with HCC more commonly had undergone right atrial to pulmonary artery or right atrial to right ventricle Fontan repair, had higher burden of cardiac comorbidities, including arrhythmia, desaturation (oxygen saturation < 90%), heart failure, and lymphatic disorders, and were more likely to have undergone prior Fontan revision and valve surgery, despite comparable echocardiographic and historical catheterization haemodynamic parameters. Just over half of HCC cases occurred in patients with FIB-4 < 1.45, a threshold which has a 90% negative predictive value for advanced fibrosis in other liver disease populations. 7 Similarly, nearly half of HCC cases occurred in patients with MELD-XI < 11 and with APRI < 0.5.

Bivariate analyses examining the relationship between select variables and HCC were performed ( Table 1 ). There was no relationship between age at Fontan or time since Fontan operation with HCC.

Bivariate analyses for the odds of hepatocellular carcinoma

P -values <0.05 are noted in bold. APRI, AST to Platelet Ratio Index; AST, aspartate transaminase; CI, confidence interval; FIB-4, Fibrosis-4; MELD-XI, Model for End-stage Liver Disease eXcluding International normalized ratio; OR, odds ratio.

We created two multivariable models using select variables from the bivariate analyses. Model A showed desaturation [adjusted odds ratio (aOR) 2.4, 95% confidence interval (CI) 1.1–5.2; P = .02], history of Fontan revision (aOR 2.3, 95% CI 1.1–4.8; P = .02), and thrombocytopenia (aOR 2.3, 95% CI 1.2–4.5; P = .02) were associated with increased odds of HCC. Model B showed desaturation (aOR 2.2, 95% CI 1.0–4.7; P = .05) and FIB-4 ≥ 1.45 (aOR 3.9, 95% CI 2.0–8.0; P < .001) as associated with higher odds of developing HCC. Both models had ROC AUC = 0.72.

We hypothesized that HCC is time-dependent and that those affected would be older than controls, but the data do not suggest that length of exposure to Fontan physiology is the main driver of HCC. Instead, we found that advanced FALD and cardiac comorbidities were more prevalent in HCC cases. Progression of liver fibrosis in FALD is not uniform 8 and is likely driven by circulatory factors, which hypothetically could explain why length of exposure to Fontan physiology alone was not found to be significant. It is important to emphasize that non-invasive fibrosis scores, such as APRI and FIB-4, do not have adequate discrimination for the detection of HCC and should be interpreted in the context of other clinical factors. Our results support the concept that worse FALD (by liver function tests and imaging) is the primary substrate for the development of HCC in the Fontan liver and suggest that ‘sicker’ Fontan patients—those with desaturation and need for cardiac surgery beyond the Fontan operation itself—may be at highest risk.

The numbers studied were relatively small but represent the largest collection of HCC in the Fontan population published to date. This was a study on Fontan patients of adult age and therefore results may not be applicable to the paediatric population. We also acknowledge that the imaging-based inclusion criteria as described are not standard, as LI-RADS is not applicable in ‘cardiac congestion’. By additionally requiring either elevated AFP or evidence of rapid lesion growth, we attempted to improve the diagnostic accuracy of LI-RADS in the Fontan liver.

Hepatocellular carcinoma is diagnosed in up to 2% of adult Fontan patients. Those with more advanced FALD represented by abnormal liver biochemistries and signs of circulatory failure may be at increased risk. Until more clearly defined risk factors are identified, we recommend abdominal ultrasounds and AFP every 6 months for adult Fontan patients in accordance with guidelines for HCC screening. 9

We would like to acknowledge the Alliance for Adult Research in Congenital Cardiology for its support rendered to this study.

Disclosure of Interest

All authors declare no disclosure of interest for this contribution.

No data were generated or analysed for or in support of this paper.

This study was supported by a grant from the Children’s Hospital of Philadelphia Cardiac Center.

Ethical approval was not required.

None supplied.

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