Chapter 33 Therapy of Heart Failure PDF

33 Chapter PATHOPHYSIOLOGY OF HEART FAILURE Definitions Therapy of Heart Failure Thomas Eschenhagen Common Final Pathway of Multiple Cardiac Diseases...

33 Chapter PATHOPHYSIOLOGY OF HEART FAILURE Definitions Therapy of Heart Failure Thomas Eschenhagen Common Final Pathway of Multiple Cardiac Diseases DRUG TREATMENT OF ACUTELY DECOMPENSATED HEART FAILURE Diuretics Pathophysiological Mechanisms Vasodilators Heart Failure With Preserved Ejection Fraction Positive Inotropic Agents Heart Failure Staging Myofilament Calcium Sensitizers (Levosimendan, Pimobendan) Prevention and Treatment Other Drugs Used in Heart Failure Role of Standard Combination Therapy DRUG TREATMENT OF CHRONIC SYSTOLIC HEART FAILURE Treatment Principle I: Neurohumoral Modulation LESSONS FROM HEART FAILURE DRUG DEVELOPMENT Treatment Principle II: Preload Reduction Lessons From Failed Drugs Treatment Principle III: Afterload Reduction Lessons From Treating Acute Heart Failure Treatment Principle IV: Increasing Cardiac Contractility Recent Developments; Novel Approaches Treatment Principle V: Heart Rate Reduction Myosin Modulators Treatment Principle VI: SGLT2 Inhibition Heart failure is responsible for more than half a million deaths annually in categorized as heart failure (e.g., chronic obstructive pulmonary the U.S. Its prevalence is stable in developed countries but increasing world- disease). wide, mainly due to an adoption of western lifestyle and an aging popu- lation. Median survival rates after the first hospitalization associated with Common Final Pathway of Multiple heart failure are worse than in most cancers but have improved over the past 30 years (1.3 to 2.3 years in men and 1.3 to 1.7 years in women) (Jhund Cardiac Diseases et al., 2009). This positive survival trend was associated with a 2- to 3-fold Heart failure is not a single disease entity but a clinical syndrome that higher prescription rate of angiotensin-converting enzyme (ACE) inhibitors represents the final pathway of multiple cardiac diseases. The most com- (ACEIs) and angiotensin receptor blockers (ARBs), β receptor antagonists mon reason for systolic heart failure today is ischemic heart disease caus- (β blockers), and mineralocorticoid receptor antagonists (MRAs), sug- ing either acute (myocardial infarction) or chronic loss of viable heart gesting that improved drug therapy has contributed to enhanced survival muscle mass. Other reasons include chronic arterial hypertension and of patients with heart failure. However, a more complex picture evolved valvular diseases (both are decreasing in incidence due to improved over the past decade with an increasing incidence in people younger than therapy), genetically determined primary heart muscle defects (cardio- 55 years of age, a decrease in heart failure with reduced ejection fraction myopathies), viral infections (cytomegalovirus and possibly parvovirus), (HFrEF); and an increase in heart failure with preserved ejection fraction and cardiotoxic agents. The last encompass excessive alcohol, cocaine, (HFpEF; Chan et al., 2021; Tsao et al., 2018). amphetamines, and cancer drugs such as doxorubicin, trastuzumab (the monoclonal antibody directed against the growth factor receptor Her-2/ Erb-B2), and immune checkpoint inhibitors (see Section VII). Pathophysiology of Heart Failure Pathophysiological Mechanisms Definitions Systolic heart failure (i.e., HFrEF) is relatively well understood, whereas mechanisms underlying HFpEF are much less clear. The pathophysiology Heart failure is a state in which the heart is unable to pump blood at of heart failure involves four major interrelated systems (Figure 33–1): a rate commensurate with the requirements of the body’s tissues or can do so only at elevated filling pressure. This leads to symptoms that The heart itself define the heart failure syndrome clinically. Low output (forward fail- The vasculature ure) causes fatigue, dizziness, muscle weakness, and shortness of breath, The kidney which is aggravated by physical exercise. Increased filling pressure leads Neurohumoral regulatory circuits to congestion of the organs upstream of the heart (backward failure), clinically apparent as peripheral or pulmonary edema, maldigestion, The Heart Itself: Cardiomyopathy of the Overload and ascites. Any overload of the myocardium—loss of relevant muscle mass, which Most patients with heart failure are diagnosed exclusively on the basis overloads the remaining healthy myocardium; chronic hypertension; or of symptoms; that is, their heart function has never been directly mea- valvular defects—will eventually lead to the organ’s failure to produce sured (e.g., by echocardiography). Under these circumstances, it is not sufficient cardiac output. This concept can be extended to the geneti- possible to differentiate between HFrEF (or systolic heart failure) and cally determined cardiomyopathies in which essentially any defect in an HFpEF (or diastolic heart failure, see discussion that follows). Other organelle of cardiac myocytes can lead to primary myocyte contractile diseases associated with similar symptoms can therefore be wrongly dysfunction and then, secondarily, to the picture commonly seen in the https://ebooksmedicine.net/  648 Abbreviations The overload (or the primary contractile defect) leads to alterations of the heart that can partially compensate but that come at a price. Because cardiac myocytes essentially stop replicating in the early postnatal period, ACC: American College of Cardiology the usual response to overload is not myocyte division but rather hyper- ACE: angiotensin-converting enzyme trophy, growing in size and assembling more sarcomeres that can contrib- ACEI: angiotensin-converting enzyme inhibitor ute to contractile force development. Whereas hypertrophy is principally ADR: adverse drug reaction a normal response to physiological needs such as body growth, preg- AHA: American Heart Association nancy, and physical exercise (“physiological hypertrophy”), hypertrophy in response to chronic overload comes with features that make it a major AngII: angiotensin II risk factor for the development of heart failure (“pathological hypertro- ANP: atrial natriuretic peptide phy”). A direct consequence of cardiac myocyte hypertrophy is a reduced ARB: AT1 angiotensin receptor antagonist (blocker) capillary/myocyte ratio (i.e., less O2 and nutrient supply per myocyte), ARNI: angiotensin receptor–neprilysin inhibitor causing an energy deficit and metabolic reprogramming. Altered gene AV: atrioventricular expression of ion channels, Ca2+-regulating proteins, and contractile AVP: arginine vasopressin proteins can be interpreted as partially beneficial, energy-saving adap- BNP: brain-type natriuretic peptide tations; on the other hand, the adaptations also aggravate contractile CG: cardiac glycoside failure and favor arrhythmias. Concurrently, fibroblasts proliferate and CHF: congestive heart failure deposit increased amounts of extracellular matrix (e.g., collagen). This CNP: C-type natriuretic peptide fibrosis in heart failure also favors arrhythmias, increases the stiffness of CYP: cytochrome P450 the heart, and interrupts myocyte-to-myocyte communication (coordi- CHAPTER 33 THERAPY OF HEART FAILURE DA: dopamine nated conduction and force transmission). Finally, overload leads to car- ECG: electrocardiogram diac myocyte death by apoptosis or necrosis. Collectively, these adverse EF: ejection fraction adaptations are called pathological remodeling. eNOS: endothelial nitric oxide synthase Some of these alterations are direct, heart-intrinsic consequences of EPI: epinephrine overload (e.g., hypertrophy, altered gene expression); others are second- ESC: European Society of Cardiology ary to neurohumoral activation and thereby susceptible to neurohumoral ET: endothelin blocking agents (see discussion that follows and Figure 33–1). GC: guanylyl cyclase GFR: glomerular filtration rate The Vasculature GI: gastrointestinal A critical parameter of cardiac function is the stiffness of the vasculature. GPCR: G protein-coupled receptor It determines the resistance against which the heart must expel the blood. HCN: hyperpolarization-activated, cyclic nucleotide–gated cation Vascular stiffness increases with aging. Heart failure may be the conse- channel quence of premature aging of the vasculature (Strait and Lakatta, 2012). HFpEF: heart failure with preserved ejection fraction (diastolic Aging-induced loss of elasticity of the great blood vessels reduces their heart failure) compliance, that is, the elasticity that permits vessels to extend in systole and contract in diastole. Good compliance reduces peak systolic pressure HFrEF: heart failure with reduced ejection fraction (systolic and increases diastolic pressure, which favors perfusion in diastole. It is heart failure) negatively correlated with pulse pressure, that is, the difference between iNOS: inducible nitric oxide synthase systolic and diastolic blood pressure, which is low in children and high in ISDN: isosorbide 2,5′-dinitrate the elderly. Arterial hypertension and diabetes mellitus are the major rea- ISMN: isosorbide 5′-mononitrate sons for premature stiffening of blood vessels, which imposes increased MRA: mineralocorticoid receptor antagonist afterload to the heart and contributes to heart failure. Theoretically, NCX: Na+/Ca2+ exchanger stiffening and loss of compliance could be directly tackled by drugs (see NE: norepinephrine section Recent Developments; Novel Approaches). NO: nitric oxide Another critical aspect of vascular function is the ability to adapt the NOS: nitric oxide synthase vessel diameter to hemodynamic and neurohumoral stimuli, a function NSAID: nonsteroidal anti-inflammatory drug that is governed by cross talk between luminal endothelial and underly- NYHA: New York Heart Association ing smooth muscle cells (see Chapter 32). The main signaling pathway PKA: protein kinase A involves receptors that increase intracellular Ca2+ levels in endothelial RAAS: renin-angiotensin-aldosterone system cells, which activates endothelial nitric oxide synthase (eNOS) to pro- RAS: renin-angiotensin system duce nitric oxide (NO). This gaseous transmitter diffuses into smooth ROS: reactive oxygen species muscle cells and activates soluble guanylyl cyclase (sGC) to produce SERCA: sarco/endoplasmic reticulum Ca2+ ATPase cGMP, which causes relaxation of vascular smooth muscle. Heart fail- sGC: soluble guanylyl cyclase ure is always accompanied by endothelial dysfunction, which is a dis- SGLT2: sodium glucose co-transporter 2 turbed balance between vasodilating NO and proconstrictor reactive SNS: sympathetic nervous system oxygen species (ROS). ROS, by inactivating the two critical enzymes SR: sarcoplasmic reticulum eNOS and sGC and converting NO in peroxynitrite, a strong ROS, favor TnC: troponin C vasoconstriction. Several common cardiovascular drugs (ACEIs/ARBs, TNF: tumor necrosis factor MRAs, statins) improve endothelial function by reducing ROS produc- tion. Cyclic nucleotide phosphodiesterase (PDE)5 inhibitors have similar consequences by inhibiting cGMP degradation in smooth muscle cells and thereby promoting relaxation. Stimulators of sGC like the recently cardiomyopathy of the overload. Not surprisingly, the most common approved new heart failure drug vericiguat dilate blood vessels by direct cardiomyopathies (dilated cardiomyopathy, hypertrophic cardiomyop- stimulation of the enzyme and sensitization to endogenous NO. athy) are due to mutations in genes encoding proteins of the contrac- tile machinery, the sarcomere, proteins anchoring the sarcomere to The Kidney the plasma membrane, or proteins mediating and maintaining cell-cell The kidney regulates Na+ and H2O excretion and thereby intravascular contact. volume. Under normal conditions, autoregulatory and neurohumoral  649 Blood pressure Cardiac Organ perfusion glycosides ACEI/ARB a blockers MRA CM hypertrophy ARNI SNS Cell death ANP Cardiac output RAAS Fibrosis BNP Vasopressin Arrhythmias ACEI/ARB a blockers ARNI MRA + ARNI Heart rate Force – Blood pressure Vasoconstriction Afterload SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR Vasodilators Preload Diuretics Renal perfusion Natriuresis Diuresis Figure 33–1 Pathophysiologic mechanisms of systolic heart failure (HFrEF) and therapeutic interventions. Any major decrease in cardiac contractile function leads to activation of neurohumoral systems, including the SNS, the RAAS, and vasopressin (antidiuretic hormone) secretion, which acutely stabilize blood pressure and organ perfusion by stimulating cardiac output, constricting resistance vessels, decreasing kidney perfusion, and increasing Na+ and H2O retention. Unfortunately, these responses are maladaptive, causing chronic overloading and overstimulation of the failing heart. Direct hypertrophic, proapoptotic, fibrotic, and arrhythmogenic effects of NE and AngII further accelerate the deleterious process. Note that the concomitant activation of the ANP/BNP system is the con- sequence of stretch and increased wall stress in the heart and has opposite and beneficial effects. See Abbreviations list at the beginning of the chapter. mechanisms ensure an adequate glomerular filtration rate (GFR) and cardiac O2 consumption. Tachycardic and positive inotropic actions of diuresis over a wide range of renal perfusion pressures. Prominent regula- catecholamines not only acutely increase cardiac output but also promote tory mechanisms with relevance for heart failure are (1) the angiotensin II arrhythmias and increase O2 consumption in a failing, energy-depleted (AngII)-mediated regulation of filtration rate by regulating the diameter heart. AngII, norepinephrine (NE), and ET accelerate pathological car- of the efferent glomerular arteriole; (2) the regulation of kidney perfu- diac remodeling (hypertrophy, fibrosis, and cell death). Aldosterone has sion by a balance between constrictor-promoting effects of AngII (via AT1 prominent profibrotic actions. This spectrum of adverse consequences receptors) and vasopressin (arginine vasopressin [AVP], via V1 receptors) of chronic neurohumoral activation explains why inhibitors of these sys- and the vasodilating influence of prostaglandins (hence the deleteri- tems (ACEIs/ARBs, β blockers, and MRAs) exert long-term, life-prolonging ous effects of nonsteroidal anti-inflammatory drugs [NSAIDs]); (3) the effects in heart failure and are the cornerstones of current therapy. aldosterone-mediated regulation of Na+ reabsorption in the distal tubule; Unexpectedly, ET and AVP receptor antagonists provide no beneficial and (4) AVP-regulated water transport in the collecting ducts (via V2 effect in patients with heart failure, despite promising results in preclin- receptors). In heart failure, all mechanisms are dysregulated and constitute ical studies. Clinical trials suggested that neurohumoral activation in therapeutic targets of ACEIs/ARBs, MRAs, and diuretics. Newer agents, response to altered cardiac function may be sufficiently inhibited by the such as adenosine A1 receptor antagonists and AVP receptor antagonists, standard combination therapy, leaving no room for improvement from have failed to exert therapeutic benefit in clinical studies. the addition of ET and AVP antagonists; however, recent data indicate that additional benefit may accrue via another therapeutic route: a drug Neurohumoral Regulation and HFrEF combination called angiotensin receptor–neprilysin inhibitors (ARNIs). The decrease in cardiac output in heart failure leads to the activation The FDA has approved a fixed-dose combination of the ARB valsartan of the sympathetic nervous system (SNS) and the renin-angiotensin- with the neprilysin inhibitor sacubitril. Valsartan blocks AT1 receptors, aldosterone system (RAAS) and increases in plasma levels of AVP and reducing the deleterious effects of AngII. Sacubitril inhibits the degra- endothelin (ET) (Figure 33–1). This concerted response ensures the per- dation of the natriuretic peptides atrial natriuretic peptide (ANP) and fusion of centrally important organs such as the brain and the heart (at brain-type natriuretic peptide (BNP). The valsartan/sacubitril combina- the expense of kidney, liver, and skeletal muscle perfusion) in situations tion appears superior to the ACEI enalapril, reducing the rates of hos- of acute blood loss. These responses are components of the “fight-or- pitalization and death from all cardiovascular causes in patients with flight response” and provide useful short-term physiological responses HFrEF (Hubers and Brown, 2016). to alarm and danger. Chronically, however, neurohumoral activation This finding reflects the fact that neurohumoral activation in heart exerts deleterious effects that constitute a vicious cycle in heart failure. failure includes one system that exerts beneficial effects: the natriuretic Vasoconstriction initially not only stabilizes blood pressure but also peptides. Normally, ANP and BNP are expressed in the atria and released increases afterload, which is the resistance against which the heart works upon increased preload (stretch). During heart failure, ANP and BNP to expel blood (see Figures 33–4 and 31–1). Because of the decreased are also produced by the ventricles, such that plasma levels are elevated. contractile reserve, the failing heart is particularly sensitive to increases Indeed, BNP is used as a biomarker of heart failure. ANP and BNP stim- in afterload (see Figure 33–4); such increases further decrease cardiac ulate the plasma membrane guanylyl cyclase. In the kidney, elevated output. Decreased kidney perfusion and increased aldosterone produc- cGMP has diuretic effects. Elevated cellular cGMP mediates vasodila- tion reduce diuresis and promote volume overload, which increases car- tion in the vasculature and, in the heart, antihypertrophic, antifibrotic, https://ebooksmedicine.net/ diac preload, dilation, and ventricular wall stress, a major determinant of and compliance-increasing effects related to phosphorylation of titin.  650 Enhancing these effects by inhibiting the degradation of ANP/BNP likely preserves and elevates cellular cGMP in some cells (see Chapters 3, 35, explains the clinical benefits of sacubitril/valsartan. and 49), failed to show benefit (Redfield et al., 2013). This lack of efficacy is, unfortunately, also true for all other pharmacological interventions in Heart Failure With Preserved Ejection Fraction HFpEF, including ACEIs, ARBs, and spironolactone. A new facet of HFpEF Systematic echocardiographic determination of left ventricular ejection may be upregulation of inducible nitric oxide synthase (iNOS), the induc- fraction (EF) in thousands of patients with heart failure revealed that ible isoform of nitric oxide synthase (NOS), in the myocardium, leading about 50% had no reduction; that is, they exhibited EF values greater to increased nitrosylation and disturbance of the endoplasmic reticulum than 50%. Still, patients had typical heart failure symptoms, including stress response (Schiattarella et al., 2019). The hypothesis is attractive as acute decompensation with pulmonary edema and a survival prognosis it is based on a mouse model integrating both hypertensive and metabolic not much better or even identical to patients with reduced EF (HFrEF). stress, classical risk factors of HFpEF in humans. This hypothesis offers These data point to a different pathophysiology in which abnormalities of potential new therapy targets. Presently, exercise training is the only inter- the diastolic and not the systolic component of cardiac function prevail. vention that significantly increases exercise capacity (maximal oxygen con- Due to difficulties in defining diastolic function by standard techniques, sumption, peak VO2) in HFpEF patients. In the absence of evidence-based the term HFpEF has been introduced and applies to patients with typical clinical trial data, current therapy recommendations concentrate on opti- heart failure symptoms and “normal” (>50%) or only mildly reduced EF. mal treatment of the underlying diseases, such as hypertension, diabetes, Even more than HFrEF, HFpEF is a multifactorial disease (Figure 33–2). and obesity. HFpEF is typically associated with arterial hypertension, ischemic heart Heart Failure Staging disease, diabetes mellitus, and obesity (metabolic syndrome); it is more frequent in women than men and shows a strong increase in prevalence Heart failure was one of the first diseases for which guidelines described with age (Shah et al., 2020). Hearts of patients with HFpEF are generally specific therapies for each stage of the disease. An early classification of CHAPTER 33 THERAPY OF HEART FAILURE not dilated, wall thickness is enlarged (hypertrophy), and left atrial size the stages of heart failure was that of the New York Heart Association often is enlarged as a sign of chronically elevated end-diastolic pressures. (NYHA), a classification still in use: class I (left ventricular dysfunction, Central to the pathophysiology of HFpEF is, presumably, compromised no symptoms); class II (symptoms at medium-to-high levels of physical diastolic relaxation of the left ventricle, which causes congestion of the exercise); class III (symptoms at low levels of physical exercise); and class lung, shortness of breath, or pulmonary edema. Clinical decompensation IV (symptoms at rest or daily life physical activities such as brushing teeth). is often associated with strongly elevated blood pressure. The more recent guidelines of the American Heart Association (AHA) and Molecular alterations include increased myocardial fibrosis (causing a American College of Cardiology (ACC) extended this classification by permanent relaxation deficit) as well as more dynamic changes, such as considering the following: reduced phosphorylation of titin, the sarcomeric protein that spans the Heart failure is part of the cardiovascular continuum with preventable large region from the Z to the M band. Titin contains several molecular risk factors (stage A). spring domains whose elastic modulus determines the passive tension An asymptomatic stage exists that requires treatment to delay transi- of cardiomyocytes, particularly at low-to-medium levels of stretch. Titin tion to symptomatic heart failure (stage B). stiffness is determined by its isoforms and by cGMP-dependent phos- Patients oscillate between different degrees of symptoms and there- phorylation, suggesting that agents that increase cellular cGMP might fore between class II and III (class C, which generally includes NYHA be beneficial in HFpEF. However, the PDE5 inhibitor sildenafil, which class II/III patients). CAD Hypertension Diabetes Obesity Microvessels Overload Oxidative stress Disseminated Overload RAGE activation Ischemia MRA ACEI/ARB Cardiomyocyte hypertrophy PDE5 inhibitors CCB Cardiomyocyte stiffening (titin) GC activators Diuretics Interstitial and perivascular fibrosis ARNI a blockers MRA Diastolic relaxation defect Reduced regulatory reserve Pulmonary congestion Peripheral congestion Diuretics Decreased output Figure 33–2 Pathophysiological mechanisms of diastolic heart failure HFpEF and possible therapeutic interventions. Unlike the case with HFrEF, the pharmaco- logical agents shown have not been proven to have clinical efficacy toward HFpEF, although these agents can help to control underlying diseases, such as hyper- tension, diabetes, and obesity. Only exercise training has proven effective in increasing maximal exercise capacity. RAGE, receptor for advanced glycosylation end-products. CAD, coronary artery disease; CCB, calcium channel blocker.  A final stage of the disease requires different treatment and special (sympathomimetics and PDE inhibitors) that exert acute symptom- 651 considerations, such as heart transplantation and left ventricular assist atic benefit reduce life expectancy when chronically administered. In device implantation (stage D). contrast, β blockers decrease cardiac output acutely and may make people feel weak at the start of therapy but prolong life expectancy This chapter uses the AHA/ACC classification and considers the recent when given in increasing doses for extended periods. Vasodilators guidelines of the European Society of Cardiology (ESC) (Ponikowski once seemed a logical choice for heart failure, but pure vasodilators et al., 2016), which provide more specific treatment algorithms, and the such as the α1 receptor antagonist prazosin or the nitrate isosorbide 2017 AHA/ACC update (Yancy et al., 2017). Treatment guidelines are 2,5′-dinitrate (ISDN), in combination with the vasodilator hydrala- summarized in Figure 33–3. zine, do not positively affect the prognosis in Caucasians (see further discussion). Finally, successful trials can occur unexpectedly and Prevention and Treatment before the mechanism of action is fully understood. A recent exam- ple is the beneficial effect of sodium glucose co-transporter 2 (SGLT2) Ischemic heart disease, hypertension, and valvular diseases are the most inhibitors on outcome in patients with heart failure and without dia- prevalent causes of heart failure. People at high risk of heart failure betes. Thus, clinical trials have established important principles for (stage A) should be treated with drugs that mitigate the harmful effects assessing efficacy of therapies for heart failure: of these diseases, in conjunction with appropriate lifestyle changes. Stud- ies in thousands of patients have reproducibly shown that blood pressure 1. Drugs treating chronic heart failure should reduce the patient morbid- lowering in hypertensive patients and lipid lowering with statins in dys- ity and mortality. lipidemic patients reduce not only the incidence of myocardial infarction 2. Short-term drug effects poorly predict the outcome of randomized and death but also the incidence of heart failure. The data are weaker clinical trials and optimal therapies for heart failure. SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR for antidiabetic drugs, but consensus exists that blood glucose should be 3. Considerations for stage of disease are critical. controlled with a hemoglobin A1C goal of 7% to 7.5%. 4. New drugs for heart failure should be compared to the most effective Treatment of heart failure has seen a dramatic change over the past current combination therapy, a principle often ignored in preclinical decades. Until the late 1980s, choice of drugs and dosing was symp- animal work. tom oriented and based on pathophysiological considerations of acute 5. Clinical trials often provide unexpected results, which then initiate systolic heart failure. Treatment was mainly directed toward symp- research into advanced understanding of mechanisms. tom relief and short-term improvement of hemodynamic function. 6. Nonpharmacological treatment options such as cardiac resyn- Subsequent randomized clinical trials, which mainly tested effects of chronization devices and intracardiac defibrillator/cardioverters drugs on long-term morbidity (hospitalizations) and mortality, dis- are important for their documented lifesaving effect in selected proved many former beliefs. For example, positive inotropic drugs patient populations. Step 1: Establish Step 3: Implement indicated Step 2: Consider the Step 4: diagnosis of GDMT, choices are not Step 5: Consider following patient Reassess HFrEF, assess mutually exclusive, no order additional therapy scenarios symptoms volume, initiate GDMT is inferred NYHA II–IV, provided CrCl >30 mL/min Add MRA and K+ 1 yr ICD LVAD improved survival, >40 d after MI) NYHA II–IV NSR and QRS >150 ms CRT or CRT-D with LBBB pattern NYHA II–III, NSR, HR >70 bpm on maximally Add ivabradine tolerated beta blocker dose Continue GDMT with serial reassessment & optimized dosing and adherence Figure 33–3 AHA/ACC 2017 Heart Failure Treatment Guidelines (adapted from Yancy et al., 2017). Colors indicate the guideline class of recommendation (green Ia— clinical efficacy established, yellow IIa—clinical efficacy likely). C/I, contraindication; CrCl, estimated creatinine clearance; CRT-D, cardiac resynchronization therapy device; GDMT, guideline-directed medical therapy; ICD, implantable cardioverter-defibrillator; LBBB, left bundle branch block; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSR, normal sinus rhythm. https://ebooksmedicine.net/  652 TABLE 33–1 LANDMARK STUDIES IN THE TREATMENT OF PATIENTS WITH CHRONIC HFrEF STUDY ACRONYM NO. OF BASELINE DRUGS EFFECT ON ALL-CAUSE MORTALITY AND/OR AUTHOR YEAR STUDY POPULATION PATIENTS (% of patients on each drug) (vs. placebo or another drug) Cohn et al. 1986 Men, impaired cardiac 642 CG, diuretics ISDN/hydralazine, –34% function and exercise Prazosin +/– capacity vs. placebo (absolute mortality 19%/year) CONSENSUS Trial 1987 Severe HF, NYHA 253 Diuretics 100%, Enalapril, –40% Study Group class IV spironolactone 52%, CG 93%, vs. placebo (absolute mortality 54%/year) vasodilators ~50%, BB 2% SOLVD Treatment 1991 NYHA II–III, 2569 Diuretics 86%, CG 67%, Enalapril, –16% vs. placebo (absolute EF 12b 1 × 12.5b 1 × 200 Yes succinateb Nebivolol Yes Yes 10 1 × 1.25 1 × 10 Yes a CYP2D6 indicates dependence on polymorphic cytochrome P450 metabolism; likely less relevant for nebivolol as first metabolite is active. b Clinical studies in heart failure have mainly used metoprolol succinate in a slow-release formulation (zero order of kinetics); metoprolol itself has a half-life of 3–5 h.  The major cardiovascular responses associated with use of β blockers Be careful with elderly patients, in whom improvement in prognosis 655 are the following: may be less relevant than prevention of serious side effects. Be careful with diabetics, who carry a higher risk of hyperkalemia. Heart rate lowering, a desirable effect that indicates proper dosing (no Do not combine with NSAIDs, which are contraindicated in heart fail- decrease indicates insufficient dosing). A reasonable target resting ure but are frequently prescribed for chronic degenerative diseases of heart rate is 60 to 70 beats/min. the musculoskeletal system. AV block (beware preexisting conduction disturbance; consider pace- Do not combine with other K+-sparing diuretics. maker implantation). Bronchoconstriction. Asthma is a contraindication for all β blocker Angiotensin Receptor and Neprilysin Inhibitors use; however, chronic obstructive lung disease is not, because the β2 An addition to standard combination therapy of heart failure is sacubitril/ receptor–dependent dynamic range is low in these patients, and stud- valsartan. It is made by co-crystallizing the well-known ARB valsartan ies have documented safety. Nonetheless, only β1-selective compounds with sacubitril, a prodrug that, after deesterization, inhibits neprilysin, should be used in patients with chronic obstructive pulmonary disease. a peptidase mediating the enzymatic degradation and inactivation of Peripheral vasoconstriction (cold extremities). Initial vasoconstriction natriuretic peptides (ANP, BNP, C-type natriuretic peptide [CNP]), turns into vasodilation under chronic therapy with β blockers. Cold bradykinin, and substance P. Thus, the drug combines inhibition of extremities are generally not a problem in patients with heart failure. the RAAS with activation of a beneficial axis of neurohumoral activa- Yet, patients with peripheral artery disease or symptoms of claudica- tion, the natriuretic peptides. Consequently, the ARNI is expected to tion or Raynaud disease should be carefully monitored and treated promote the beneficial effects of natriuresis, diuresis, and vasodilation with carvedilol if a β blocker is employed. of arterial and venous blood vessels and to inhibit thrombosis, fibrosis, cardiac myocyte hypertrophy, and renin release. Augmentation of ANP/ SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR Mineralocorticoid Receptor Antagonists BNP levels by inhibiting degradation is a better pharmacological prin- The third group of drugs with a documented life-prolonging effect in ciple than giving the agonist BNP (nesiritide; see under acute heart fail- patients with heart failure are MRAs. They should be given in low doses ure) directly because it enhances endogenous regulation of plasma and to all patients in stage C (NYHA class II–IV), that is, with symptomatic tissue levels. Sacubitril/valsartan causes smaller increases in bradykinin HFrEF, even though the combination of ACEIs/ARBs and MRA is for- and substance P than omapatrilat, an earlier drug combining a neprilysin mally contraindicated due to the risk of hyperkalemia. The safety of a inhibitor and an ACEI (which itself and additionally inhibits degradation low-dose MRA (25 mg vs. the standard 100 mg of spironolactone) was of these peptides). This difference may explain why sacubitril/valsartan demonstrated in a large, randomized trial in a patient cohort with severe is not associated with an increased rate of angioedema, the adverse effect heart failure (NYHA III–IV), with the MRA added to ACEIs, diuretics, that stopped the development of omapatrilat. A large head-to-head com- and digoxin (Pitt, 2004). Later studies with eplerenone in less-severe heart parison study in patients with stable heart failure showed superiority of failure essentially confirmed the efficacy of this class of drugs. sacubitril/valsartan over enalapril (McMurray et al., 2014). It is currently Mechanism of Action. The MRAs act as antagonists of nuclear recep- recommended as a replacement for an ACEI or ARB in all patients with tors of aldosterone (see Figure 29–6). They are K+-sparing diuretics (see NYHA class II–III (U.S.; Yancy et al., 2017) or, in the ESC guidelines, discussion that follows) but gained more importance in the treatment of for all patients still symptomatic under triple therapy including MRA heart failure for their additional efficacy in suppressing the consequences (Ponikowski et al., 2016). of neurohumoral activation. Aldosterone, as the second major actor of the RAAS, promotes Na+ and fluid retention, loss of K+ and Mg2+, sym- Treatment Principle II: Preload Reduction pathetic activation, parasympathetic inhibition, myocardial and vascu- Fluid overload with increased filling pressures (increased preload) and lar fibrosis, baroreceptor dysfunction, and vascular damage, all adverse dilation of the ventricles in heart failure is the consequence of decreased effects in the setting of heart failure. Aldosterone plasma levels decrease kidney perfusion and activation of the RAAS. Normally, increased under therapy with ACEIs or ARBs, but quickly increase again, a phe- preload and stretch of the myofilaments increase contractile force in nomenon called aldosterone escape. It is likely explained by incomplete an autoregulatory manner, the positive force-length relationship or blockade of the RAAS (e.g., AngI can be converted to AngII by chymase, Frank-Starling mechanism. However, the failing heart in congestion in addition to ACE; see Chapter 30) and by the fact that aldosterone operates at the flat portion of this relationship (Figure 33–4) and cannot secretion is regulated not only by AngII but also by plasma concentra- generate sufficient force with increasing preload, leading to edema in the tions of Na+ and K+. MRAs inhibit all the effects of aldosterone, of which lungs and the periphery. reduction in fibrosis may be of particular importance. Diuretics increase Na+ and water excretion by inhibiting transport- ers in the kidney and thereby improve symptoms of congestive heart Clinical Use; Adverse Responses. Currently, two steroidal MRAs are failure (CHF) by moving patients to lower cardiac filling pressures available, spironolactone and eplerenone. Spironolactone is a nonspecific along the same ventricular function curve. Diuretics are an inte- steroid hormone receptor antagonist with similar affinity for progester- gral part of the combination therapy of symptomatic forms of heart one and androgen receptors; it causes gynecomastia (painful breast swell- failure. Prognostic efficacy of diuretics in heart failure will remain ing, 10% of patients) in men and dysmenorrhea in women. Eplerenone is an academic question, simply because randomization for a trial of selective for the mineralocorticoid receptor and therefore does not cause diuretics would be ethically impermissible. Diuretics should not be gynecomastia. A nonsteroidal MRA (finerenone) received FDA approval given to patients without congestion because they activate the RAAS in 2021. It has a higher selectivity for mineralocorticoid over other steroid and may accelerate a vicious downward spiral. On the other hand, in receptors and may cause relatively less hyperkalemia. severe heart failure, diuretic resistance may occur for various reasons The most important ADR of MRAs is hyperkalemia. Under the and cause clinical deterioration (Table 33–4). well-controlled conditions of clinical trials, serious hyperkalemia (>5.5 mmol/L) occurred in 12% in the eplerenone group versus 7% in Loop Diuretics the placebo group (Zannad et al., 2011). Rates of hyperkalemia may be Loop diuretics (furosemide, torsemide, bumetanide; Table 33–5) inhibit the higher in clinical practice when risk conditions, comedication, and dose Na+-K+-2Cl symporter in the ascending limb of the loop of Henle, where restrictions are not well controlled (Juurlink et al., 2004). Guidelines for up to 15% of the primary filtrate (~150 L/d) is reabsorbed, explaining the use of MRAs in patients with heart failure are as follows: their strong diuretic action. The increase in Na+ and fluid delivery to dis- tal nephron segments has two consequences: Administer no more than 50 mg/d. Do not use if the GFR is less than 30 mL/min (creatinine ~2 mg/dL It is sensed in the macula densa and normally activates tubuloglomer- or higher). ular feedback to decrease GFR. This autoregulation explains the quick https://ebooksmedicine.net/  656 Congestive retention normally requires dosing twice a day or more. Bumetanide Normal symptoms reaches maximal plasma concentrations in 0.5 to 2 h and has a t1/2 of 1 to 1.5 h. Torsemide has a slower onset of action (maximal effect 1–2 h after ingestion) and a plasma t1/2 of 3 to 4 h. Kidney failure does not critically I+V affect the elimination of bumetanide or torsemide. Ethacrynic acid, in con- Stroke volume trast to other loop diuretics, thiazides, and thiazide-like diuretics, is not I a sulfonamide and is generally reserved for patients with sulfa allergy. It I+V+D V acts like furosemide and causes ototoxicity at high doses. Thiazide Diuretics Thiazide diuretics (hydrochlorothiazide, chlorthalidone; Table 33–5) have D Low- a limited role in heart failure for their low maximal diuretic effect and output loss of efficacy at a GFR below 30 mL/min. Thiazide-like diuretics such symptoms as metolazone and xipamide (not available in the U.S.) retain their diuretic effect at low GFR and are therefore somewhat positioned in between Ventricular filling pressure loop diuretics and classical thiazides. Combination therapy of thiazides with loop diuretics is often effective in those refractory to loop diuretics Figure 33–4 Hemodynamic responses to pharmacologic interventions in heart alone (“sequential tubulus blockade”), as refractoriness is often caused by failure. The relationships between diastolic filling pressure (preload) and upregulation of the Na+-Cl cotransporter in the distal convoluted tubule, stroke volume (ventricular performance) are illustrated for a normal heart the main target of thiazide diuretics (see Chapter 29). Thiazides are asso- CHAPTER 33 THERAPY OF HEART FAILURE (green line; the Frank-Starling relationship) and for a patient with heart fail- ciated with a greater degree of K+ wasting per fluid volume reduction ure with systolic dysfunction (red line). Note that positive inotropic agents (I), than loop diuretics, and combination therapy requires particularly care- such as CGs or dobutamine, move patients to a higher ventricular function ful monitoring of K+ loss. curve (lower dashed line), resulting in greater cardiac work for a given level of ventricular filling pressure. Vasodilators (V), such as ACEIs or nitroprusside, K+-Sparing Diuretics also move patients to improved ventricular function curves while reducing K+-Sparing diuretics (see Chapter 29) inhibit apical Na+ channels in dis- cardiac filling pressures. Diuretics (D) improve symptoms of CHF by moving tal segments of the tubulus directly (ENaC; e.g., amiloride, triamterene) patients to lower cardiac filling pressures along the same ventricular function or reduce its gene expression (MRAs spironolactone and eplerenone). curve. These agents are weak diuretics, but they are often used in the treat- ment of hypertension in combination with thiazides or loop diuretics to loss of efficacy of older diuretics of the carbonic anhydrase inhibitor reduce K+ and Mg2+ wasting. The prognostic efficacy of MRAs, which is class (e.g., acetazolamide), acting in the proximal tubule. Thiazides at least partially independent of its K+-sparing activity, makes amiloride (see discussion that follows) are derived from this class and cause a and triamterene largely dispensable in the therapy of heart failure. They small decrease in the GFR. Loop diuretics inhibit the feedback mecha- should not be combined with ACEIs and MRAs. nism because it is mediated by the Na+-K+-2Cl symporter; they exhibit stable action and do not affect the GFR. Treatment Principle III: Afterload Reduction It leads to increased ENaC-mediated reabsorption of Na+ and, in The failing heart is exquisitely sensitive to increased arterial resistance exchange, to more K+ excretion in the distal tubule, explaining the (i.e., afterload; Figure 33–5). Vasodilators, therefore, should have ben- main side effect, hypokalemia. eficial effects on patients with heart failure by reducing afterload and The bioavailability of orally administered furosemide ranges from allowing the heart to expel blood against lower resistance. However, 40% to 70%. High drug doses are often required to initiate diuresis in clinical trials with pure vasodilators were mainly disappointing, whereas patients with worsening symptoms or in those with impaired gastroin- inhibitors of the RAAS, vasodilators with a broader mode of action, were testinal (GI) absorption, as may occur in severely hypervolemic patients successful. Likely reasons include reflex tachycardia and tachyphylaxis with CHF-induced GI edema. Oral bioavailabilities of bumetanide and (prazosin, ISDN) and negative inotropic effects (dihydropyridine calcium torsemide are greater than 80%, and as a result, these agents are more channel antagonists). consistently absorbed than furosemide. Furosemide and bumetanide are Hydralazine–Isosorbide Dinitrate short-acting drugs. The t1/2 of furosemide in normal kidney function is A remarkable exception is the therapeutic effect of a fixed combination about 1 h (increases in terminal kidney failure to >24 h). Rebound Na+ of hydralazine and ISDN. In a pioneering trial, Cohn and colleagues showed moderate efficacy of this combination in patients with heart fail- ure (Cohn et al., 1986). The benefit was restricted to improvement in the TABLE 33–4 CAUSES OF DIURETIC RESISTANCE IN HF cohort of African Americans. In a second trial in African Americans only, Noncompliance with medical regimen; excess dietary Na+ intake the combination conferred a 43% survival benefit (Taylor et al., 2004). It was FDA approved in 2006, the first ethnically restricted approval. Decreased renal perfusion and glomerular filtration rate due to: As an orally available organic nitrate, ISDN, like nitroglycerine and Excessive vascular volume depletion and hypotension due to   isosorbide 5′-mononitrate (ISMN), preferentially dilates large blood ves- aggressive diuretic or vasodilator therapy sels, for instance, venous capacitance and arterial conductance vessels Decline in cardiac output due to worsening heart failure,   (see Chapter 31). The main effect is “venous pooling” and reduction of arrhythmias, or other primary cardiac causes diastolic filling pressure (preload) with little effect on systemic vascular resistance (which is regulated by small-to-medium arterioles). Sustained Selective reduction in glomerular perfusion pressure following   monotherapy is compromised by nitrate tolerance (i.e., loss of effect and initiation (or dose increase) of ACEI therapy induction of a pro-constrictory state with high levels of ROS). Hydral- Nonsteroidal anti-inflammatory drugs azine is a direct vasodilator whose mechanism of action remains unre- Primary renal pathology (e.g., cholesterol emboli, renal artery solved (see Chapter 32). It was suggested that hydralazine prevents nitrate stenosis, drug-induced interstitial nephritis, obstructive uropathy) tolerance by reducing ROS-mediated inactivation of NO (Munzel et al., 2005), an action that could explain the efficacy of this drug combina- Reduced or impaired diuretic absorption due to gut wall edema and tion in heart failure among African Americans. A test of this hypothesis reduced splanchnic blood flow in patients with NYHA class II–III heart failure (Chirkov et al., 2010)  657 TABLE 33–5 PROPERTIES AND THERAPEUTIC DOSES OF DIURETICS FOR THE THERAPY OF HFrEFa TIME TO COMMON DAILY START OF HALF- DIURETIC START DOSE (mg) DOSE (mg) EFFECT (h) LIFE (h) ADVERSE EFFECTS AND INTERACTIONS Loop diuretics Bumetanide 0.5–1 1–5 0.5 1–1.5 Adverse effects: Hypokalemia, hyponatremia, Furosemide 20–40 40–240 0.5 1 hypomagnesemia, hyperuricemia, hypocalcemia, nephrotoxicity, ototoxicity (loop diuretics), Torsemide 5–10 10–20 1 3–4 hypercalcemia (thiazides), glucose intolerance, sulfonamide hypersensitivity Interactions: Can increase lithium levels (PK) and cardiac glycoside toxicity (PD, hypokalemia), anion exchanger resins (PK), NSAIDs and glucocorticoids (PD) can decrease effect of diuretics Thiazides Chlorthalidone 50 50–100 2 50 SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR Hydrochlorothiazide 25 12.5–100 1–2 6–8 Potassium-sparing diuretics +RAS –RAS +RAS –RAS Adverse effects: Hyperkalemia (all), blocker blocker blocker blocker gynecomastia, erectile dysfunction, and Eplerenone, 12.5–25 50 50 100–200 2–6 24–36 menstrual bleeding disorders (spironolactone) spironolactone Interactions: Increased risk of hyperkalemia when given with ACE or ARB (note different Amiloride 2.5 5 5–10 10–20 2 10–24 dosing!), but also cyclosporine, NSAIDs Triamterene 25 50 100 200 2 8–16 Contraindication: Renal insufficiency with creatinine clearance