Heart Failure Pathophysiology & Diagnosis PDF

University of the Philippines ­ Manila Access Provided by: Harrison...

University of the Philippines ­ Manila Access Provided by: Harrison's Principles of Internal Medicine, 21e Chapter 257: Heart Failure: Pathophysiology and Diagnosis Michael M. Givertz; Mandeep R. Mehra CLINICAL DEFINITIONS, EPIDEMIOLOGY, AND PHENOTYPES DEFINITIONS Heart failure (HF) is a common final pathway for most chronic cardiovascular diseases including hypertension, coronary artery disease, and valvular heart disease. The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) and Heart Failure Society of America (HFSA) guidelines define HF as a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood leading to cardinal manifestations of dyspnea, fatigue, and fluid retention. The European Society of Cardiology’s (ESC) definition emphasizes typical symptoms (e.g., breathlessness, ankle swelling, and fatigue) and signs (e.g., elevated jugular venous pressure, pulmonary crackles, and peripheral edema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. Because some patients present without signs or symptoms of volume overload, the term heart failure is preferred over the older term congestive heart failure. Cardiomyopathy and left ventricular dysfunction are more general terms that describe disorders of myocardial structure and/or function, which may lead to HF. In pathophysiologic terms, HF has been defined as a syndrome characterized by elevated cardiac filling pressure and/or inadequate peripheral oxygen delivery, at rest or during stress, caused by cardiac dysfunction. Chronic heart failure describes patients with longstanding (e.g., months to years) symptoms and/or signs of HF typically treated with medical and device therapy as described in Chap. 258. Acute heart failure, previously termed acute decompensated HF, refers to the rapid onset or worsening of symptoms of HF. Most episodes of acute HF result from worsening of chronic HF, but ~20% are due to new­onset HF that can occur in the setting of acute coronary syndrome, acute valvular dysfunction, hypertensive urgency, or postcardiotomy syndrome. Similarly, acute pulmonary edema in HF describes a clinical scenario in which a patient presents with rapidly worsening signs and symptoms of pulmonary congestion, typically due to severe elevation of left heart filling pressure. EPIDEMIOLOGY Global Incidence and Prevalence HF is a major cause of morbidity and mortality worldwide. An estimated 6.2 million American adults are being treated for HF, with >600,000 new cases diagnosed each year. Globally, >26 million people are affected by HF. The prevalence of HF increases significantly with age, occurring in 1–2% of the population aged 40–59 years and up to 12% of adults >80 years old (Fig. 257­1). The lifetime risk of HF at age 55 years is 33% for men and 28% for women. Projections show that the prevalence of HF in the United States will increase by 46% from 2012 to 2030. Between 1980 and 2000, the number of HF hospitalizations rose steadily in both men and women to ~1 million per year. However, according to the most recent AHA statistics, hospitalizations decreased from 1,020,000 in 2006 to 809,000 in 2016. While prevalence of HF continues to rise, incidence may be decreasing due to improved recognition and treatment of cardiovascular disease and its comorbidities as well as disease prevention. However, as rates of obesity rise globally, these favorable trends in HF incidence may reverse. FIGURE 257­1 Prevalence of heart failure. Prevalence of heart failure among U.S. adults ≥20 years of age by sex and age, from the National Health and Nutrition Examination Survey (NHANES), 2013–2016. (Source: SS Virani et al: Circulation 141:e139, 2020.) Downloaded 2024­6­29 7:14 P Your IP is 175.176.67.95 Chapter 257: Heart Failure: Pathophysiology and Diagnosis, Michael M. Givertz; Mandeep R. Mehra Page 1 / 24 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility FIGURE 257­1 University of the Philippines ­ Manila Access Provided by: Prevalence of heart failure. Prevalence of heart failure among U.S. adults ≥20 years of age by sex and age, from the National Health and Nutrition Examination Survey (NHANES), 2013–2016. (Source: SS Virani et al: Circulation 141:e139, 2020.) There are distinct racial and ethnic differences in HF epidemiology (Fig. 257­2). In community­based studies, blacks have the highest risk of developing HF, followed by Hispanic, white, and Chinese Americans. These differences are attributed to disparities in risk factors (e.g., obesity, hypertension, diabetes), socioeconomic status, and access to health care. Similarly, studies have shown that age­adjusted rates of HF hospitalization are highest for black men, followed by black women, white men, and white women. Accurate data on HF prevalence from emerging nations are lacking. As developing nations undergo socioeconomic development, the epidemiology of HF is becoming similar to that of Western Europe and North America, with coronary artery disease emerging as the most common cause of HF. FIGURE 257­2 Incidence of heart failure. First acute heart failure annual event rates per 1000 from Atherosclerosis Risk in Communities (ARIC) Community Surveillance by sex and race in the United States from 2005 to 2014. (Source: SS Virani et al: Circulation 141:e139, 2020.) Morbidity and Mortality In primary care, the overall 5­year survival following the diagnosis of HF is ~50%. For patients with severe HF, the 1­year mortality may be as high as 40%. In the United States, 1 in 8 deaths list HF on the death certificate. The majority of these patients die of cardiovascular causes, most commonly progressive HF or sudden cardiac death. A number of clinical and laboratory parameters are independent predictors of mortality (Table 257­1). In a population­based study, hospitalizations were common after an HF diagnosis, with 83% hospitalized at least once, and 67%, 54%, and 43% hospitalized at least two, three, and four times, respectively. Following an HF admission, mortality rates range from 8–14% at 30 days to 26–37% at 1 year to up to 75% at 5 years. Readmission with HF is also common, ranging from 20–25% at 60 days to nearly 50% at 6 months. With each subsequent admission, the risk of death rises. There are racial disparities in outcomes with blacks having higher case–fatality rates compared to whites. Despite Downloaded 2024­6­29 7:14 P Your IP is 175.176.67.95 these statistics, Chapter the overall 257: Heart Failure:prognosis for patients Pathophysiology andwith HF is improving Diagnosis, Michael due to treatment M. Givertz; of riskR.factors Mandeep Mehraand increased use of guideline­directed Page 2 / 24 therapies. ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility TABLE 257­1 40%. In the United States, 1 in 8 deaths list HF on the death certificate. The majority of these patients die of cardiovascular causes, most commonly progressive HF or sudden cardiac death. A number of clinical and laboratory parameters are independent predictors University of the(Table of mortality Philippines ­ Manila 257­1). In a population­based study, hospitalizations were common after an HF diagnosis, with 83% hospitalized at least once,Access and Provided 67%, 54%, by: and 43% hospitalized at least two, three, and four times, respectively. Following an HF admission, mortality rates range from 8–14% at 30 days to 26–37% at 1 year to up to 75% at 5 years. Readmission with HF is also common, ranging from 20–25% at 60 days to nearly 50% at 6 months. With each subsequent admission, the risk of death rises. There are racial disparities in outcomes with blacks having higher case–fatality rates compared to whites. Despite these statistics, the overall prognosis for patients with HF is improving due to treatment of risk factors and increased use of guideline­directed therapies. TABLE 257­1 Independent Predictors of Adverse Outcomes in Heart Failure Clinical Male sex Increasing age Diabetes mellitus Chronic kidney disease Coronary artery disease Advanced NYHA classa Presence of third heart sound or elevated JVP Decreased exercise capacity Cardiac cachexia Depression Structural Reduced left ventricular ejection fraction Reduced right ventricular ejection fraction Increased ventricular volumes and mass Secondary mitral or tricuspid regurgitation Hemodynamic Elevated pulmonary capillary wedge pressure Reduced cardiac index Reduced peak oxygen consumption Pulmonary hypertension Diastolic dysfunction Biochemical Worsening renal function Hyponatremia Hyperuricemia Elevated cardiac biomarkers (troponin and natriuretic peptides) Elevated plasma neurohormones (norepinephrine, renin, aldosterone, and endothelin­1) Electrophysiologic Tachycardia Widened QRS interval or LBBB Atrial fibrillation Ventricular ectopic activity Ventricular tachycardia and sudden death aSee Table 257­4. Abbreviations: JVP, jugular venous pressure; LBBB, left bundle branch block; NYHA, New York Heart Association. Costs The overall cost of HF care is high (estimated $30.7 billion in the United States in 2012) and rising. Projections for 2030 are that hospitalization costs for HF in the United States will increase to $70 billion. Indirect costs due to lost work and productivity may equal or exceed this amount. The global Downloaded 2024­6­29 economic burden of HF in7:14 2012Pwas Your IP is 175.176.67.95 estimated at $108 billion, with direct costs accounting for 60%. For pediatric patients with acute HF, inpatient costs Chapter are estimated at nearly $1 billion annually and and 257: Heart Failure: Pathophysiology Diagnosis, Michael M. Givertz; Mandeep R. Mehra rising. Page 3 / 24 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility PHENOTYPES AND CAUSES  Abbreviations: JVP, jugular venous pressure; LBBB, left bundle branch block; NYHA, New York Heart Association. University of the Philippines ­ Manila Access Provided by: Costs The overall cost of HF care is high (estimated $30.7 billion in the United States in 2012) and rising. Projections for 2030 are that hospitalization costs for HF in the United States will increase to $70 billion. Indirect costs due to lost work and productivity may equal or exceed this amount. The global economic burden of HF in 2012 was estimated at $108 billion, with direct costs accounting for 60%. For pediatric patients with acute HF, inpatient costs are estimated at nearly $1 billion annually and rising. PHENOTYPES AND CAUSES HF with Reduced Versus Preserved Ejection Fraction Epidemiologic studies have shown that approximately one­half of patients who develop HF have reduced left ventricular ejection fraction (EF; ≤40%) while the other half have near­normal or preserved EF (≥50%). Because most patients with HF (regardless of EF) have abnormalities in both systolic and diastolic function, the older terms of systolic heart failure and diastolic heart failure have fallen out of favor. Classifying patients based on their EF (HF with reduced EF [HFrEF] vs HF with preserved EF [HFpEF]) is important due to differences in demographics, comorbidities, and response to therapies (Chap. 258). Underlying causes of HF may be associated with reduced or preserved EF and include disorders of the coronary arteries, myocardium, pericardium, heart valves and great vessels (Table 257­2). The diagnosis of HFpEF is often more challenging due to the need to rule out noncardiac causes of shortness of breath and/or fluid retention. TABLE 257­2 Selected Causes of Heart Failure Heart Failure with Reduced Ejection Fraction Coronary artery disease Nonischemic cardiomyopathy Myocardial infarction Infiltrative disorders Myocardial ischemia Familial disorders Tachycardia induced Valvular heart disease Toxic cardiomyopathy Aortic stenosis or regurgitation Chemotherapy, immunotherapy Mitral or tricuspid regurgitation Drugs such as hydroxychloroquine Alcohol, cocaine Congenital heart disease Chronic lung/pulmonary vascular disease Intracardiac shunts Cor pulmonale Repaired defects Pulmonary arterial hypertension Systemic right ventricular failure Infectious Autoimmune disease Chagas Giant cell myocarditis HIV Lupus myocarditis Heart Failure with Preserved Ejection Fraction Hypertension Coronary artery disease Valvular heart disease Restrictive cardiomyopathy Aortic stenosis Amyloidosis Mitral stenosis Sarcoidosis Hemochromatosis Glycogen storage disease Hypertrophic cardiomyopathy Radiation therapy Downloaded 2024­6­29 7:14 P Your IP is 175.176.67.95 Chapter 257: Heart Constrictive Failure: Pathophysiology and Diagnosis, Michael Aging pericarditis M. Givertz; Mandeep R. Mehra Page 4 / 24 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Myocarditis Endomyocardial fibroelastosis pericardium, heart valves and great vessels (Table 257­2). The diagnosis of HFpEF is often more challenging due to the need to rule out noncardiac causes of shortness of breath and/or fluid retention. University of the Philippines ­ Manila Access Provided by: TABLE 257­2 Selected Causes of Heart Failure Heart Failure with Reduced Ejection Fraction Coronary artery disease Nonischemic cardiomyopathy Myocardial infarction Infiltrative disorders Myocardial ischemia Familial disorders Tachycardia induced Valvular heart disease Toxic cardiomyopathy Aortic stenosis or regurgitation Chemotherapy, immunotherapy Mitral or tricuspid regurgitation Drugs such as hydroxychloroquine Alcohol, cocaine Congenital heart disease Chronic lung/pulmonary vascular disease Intracardiac shunts Cor pulmonale Repaired defects Pulmonary arterial hypertension Systemic right ventricular failure Infectious Autoimmune disease Chagas Giant cell myocarditis HIV Lupus myocarditis Heart Failure with Preserved Ejection Fraction Hypertension Coronary artery disease Valvular heart disease Restrictive cardiomyopathy Aortic stenosis Amyloidosis Mitral stenosis Sarcoidosis Hemochromatosis Glycogen storage disease Hypertrophic cardiomyopathy Radiation therapy Constrictive pericarditis Aging Myocarditis Endomyocardial fibroelastosis Obesity High­Output Heart Failure Thyrotoxicosis Arteriovenous shunt Obesity Cirrhosis Anemia Vitamin B deficiency (beriberi) Chronic lung disease Myeloproliferative disorder Abbreviation: HIV, human immunodeficiency virus. Downloaded 2024­6­29 7:14 P Your IP is 175.176.67.95 Chapter 257: Heart Failure: Pathophysiology and Diagnosis, Michael M. Givertz; Mandeep R. Mehra Page 5 / 24 ©2024 HF withMcGraw Hill. All Recovered EFRights Reserved. Terms of Use Privacy Policy Notice Accessibility A subgroup of patients who are diagnosed with HFrEF and treated with guideline­directed therapy have rapid or gradual improvement in EF to the  Anemia Vitamin B deficiency (beriberi) University of the Philippines ­ Manila Access Provided by: Chronic lung disease Myeloproliferative disorder Abbreviation: HIV, human immunodeficiency virus. HF with Recovered EF A subgroup of patients who are diagnosed with HFrEF and treated with guideline­directed therapy have rapid or gradual improvement in EF to the normal range and are referred to as having HF with recovered EF (HFrecEF). Predictors of HFrecEF include younger age, shorter duration of HF, nonischemic etiology, smaller ventricular volumes, and absence of myocardial fibrosis. Specific clinical examples include fulminant myocarditis, stress cardiomyopathy, peripartum cardiomyopathy, and tachycardia­induced cardiomyopathy, as well as reversible toxin exposures such as chemotherapy, immunotherapy, or alcohol. Despite recovery of EF, patients may remain symptomatic due to persistent abnormalities in diastolic function or exercise­ induced pulmonary hypertension. For patients who become asymptomatic, withdrawal of therapy can lead to recurrence of HF symptoms and decrease in EF. In general, prognosis of patients with HFrecEF is superior to that of patients with either HFrEF or HFpEF. Heart Failure with Mildly Reduced EF (HFmrEF) Patients with HF and an EF between 40 and 50% represent an intermediate group that are often treated for risk factors and comorbidities and with guideline­directed medical therapy similar to patients with HFrEF. They are felt to have primarily mild systolic dysfunction, but with features of diastolic dysfunction. They may also include either patients with reduced EF who experience improvement in their EF or those with initially preserved EF who suffer a mild decline in their systolic performance. Unlike the ACCF/AHA and HFSA guidelines, the ESC guideline has identified HFmrEF as a separate group in order to stimulate research into underlying characteristics, pathophysiology, and treatment. Acquired Versus Familial, Congenital, and Other Disorders In developed countries, coronary artery disease is responsible for approximately two­thirds of the cases of HF, with hypertension as a principal contributor in up to 75% and diabetes mellitus in 10–40% (Fig. 257­3). While most cardiovascular disease underlying HF is acquired in mid and later life (Chaps. 261, 273, and 277), a wide range of congenital and inherited disorders leading to HF may be diagnosed in children and younger adults. It is currently estimated that >1.4 million U.S. adults are living with congenital heart disease (CHD), which surpasses the number of children with CHD. In general, adults with CHD who develop HF can be divided into one of three pathophysiologic groups: uncorrected defects with late presentation due to missed diagnosis, nonintervention, or lack of access to care; repaired or palliated defects with late valvular and/or ventricular failure; or failing single­ ventricle physiology. In addition, each adult with CHD often presents with unique anatomic and physiologic challenges that affect HF and its treatment. FIGURE 257­3 Population attributable risk of heart failure (HF) incidence. Based on longitudinal data from the Framingham Heart Study, the risk factors contributing most significantly to the population attributable risk (PAR) of HF in men were previous myocardial infarction and hypertension (in men, both represented equal contributions to HF PAR). In contrast, hypertension was the risk factor accounting for the majority of total PAR in women. In women, previous myocardial infarction accounted for only 13% of the PAR of HF compared with 34% in men. PAR values are developed based on individual calculations for each variable using hazard ratio and prevalence statistics. Thus, they may not, in aggregate equal 100%. LVH, left ventricular hypertrophy. (From MM Givertz, WS Colucci: Heart failure. In Peter Libby, Essential Atlas of Cardiovascular Disease, 2009, Current Medicine Group. Reproduced with permission of SNCSC.) Inherited cardiomyopathies are also increasingly recognized in adults presenting with HF. These include more common disorders, such as Downloaded 2024­6­29 hypertrophic and 7:14 P Your arrhythmogenic IP is 175.176.67.95 cardiomyopathies, and lesser known heart muscle disease related to pathogenic variants in genes encoding lamin Chapter 257: Heart Failure: Pathophysiology and Diagnosis, and titin, muscular dystrophies, and mitochondrial Michael disease. Most formsM. of Givertz; Mandeep R. Mehra familial cardiomyopathy are inherited in an autosomal dominantPage 6 / 24 fashion. ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Society guidelines have been published documenting the importance of taking a detailed family history and indications for (and limitations of) clinical genetic testing.  University of the Philippines ­ Manila Access Provided by: Inherited cardiomyopathies are also increasingly recognized in adults presenting with HF. These include more common disorders, such as hypertrophic and arrhythmogenic cardiomyopathies, and lesser known heart muscle disease related to pathogenic variants in genes encoding lamin and titin, muscular dystrophies, and mitochondrial disease. Most forms of familial cardiomyopathy are inherited in an autosomal dominant fashion. Society guidelines have been published documenting the importance of taking a detailed family history and indications for (and limitations of) clinical genetic testing. A myriad of systemic diseases with cardiac and extracardiac manifestations (e.g., amyloidosis, sarcoidosis), autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis), infectious diseases (e.g., Chagas, HIV), and drug toxicities (chemotherapy, other prescribed or illicit agents) can result in HF with either reduced or preserved EF. In Africa and Asia, rheumatic heart disease remains a major cause of HF, especially in the young. Finally, disorders associated with a high cardiac output state (e.g., anemia, thyrotoxicosis) are seldom associated with HF in the absence of underling structural heart disease. However, diagnosis and treatment of high­output HF will be missed if not considered in the differential diagnosis of patients with predisposing conditions (e.g., cirrhosis, end­stage renal disease with arteriovenous fistula, Paget’s disease, or nutritional deficiency such as beriberi). PATHOPHYSIOLOGY PROGRESSIVE DISEASE HFrEF is a progressive disease that typically involves an index event followed by months to years of structural and functional cardiovascular remodeling (Fig. 257­4). The primary event may be sudden in onset, such as an acute myocardial infarction; more gradual, as occurs in the setting of chronic pressure or volume overload; inherited, as seen with genetic cardiomyopathies; or congenital disease. Despite an initial reduction in cardiac performance, patients may be asymptomatic or mildly symptomatic for prolonged periods due to the activation of compensatory mechanisms (described below) that ultimately contribute to disease progression. FIGURE 257­4 Remodeling stimuli in heart failure. Chronic hemodynamic stimuli such as pressure and volume overload lead to ventricular remodeling through increases in myocardial wall stress, inflammatory cytokines, signaling peptides, neuroendocrine signals, and oxidative stress. The myocardium responds with adaptive as well as maladaptive changes. Reexpression of fetal contractile proteins and calcium handling proteins may contribute to impaired contraction and relaxation. Myocytes unable to adapt might be triggered to undergo programmed cell death (apoptosis). The net result of these changes is further impairment in pump function and increased wall stress, thus completing a vicious cycle that leads to further progression of myocardial dysfunction. (From MM Givertz, WS Colucci: Heart failure. In Peter Libby, Essential Atlas of Cardiovascular Disease, 2009, Current Medicine Group. Reproduced with permission of SNCSC.) Downloaded 2024­6­29 7:14 P Your IP is 175.176.67.95 Chapter 257: Heart Failure: Pathophysiology and Diagnosis, Michael M. Givertz; Mandeep R. Mehra Page 7 / 24 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Ventricular Remodeling impaired contraction and relaxation. Myocytes unable to adapt might be triggered to undergo programmed cell death (apoptosis). The net result of University of the Philippines ­ Manila these changes is further impairment in pump function and increased wall stress, thus completing a vicious cycle that leads to further progression of Access Provided by: myocardial dysfunction. (From MM Givertz, WS Colucci: Heart failure. In Peter Libby, Essential Atlas of Cardiovascular Disease, 2009, Current Medicine Group. Reproduced with permission of SNCSC.) Ventricular Remodeling As demonstrated in both animal and human studies, different patterns of ventricular remodeling occur in response to excess cardiac workload. Concentric hypertrophy, in which increased mass is out of proportion to chamber volume, effectively reduces wall stress under conditions of pressure overload (e.g., hypertension, aortic stenosis). By contrast, an increase in cavity size or volume (eccentric hypertrophy) occurs in volume overload conditions (e.g., aortic regurgitation, mitral regurgitation). In both forms of remodeling, an increase in ventricular mass is accompanied at the cellular level by myocyte hypertrophy and interstitial fibrosis, at the protein level by alteration in calcium­handling and cytoskeletal function, and at the molecular level by re­expression of fetal genes (Table 257­3). In addition to cell loss from necrosis, myocytes that are unable to adapt to remodeling stimuli may be triggered to undergo apoptosis or programmed cell death. Further impairment in pump function and increased wall stress in the face of systemic vasoconstriction and loss of neurohormonal adaptation (discussed below) can lead to afterload mismatch. These events feed back on remodeling stimuli, setting up a cycle of deleterious processes resulting in clinical HF. TABLE 257­3 Mechanisms of Ventricular Remodeling Changes in Myocyte Biology Abnormal excitation­contraction coupling and crossbridge interaction Fetal gene expression (e.g., β­myosin heavy chain) β­Adrenergic receptor desensitization Myocyte hypertrophy Impaired cytoskeletal proteins Changes in Myocardial Makeup Myocyte necrosis, apoptosis, and autophagy Downloaded 2024­6­29 7:14 P Your IP is 175.176.67.95 Chapter Interstitial 257: Heart and perivascular Failure: fibrosis Pathophysiology and Diagnosis, Michael M. Givertz; Mandeep R. Mehra Page 8 / 24 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Matrix degradation molecular level by re­expression of fetal genes (Table 257­3). In addition to cell loss from necrosis, myocytes that are unable to adapt to remodeling University of the Philippines ­ Manila stimuli may be triggered to undergo apoptosis or programmed cell death. Further impairment in pump function and increased wall stress in the face of Access Provided by: systemic vasoconstriction and loss of neurohormonal adaptation (discussed below) can lead to afterload mismatch. These events feed back on remodeling stimuli, setting up a cycle of deleterious processes resulting in clinical HF. TABLE 257­3 Mechanisms of Ventricular Remodeling Changes in Myocyte Biology Abnormal excitation­contraction coupling and crossbridge interaction Fetal gene expression (e.g., β­myosin heavy chain) β­Adrenergic receptor desensitization Myocyte hypertrophy Impaired cytoskeletal proteins Changes in Myocardial Makeup Myocyte necrosis, apoptosis, and autophagy Interstitial and perivascular fibrosis Matrix degradation Changes in Ventricular Geometry Ventricular dilation and wall thinning Increased sphericity and displacement of papillary muscles Atrioventricular valve regurgitation While our understanding of ventricular remodeling in HFrEF is well supported by animal and human studies, the mechanisms underlying HFpEF are less clear. The original descriptions of HFpEF focused on diastolic dysfunction as the primary mediator of HF signs and symptoms as exemplified in older women with hypertension. At the myocyte level, impaired uptake of cytosolic calcium into the sarcoplasmic reticulum by reductions in adenosine triphosphate explained abnormalities in myocardial relaxation. As different phenotypes of HFpEF have emerged, many pathophysiologic processes other than diastolic dysfunction have been implicated in disease progression, including vascular stiffness, renal dysfunction, sodium avidity, and metabolic inflammation related to regional adiposity. Furthermore, biologic alterations including oxidative stress and impaired nitric oxide signaling leading to nitrosative stress may play a role in disease activity and inform future therapies. MECHANISMS OF DISEASE PROGRESSION A number of compensatory mechanisms become activated during the development of HF and contribute to disease progression. Our understanding of these mechanisms derives from preclinical studies, in vivo human studies, and randomized clinical trials demonstrating benefit of therapies targeted to attenuating or reversing these biologic processes. Neurohormonal Activation Activation of the sympathetic nervous system (SNS) and renin­angiotensin­aldosterone system (RAAS) plays a critical role in the development and progression of HF. Initially, neurohormonal activation leads to increases in heart rate, blood pressure, and cardiac contractility and retention of sodium and water to augment preload and maintain cardiac output at rest and during exercise. Over time, these unchecked compensatory responses lead to excessive vasoconstriction and volume retention, electrolyte and renal abnormalities, baroreceptor dysfunction, direct myocardial toxicity, and Downloaded 2024­6­29 7:14 P Your IP is 175.176.67.95 cardiac arrhythmias. At the tissue level, neurohormonal activation contributes to remodeling of the heart, blood vessels (atherosclerosis), kidneys, and Chapter 257: Heart Failure: Pathophysiology and Diagnosis, Michael M. Givertz; Mandeep R. Mehra Page 9 / 24 other ©2024organs McGraw(Fig. 257­5) Hill. and the All Rights development Reserved. of symptomatic Terms HF.Policy of Use Privacy Landmark clinical Notice trials in HF have demonstrated that antagonism of the RAAS and Accessibility SNS with renin­angiotensin system inhibitors, mineralocorticoid receptor antagonists, and beta blockers attenuates or reverses ventricular and vascular remodeling and reduces morbidity and mortality (Chap. 258). Neurohormonal Activation University of the Philippines ­ Manila Activation of the sympathetic nervous system (SNS) and renin­angiotensin­aldosterone system (RAAS) plays a critical role Access in the Provided by: development and progression of HF. Initially, neurohormonal activation leads to increases in heart rate, blood pressure, and cardiac contractility and retention of sodium and water to augment preload and maintain cardiac output at rest and during exercise. Over time, these unchecked compensatory responses lead to excessive vasoconstriction and volume retention, electrolyte and renal abnormalities, baroreceptor dysfunction, direct myocardial toxicity, and cardiac arrhythmias. At the tissue level, neurohormonal activation contributes to remodeling of the heart, blood vessels (atherosclerosis), kidneys, and other organs (Fig. 257­5) and the development of symptomatic HF. Landmark clinical trials in HF have demonstrated that antagonism of the RAAS and SNS with renin­angiotensin system inhibitors, mineralocorticoid receptor antagonists, and beta blockers attenuates or reverses ventricular and vascular remodeling and reduces morbidity and mortality (Chap. 258). FIGURE 257­5 Activation of neurohormonal systems in heart failure. Decreased cardiac output in heart failure (HF) results in an “unloading” of high­pressure baroreceptors (circles) in the left ventricle, carotid sinus, and aortic arch, which in turn causes reduced parasympathetic tone. This decrease in afferent inhibition results in a generalized increase in efferent sympathetic tone and nonosmotic release of arginine vasopressin from the pituitary. Vasopressin is a powerful vasoconstrictor that also leads to reabsorption of free water by the kidney. Afferent signals to the central nervous system also activate sympathetic innervation of the heart, kidney, peripheral vasculature, and skeletal muscles. Sympathetic stimulation of the kidney leads to the release of renin, with a resultant increase in circulating levels of angiotensin II and aldosterone. The activation of the renin­angiotensin­ aldosterone system promotes salt and water retention, peripheral vasoconstriction, myocyte hypertrophy, cell death, and myocardial fibrosis. Although these neurohormonal mechanisms facilitate short­term adaptation by maintaining blood pressure, they also result in end­organ changes in the heart and circulation. (Modified from A Nohria et al: Atlas of Heart Failure: Cardiac Function and Dysfunction, 4th ed, WS Colucci [ed]. Philadelphia, Current Medicine Group, 2002, p. 104, and J Hartupee, DL Mann: Nat Rev Cardiol 14:30, 2017.) Vasodilatory Hormones While RAAS and SNS activation contributes to disease progression in HF, a number of counterregulatory hormones are upregulated and exert beneficial effects on the heart, kidney, and vasculature. These include the natriuretic peptides (atrial natriuretic peptide [ANP] and B­type natriuretic peptide [BNP]), prostaglandins (prostaglandin E1 [PGE1] and prostacyclin [PGI2]), bradykinin, adrenomedullin, and nitric oxide. ANP and BNP are stored and released primarily from the atria and ventricles, respectively, in response to increased stretch or pressure. Beneficial actions are mediated through stimulation of guanylate cyclase and include systemic and pulmonary vasodilation, increased sodium and water excretion, inhibition of renin and aldosterone, and baroreceptor modulation. Bradykinin and natriuretic peptides are inactivated by neprilysin, a membrane bound peptidase, which explains in part the beneficial clinical impact of angiotensin receptor–neprilysin inhibition in HF (Chap. 258). As described below, natriuretic peptide levels can be used to assist in the diagnosis and risk stratification of patients with HF. Endothelin, Inflammatory Cytokines, and Oxidative Stress Endothelin is a2024­6­29 Downloaded potent vasoconstrictor 7:14 P Your peptide with growth­promoting effects that may play an important role in pulmonary hypertension and right IP is 175.176.67.95 Chapter 257: ventricular HeartEndothelin failure. Failure: Pathophysiology is released from and Diagnosis, a variety Michael of vascular and M. Givertz; Mandeep inflammatory R. Mehra cells within Pagein10 / 24 the pulmonary circulation and myocardium ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility response to increased pressure and has direct deleterious effects on the heart, leading to myocyte hypertrophy and interstitial fibrosis. Unlike RAAS and SNS inhibition, however, endothelin blockade has not been shown to slow the progression of clinical HF but is beneficial for treatment of pulmonary arterial hypertension (Chap. 283). Other factors that have the potential to cause or contribute to ventricular remodeling in HF include aldosterone, and baroreceptor modulation. Bradykinin and natriuretic peptides are inactivated by neprilysin, a membrane bound peptidase, which explains in part the beneficial clinical impact of angiotensin receptor–neprilysin inhibition in HF (Chap. 258). As described Universitybelow, of the natriuretic Philippinespeptide ­ Manila levels can be used to assist in the diagnosis and risk stratification of patients with HF. Access Provided by: Endothelin, Inflammatory Cytokines, and Oxidative Stress Endothelin is a potent vasoconstrictor peptide with growth­promoting effects that may play an important role in pulmonary hypertension and right ventricular failure. Endothelin is released from a variety of vascular and inflammatory cells within the pulmonary circulation and myocardium in response to increased pressure and has direct deleterious effects on the heart, leading to myocyte hypertrophy and interstitial fibrosis. Unlike RAAS and SNS inhibition, however, endothelin blockade has not been shown to slow the progression of clinical HF but is beneficial for treatment of pulmonary arterial hypertension (Chap. 283). Other factors that have the potential to cause or contribute to ventricular remodeling in HF include inflammatory cytokines such as tumor necrosis factor (TNF) α and interleukin (IL) 1β and reactive oxygen species such as superoxide. Potential sources of these biologically active substances are the liver and gastrointestinal tract, as described below. The role of anti­inflammatory and antioxidant therapies remains unproven. Novel Biologic Targets Sodium­glucose cotransporter­2 (SGLT­2) is a protein located on the proximal tubule of the kidney that is responsible for reabsorption of up to 90% of filtered glucose. In patients with HF, activity of SGLT­2 contributes to sodium and water retention, endothelial dysfunction, abnormal myocardial metabolism, and impaired calcium handling. Inhibitors of SGLT­2 were developed for the treatment of type 2 diabetes mellitus to take advantage of their glycosuric and metabolic effects (Chap. 404). Subsequent large clinical trials in cardiovascular disease including HF (with or without overt diabetes mellitus) have demonstrated not only safety of these agents (as required by the U.S. Food and Drug Administration) but also, more importantly, beneficial effects on morbidity and mortality. Whether benefits of SGLT­2 inhibitors in HF are due primarily to diuretic effects or to effects on cardiac and vascular remodeling, proarrhythmia, renal function, and/or metabolic function or inflammation remains to be determined. Another pathway that is downregulated in HF and contributes to endothelial dysfunction involves cyclic guanosine monophosphate (cGMP). Oral soluble guanylate cyclase stimulators enhance the cGMP pathway and exert beneficial myocardial and vascular effects in experimental and clinical HF. Dyssynchrony and Electrical Instability In up to one­third of patients with HF, disease progression is associated with prolongation of the QRS interval. Electrical dyssynchrony in the form of left bundle branch block (LBBB) or intraventricular conduction delay results in abnormal ventricular contraction. As discussed in Chap. 258, correction of electrical dyssynchrony with left or biventricular pacing can improve contractile function, decrease mitral regurgitation, and reverse ventricular remodeling. In patients with symptomatic HFrEF and LBBB on guideline­directed medical therapy, cardiac resynchronization therapy is indicated to reduce morbidity and mortality. Other forms of electrical instability, including atrial fibrillation with inadequate rate control and frequent premature ventricular complexes, can also contribute to worsening HF. In addition to the direct impact of tachycardia and irregular rhythm on disease progression, the link between these arrhythmias and cardiac remodeling (atrial and ventricular) involves increased wall stress, neurohormonal activation, and inflammation. Secondary Mitral Regurgitation A large number of patients with HFrEF demonstrate evidence of mitral regurgitation. This occurs due to a distortion in the mitral valve apparatus and includes the effects of various pathophysiologic mechanisms including reduced contractile force, which leads to decreased coaptation of the leaflets, a spherical shape of the ventricle that influences length and function of the chordal­papillary muscle structure, increased dimension of the mitral annulus (and inability of the annulus to contract during systole) with reduced leaflet alignment, and dilation of the posterior wall of the left atrium, which distorts the posterior leaflet of the valve. This worsening in regurgitant volume contributes to progression in HF and adversely influences prognosis. Ensuring that this vicious cycle is interrupted is now a therapeutic target in HF. Some success has been noted by treating the mitral valve using transcatheter techniques when patients are carefully selected after exposure to optimal medical therapy when residual and significant secondary mitral regurgitation persists. CARDIORENAL AND ABDOMINAL INTERACTIONS An important concept underlying the pathophysiology of HF recognizes the systemic nature of disease. Thus, while the primary hemodynamic problem in HF is related to abnormalities in myocardial function (preload, afterload, and contractility), many of the presenting signs and symptoms are related to end­organ failure, including dysfunction of the kidneys, liver, and lungs. The heart and kidney interaction increases circulating volume, worsens symptoms of HF, and results in disease progression, referred to as the cardiorenal syndrome. Traditionally, this relationship was deemed to be a consequence of an impairment in forward flow (cardiac output) leading to a decrease in renal arterial perfusion, worsening renal function, and neurohormonal activation with release of arginine vasopressin, resulting in water and sodium retention. However, evidence has emerged that renal dysfunction may Downloaded not be adequately 2024­6­29 explained 7:14 P Your simply by arterial underfilling and a decline in cardiac output. Systemic venous congestion in HF with IP is 175.176.67.95 Chapter increased257: Heart Failure: backward pressurePathophysiology may be operativeand Diagnosis, Michael in determining M. Givertz; the development of Mandeep R. Mehra the cardiorenal Pageis11 / 24 syndrome, and relief of venous congestion ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility associated with significant improvement in renal function in HF. Increased intraabdominal pressure, as noted in right­sided HF, and a rise in abdominal congestion are correlated with renal dysfunction in worsening HF. The interaction is not only confined to the renal component of the abdominal compartment but also involves the liver and spleen. The splanchnic veins serve as a blood reservoir and actively function in regulation of in HF is related to abnormalities in myocardial function (preload, afterload, and contractility), many of the presenting signs and symptoms are related University to end­organ failure, including dysfunction of the kidneys, liver, and lungs. The heart and kidney interaction increases of thevolume, circulating Philippines ­ Manila worsens Access Provided by: symptoms of HF, and results in disease progression, referred to as the cardiorenal syndrome. Traditionally, this relationship was deemed to be a consequence of an impairment in forward flow (cardiac output) leading to a decrease in renal arterial perfusion, worsening renal function, and neurohormonal activation with release of arginine vasopressin, resulting in water and sodium retention. However, evidence has emerged that renal dysfunction may not be adequately explained simply by arterial underfilling and a decline in cardiac output. Systemic venous congestion in HF with increased backward pressure may be operative in determining the development of the cardiorenal syndrome, and relief of venous congestion is associated with significant improvement in renal function in HF. Increased intraabdominal pressure, as noted in right­sided HF, and a rise in abdominal congestion are correlated with renal dysfunction in worsening HF. The interaction is not only confined to the renal component of the abdominal compartment but also involves the liver and spleen. The splanchnic veins serve as a blood reservoir and actively function in regulation of cardiac preload during changes in volume status, regulated by transmural pressure changes or mechanisms of systemic sympathetic activation. The liver and spleen participate in determining volume regulation in HF in addition to several additional interactive pathways. Splanchnic congestion results in portal vein distension and activation of the hepatorenal reflex as well as the splenorenal reflex, which induces renal vasoconstriction. Thus, decongestion in HF by diuretic therapy or mechanical means such as ultrafiltration reduces volume, but also facilitates a decrease in pressure within the abdominal compartment, and this combination of therapeutic effect may serve to improve renal function in HF. GUT CONGESTION, THE MICROBIOME, AND INFLAMMATION As noted above, circulating levels of proinflammatory cytokines are elevated in a number of cardiovascular disease states, including HF, and have been associated with disease progression. While the primary source of inflammation is unknown, emerging evidence suggests that an alteration in gut microbial composition and loss of microbial diversity may play an important role. The potential role of gut congestion and also altered gut microbial composition may propagate the chronic state of inflammation and immune system dysregulation, eventually leading to progression of HFrEF. Lipopolysaccharide (LPS) is a gram­negative bacterial cell wall product whose levels are increased in patients with HF and increased intestinal permeability during periods of congestion, and reduced with diuretic treatment. LPS is a strong stimulator of the immune system and can lead to dysregulated systemic inflammation via macrophage activation. Resulting increases in cytokines such as TNF­α, IL­1, and IL­6 in these pathways can cause progressive loss of cardiac function and also contribute to cardiac cachexia. A mechanistic link has been shown between gut microbe– dependent generation of trimethylamine N­oxide derived from specific dietary nutrients such as choline and carnitine and poor outcomes in patients with both acute and chronic HF. Microbe­generated uremic toxins, such as indoxyl sulfate, may play an important role in the development of HF, particularly in interaction with renal insufficiency. Thus, bowel ischemia and/or congestion depending on HF severity may be associated with morphologic and functional alterations in the intestines and result in bacterial endotoxemia and a proinflammatory state. HIGH­OUTPUT STATES Although most patients with HF, with either reduced or preserved EF, have low or normal cardiac output (CO) accompanied by elevated systemic vascular resistance (SVR), a minority of patients with HF present with a high­output state with low SVR (Table 257­2). High­output states by themselves are seldom responsible for HF, but their development in the presence of underlying cardiovascular disease can precipitate HF. For example, chronic anemia is associated with high CO when hemoglobin reduces significantly, for example, to a level that is ≤8 g/dL. An increase in vasodilatory metabolites and arteriolar vasodilation in response to decreased oxygen­carrying capacity of the blood in addition to a decrease in blood viscosity contributes to low SVR. Even when severe, anemia rarely causes high­output HF in the absence of a specific cardiac abnormality such as ischemic or valvular heart disease. Patients with end­stage renal disease (Chap. 312) are at particular risk of developing high­output HF when chronic anemia is exacerbated by increased flow through an arteriovenous fistula. In a contemporary series of patients with high­output HF, the most common causes were obesity (31%), liver disease (23%), arteriovenous shunts (23%), lung disease (16%), and myeloproliferative disorders (8%). EVALUATION HISTORY Symptoms of Congestion: Pulmonary Versus Systemic The most common symptoms of HF are related to volume overload with elevation in pulmonary and/or systemic venous pressures. Shortness of breath is a cardinal manifestation of left HF and may arise with increasing severity as exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and dyspnea at rest. Mechanisms of dyspnea include pulmonary venous congestion and transudation of fluid into the interstitium and/or alveoli, leading to decreased lung compliance, increased airway resistance, hypoxemia, and ventilation/perfusion mismatch. Stimulation of juxtacapillary J receptors leading to an increased ventilatory drive and reduced blood flow to respiratory muscles may cause lactic acidosis and a sensation of dyspnea. The New York Heart Association (NYHA) functional classification (Table 257­4) may be used to categorize patients based on the amount of effort required to provoke breathlessness. Notably, however, NYHA class does not correlate well with other objective measures of cardiac structure Downloaded 2024­6­29 (e.g., left ventricular size,7:14 EF) orPfunction Your IP(e.g., is 175.176.67.95 peak oxygen consumption). Chapter 257: Heart Failure: Pathophysiology and Diagnosis, Michael M. Givertz; Mandeep R. Mehra Page 12 / 24 ©2024 TABLEMcGraw 257­4 Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility New York Heart Association Functional Classification breath is a cardinal manifestation of left HF and may arise with increasing severity as exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and dyspnea at rest. Mechanisms of dyspnea include pulmonary venous congestion and transudation of fluid intoUniversity of the and/or the interstitium Philippines ­ Manila alveoli, leading to decreased lung compliance, increased airway resistance, hypoxemia, and ventilation/perfusion mismatch. Stimulation Access Provided by: of juxtacapillary J receptors leading to an increased ventilatory drive and reduced blood flow to respiratory muscles may cause lactic acidosis and a sensation of dyspnea. The New York Heart Association (NYHA) functional classification (Table 257­4) may be used to categorize patients based on the amount of effort required to provoke breathlessness. Notably, however, NYHA class does not correlate well with other objective measures of cardiac structure (e.g., left ventricular size, EF) or function (e.g., peak oxygen consumption). TABLE 257­4 New York Heart Association Functional Classification FUNCTIONAL LIMITATION CLINICAL ASSESSMENT CLASS Class 1 None Ordinary physical activity does not cause undue fatigue, dyspnea, palpitations, or angina. Class II Slight Comfortable at rest. Ordinary physical activity (e.g., carrying heavy packages) may result in fatigue, dyspnea, palpitations, or angina. Class III Marked Comfortable at rest. Less than ordinary physical activity (e.g., getting dressed) leads to symptoms. Class IV Severe Symptoms of heart failure or angina are present at rest and worsened with any activity. Orthopnea refers to dyspnea that occurs in the recumbent position and is due to redistribution of fluid from the abdomen and lower body into the chest, increased work of breathing due to decreased lung compliance, and, in patients with ascites or hepatomegaly, elevation of the diaphragm. Orthopnea typically occurs in the awake patient within 1–2 min of lying down and may be relieved by raising the head and chest with pillows or an adjustable bed. With more severe HF, patients may end up sleeping in a recliner chair or sitting up, although for some, orthopnea may diminish as symptoms of right HF appear. Orthopnea may be accompanied by nocturnal cough related to pulmonary congestion. Paroxysmal nocturnal dyspnea (PND) refers to episodes of shortness of breath that awaken a patient suddenly from sleep with feelings of anxiety and suffocation and require sitting upright for relief. In contrast to orthopnea, PND usually occurs after prolonged recumbency, is less predictable in occurrence, and may require 30 min or longer in the upright position for relief. Episodes are often accompanied by coughing and wheezing (so­called cardiac asthma) thought to be due to increased bronchial arterial pressure leading to airway compression and interstitial pulmonary edema causing increased airway resistance. Acute pulmonary edema, due to marked elevation of the pulmonary capillary wedge pressure, is manifested by severe shortness of breath and pink, frothy sputum (Chap. 305). Cheyne­Stokes respiration and central sleep apnea may precipitate episodes of PND in HF and are related to increased sensitivity of the respiratory center to arterial PCO2 and a prolonged circulatory time. Unlike obstructive sleep apnea, which can be treated with positive airway pressure therapy, central sleep apnea has no proven therapy beyond the directed treatment of HF (Chap. 297). In contrast to symptoms of left HF due to pulmonary venous congestion, symptoms of right HF are typically related to systemic venous congestion. Weight gain and lower extremity edema may be the initial manifestations followed by a range of gastrointestinal symptoms due to edema of the bowel wall and hepatic congestion. Abdominal bloating, anorexia, and early satiety are common. Some patients develop right upper quadrant pain related to stretching of the hepatic capsule with nausea and vomiting. When these symptoms are associated with abnormal liver function tests (see below), misdiagnosis of biliary tract disease may occur. For patients with refractory right HF, the development of massive edema involving the entire body with recurrent pleural effusions and/or ascites is termed anasarca. Symptoms of Reduced Perfusion Some patients with advanced HF present with symptoms related to decreased CO, sometimes referred to as low­output syndrome. Fatigue and weakness, particularly of the lower extremities, are nonspecific symptoms that can occur with exertion or at rest. Pathophysiology includes reduced blood flow to exercising muscles due to endothelial dysfunction and increased SVR from neurohormonal activation. Chronic alterations in skeletal muscle structure and metabolism have also been demonstrated. In older patients with HF and cerebrovascular disease, reduced systemic perfusion may result in mental dullness, depressed affect, and confusion. In addition to low CO, fatigue may be caused by volume depletion, hyponatremia, iron deficiency, and medications (e.g., beta blockers). Other Symptoms Downloaded 2024­6­29 7:14 P Your IP is 175.176.67.95 Chapter 257: Heart Failure: Pathophysiology and Diagnosis, Michael M. Givertz; Mandeep R. Mehra Page 13 / 24 ©2024 PatientsMcGraw with HF Hill. may All Rights present Reserved. with Terms of Use mood disturbances and poor Privacy Policy sleep, both of Notice which may Accessibility be exacerbated by nocturnal dyspnea and obstructive and/or central sleep apnea. Nocturia due to improved CO and renal perfusion in the supine position, in addition to delayed diuretic effects, can also contribute to sleep disturbances. Oliguria due to severe reductions in renal blood flow may be a sign of advanced­stage HF. blood flow to exercising muscles due to endothelial dysfunction and increased SVR from neurohormonal activation. Chronic alterations in skeletal University of the Philippines ­ Manila muscle structure and metabolism have also been demonstrated. In older patients with HF and cerebrovascular disease, reduced systemic perfusion Access Provided by: may result in mental dullness, depressed affect, and confusion. In addition to low CO, fatigue may be caused by volume depletion, hyponatremia, iron deficiency, and medications (e.g., beta blockers). Other Symptoms Patients with HF may present with mood disturbances and poor sleep, both of which may be exacerbated by nocturnal dyspnea and obstructive and/or central sleep apnea. Nocturia due to improved CO and renal perfusion in the supine position, in addition to delayed diuretic effects, can also contribute to sleep disturbances. Oliguria due to severe reductions in renal blood flow may be a sign of advanced­stage HF. Precipitating Factors Patients with HF may be asymptomatic or mildly symptomatic either because the cardiac impairment is mild or because compensatory mechanisms help to balance or normalize cardiac function. Symptoms of HF may develop when one or more precipitating factors increase cardiac workload and disrupt the balance in favor of decompensation. Specific factors may be identified in 50–90% of admissions and can be divided into patient­related factors, provider­related factors, HF­related disease states, and other causes (Table 257­5). Inability to recognize and correct these factors promptly may lead to persistent HF despite adequate treatment. TABLE 257­5 Precipitating Factors in Heart Failure Patient­Related Excess exertion or emotional stress Excess fluid and/or sodium intake Nonadherence with medications Heavy alcohol use Provider­Related Recommended use of mediations that cause salt and water retention (e.g., NSAIDs) Prescribed use of medications with negative inotropic properties (e.g., CCBs) Unrecognized congestion and inadequate use of diuretics Heart Failure–Related Uncontrolled hypertension Myocardial ischemia or infarction Atrial or ventricular arrhythmias Pulmonary embolism Other Disease States Systemic infection Worsening renal or hepatic failure Hyperthyroidism Downloaded 2024­6­29 7:14 P Your IP is 175.176.67.95 Chapter Untreated 257: Heart Failure: sleep apneaPathophysiology and Diagnosis, Michael M. Givertz; Mandeep R. Mehra Page 14 / 24 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Anemia help to balance or normalize cardiac function. Symptoms of HF may develop when one or more precipitating factors increase cardiac workload and University of the Philippines ­ Manila disrupt the balance in favor of decompensation. Specific factors may be identified in 50–90% of admissions and can be divided into patient­related Access Provided by: factors, provider­related factors, HF­related disease states, and other causes (Table 257­5). Inability to recognize and correct these factors promptly may lead to persistent HF despite adequate treatment. TABLE 257­5 Precipitating Factors in Heart Failure Patient­Related Excess exertion or emotional stress Excess fluid and/or sodium intake Nonadherence with medications Heavy alcohol use Provider­Related Recommended use of mediations that cause salt and water retention (e.g., NSAIDs) Prescribed use of medications with negative inotropic properties (e.g., CCBs) Unrecognized congestion and inadequate use of diuretics Heart Failure–Related Uncontrolled hypertension Myocardial ischemia or infarction Atrial or ventricular arrhythmias Pulmonary embolism Other Disease States Systemic infection Worsening renal or hepatic failure Hyperthyroidism Untreated sleep apnea Anemia Abbreviations: CCB, calcium channel blocker; NSAID, nonsteroidal anti­inflammatory drug. PHYSICAL EXAMINATION General Appearance Most patients with mild­moderate HF will appear well nourished and comfortable at rest. Even patients with more advanced disease may be in no distress after resting for a few minutes but may demonstrate dyspnea with minimal exertion such as walking across the room. In contrast, patients with Downloaded 2024­6­29 7:14 P Your IP is 175.176.67.95 severe HF may need to sit upright and appear anxious, diaphoretic, and dyspneic at rest with pallor due to anemia or duskiness due to lowPage output. Chapter 257: Heart Failure: Pathophysiology and Diagnosis, Michael M. Givertz; Mandeep R. Mehra 15 / 24 Other signs of severe HF include cool extremities and peripheral cyanosis. Cardiac cachexia ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility(Table 257­6), defined partially as unintentional edema­ free weight loss of >5% over 12 months, may be observed in patients with longstanding, severe HF as bitemporal or upper body muscle wasting. Contributing factors include poor oral intake due to anorexia, decreased fat absorption due to bowel wall edema, and catabolic/metabolic imbalance PHYSICAL EXAMINATION University of the Philippines ­ Manila Access Provided by: General Appearance Most patients with mild­moderate HF will appear well nourished and comfortable at rest. Even patients with more advanced disease may be in no distress after resting for a few minutes but may demonstrate dyspnea with minimal exertion such as walking across the room. In contrast, patients with severe HF may need to sit upright and appear anxious, diaphoretic, and dyspneic at rest with pallor due to anemia or duskiness due to low output. Other signs of severe HF include cool extremities and peripheral cyanosis. Cardiac cachexia (Table 257­6), defined partially as unintentional edema­ free weight loss of >5% over 12 months, may be observed in patients with longstanding, severe HF as bitemporal or upper body muscle wasting. Contributing factors include poor oral intake due to anorexia, decreased fat absorption due to bowel wall edema, and catabolic/metabolic imbalance from activation of inflammatory cytokines (see above) and dysregulation of the growth hormone–insulin­like growth factor 1 pathway. Rarely, scleral icterus and jaundice may result from severe right HF. TABLE 257­6 Definition of Cardiac Cachexia Edema­free weight loss of at least 5% in 12 months or less in the presence of underlying illness (or a BMI