Sleep Apnea, and Hypertrophic and Infiltrative Cardiomyopathy

Heart Failure Clin 4 (2008) 87–97

Heart Failure with Preserved Ejection Fraction: Hypertension, Diabetes, Obesity/Sleep Apnea, and Hypertrophic and Infiltrative Cardiomyopathy Akshay Desai, MDa,*, James C. Fang, MDb a Brigham and Women’s Hospital, Boston, MA, USA University Hospitals/Case Medical Center, Cleveland, OH, USA

b

Though the detailed pathophysiology of heart failure with preserved ejection fraction (HF-PEF) remains an area of active research and controversy, it is generally accepted that abnormalities of diastolic function, including delayed active myocardial relaxation, increased passive stiffness, and left atrial failure, play an important role. Most commonly, diastolic dysfunction occurs as a consequence of myocyte hypertrophy, endomyocardial fibrosis, and abnormalities of intracellular calcium handling that are related to normal myocardial aging and accelerated by comorbidities such as hypertension, diabetes, coronary artery disease, and obesity. The minority of patients with HF-PEF develop diastolic filling abnormalities in the absence of physiologic stimuli for myocardial remodeling or fibrosis; in these patients, primary pericardial or myocardial disorders result in constrictive pericarditis or restrictive cardiomyopathies that may require a very different course of therapy. In this article, three fundamental risk factors are considered for ‘‘secondary’’ diastolic dysfunction and HFd hypertension, diabetes, and obesitydwith an emphasis on the clinical epidemiology, pathophysiologic mechanisms, and treatment implications of each. The article concludes with a brief discussion of ‘‘primary’’ diastolic HF due to infiltrative or restrictive cardiomyopathies.

* Corresponding author. Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail address: [email protected] (A. Desai).

Hypertension and heart failure with preserved ejection fraction Though HF-PEF is a heterogeneous clinical syndrome, the vast majority of patients have a history of hypertension. According to data from the First National Health and Nutrition Examination Survey, hypertensive patients in the community have a 40% greater risk of developing HF than do nonhypertensives, independent of age [1]. More recent data from the Framingham Heart Study highlight that after age 40, the lifetime risk of developing HF in subjects with a blood pressure of 160/100 mmHg is twice that in those with a blood pressure below 140/90 mmHg, and is amplified by concurrent coronary artery disease, diabetes, left ventricular hypertrophy (LVH), or valve disease [2]. Hypertension may contribute to HF development either through stimulation of LVH [3] or through promotion of coronary artery disease. As systolic pressure and pulse pressure appear to have a greater impact on the risk of subsequent HF than the diastolic pressure, it has been suggested that stiffening of the central aorta, enhanced pulsatile load, and altered ventricular-vascular coupling may also play an important role in HF development [4,5]. Whether due to hypertension or other causes, LVH appears to be an important intermediate in evolving HF, with the risk of it increasing progressively in relation to increasing LV mass [6]. Among patients with HF in the general population, antecedent evidence of LVH is present in approximately 20% by ECG and 60% to 70% by echocardiogram [7]. Concentric LVH is tightly

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coupled to abnormalities of myocardial relaxation and also to systolic and diastolic ventricular stiffening. Diastolic abnormalities may be compounded in the presence of concomitant coronary artery disease, as ischemia produces exaggerated increases in filling pressures amongst patients with LVH [8]. Progressive hypertrophy is also associated with the development of subtle abnormalities of systolic function, which may also enhance the vulnerability to HF development [9,10]. Beyond myocardial changes, tandem increases in vascular stiffness with aging and hypertension are well described in the literature, and have also been implicated in the pathogenesis of HF [11–14]. By enhancing the speed of return of the reflected arterial wave, diminished vascular compliance might augment end-systolic load, enhancing ventricular wall stress and slowing myocardial relaxation [15]. In hypertensives, increased velocity of forward-wave transmission and enhanced central aortic pulse augmentation in late systole correlate with increased LV mass and left atrial volume and are associated with diminished myocardial relaxation velocity [16–18]. As well, central aortic systolic pressure and pulse pressuredboth integrated measures of proximal aortic stiffnessd are powerful predictors of incident cardiovascular events, and are increasingly thought to represent targets for medical therapy [19]. For example, in the Conduit Artery Function Evaluation substudy of the Anglo-Scandanavian Cardiac Outcomes Trial, significant reductions in central aortic stiffness in the amlodipine/perindopril-treated arm paralleled improvements in cardiovascular outcomes [19]. The factors that mediate the transition to HF-PEF in persons with hypertensive heart disease are an area of active investigation. Previous analyses of cardiac structure and function have emphasized that patients with HF-PEF are distinguished from those with hypertension by more pronounced abnormalities of active myocardial relaxation and passive diastolic stiffness [13], LV mass, and left atrial remodeling [20]. Though intrinsic myocardial factors are clearly important [21], however, hypertension-related vascular changes, particularly at the level of the elastic conduit arteries, may play an important supporting role in this transition. Exercise-induced hypertension is common in patients with HF-PEF; as well, effort intolerance in this population is tightly correlated with both diminished aortic distensibility [22] and increased end-diastolic pressure relative to end-diastolic volume, suggesting increased

ventricular stiffness and failure of the Frank-Starling mechanism [23]. Conversely, agents that lessen ventricular-arterial stiffening have been demonstrated to improve aerobic exercise performance in elderly patients without HF [24]. Coupled, age-related changes in ventricular-vascular stiffness might affect overall cardiac performance by blunting contractile reserve, increasing cardiac energy costs, enhancing blood pressure sensitivity to small changes in circulating volume, limiting ventricular ejection, and worsening diastolic function. Finally, other mechanisms may be involved; for example, investigators have shown that vasodilator and chronotropic reserve are limited in these patients during exercise and may help to explain exertional intolerance in these patients [25]. Treatment Aggressive treatment of systolic and diastolic hypertension is associated with enhanced myocardial relaxation [26,27], reduced central aortic stiffness [19], and a dramatic reduction in the incidence of HF [28,29]. Effective control of blood pressure promotes regression of LV mass and enhances long-term survival [30,31]. Although the optimal antihypertensive strategy has not been defined, there is increasing interest in attempting to generalize the benefits of neurohormonal antagonism seen in HF with reduced ejection fraction to the preserved ejection fraction population. Activation of the renin-angiotensin-aldosterone system (RAAS) contributes to hypertension, renal retention of sodium and water, myocardial fibrosis, and ventricular hypertrophy, which collectively impair myocardial performance in diastole. RAAS blockade with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blocking drugs (ARBs) has been shown to improve diastolic distensibility in both animal and human studies through regression of myocardial fibrosis [32] and reduction in ventricular mass [32]. Downstream of angiotensin II, binding of aldosterone to the mineralocorticoid receptor is a potent stimulus for fibrosis at the level of the heart, kidney, and the vasculature [33–35]. Blockade of the mineralocorticoid receptor with spironolactone was associated with important reductions in cardiovascular morbidity and mortality amongst low-ejection fraction HF patients in the Randomized Aldactone Evaluation Study [36]. In subgroup analyses of that trial, the greatest benefit to spironolactone was seen in patients with the highest serum levels of collagen

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synthesis markers, indicating that some of the benefit of aldosterone antagonism in chronic HF may be related to limitations in extracellular matrix turnover [37]. It is thought that aldosterone-related myocardial fibrosis may play a similar role in the pathogenesis of age- and hypertension-related diastolic dysfunction. Other diuretics may work through different mechanisms. For example, thiazide-based diuretics also appear to be important in preventing HF in hypertension. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, chlorthalidone decreased the development of HF when compared with other agents, potentially independent of renin-angiotensin system activation [38]. Studies in hypertensive patients suggest that ARBs may improve diastolic function [27,39] through regression of LVH [40] and reduction of LV mass [41]. As these agents are also associated with favorable effects on conduit vessel function and ventriculo-arterial coupling [42], there is a growing rationale for use of RAAS antagonists in patients with hypertension for HF prevention. The Losartan Intervention for Endpoint Reduction in Hypertension trial randomized 9193 patients with essential hypertension and electrocardiographic evidence of LVH to treatment with a losartan-based or atenolol-based antihypertensive regimen [43]. In that trial, assignment to losartan was associated with a 13% reduction in the composite primary outcome of death, myocardial infarction, or stroke, but there was no impact on HF in the overall population, perhaps owing to the small number of aggregate HF events. In a meta-analysis, Klingbeil and colleagues [41] demonstrated that ARBs are the most effective antihypertensive drugs in reducing LV mass.

plays in the development and progression of HF has led the American College of Cardiology and American Heart Association to classify diabetic patients as having Stage A heart failure, acknowledging that, even in the absence of apparent structural heart disease, they are at high risk for developing HF [48]. Roughly 30% to 50% of patients with HF-PEF have comorbid diabetes [49]. Although diabetes predisposes to coronary artery disease, renal dysfunction, and hypertension [50–53], diabetics may be particularly susceptible to HF owing to hyperglycemia-associated ultrastructural and metabolic abnormalities in the myocardium that impair myocardial relaxation (‘‘diabetic cardiomyopathy’’). Echocardiographic studies document increased LV wall thickness and increased LV mass in patients with diabetes, even after accounting for differences in body-mass index and blood pressure [54]. Increased echodensity of the myocardial wall in diabetic patients [55] correlates with findings of myocyte hypertrophy, interstitial and perivascular fibrosis, and increased deposition of matrix collagen on histology [56]. Doppler studies reveal patterns suggestive of impaired myocardial relaxation and diastolic ventricular compliance that track with the severity and duration of diabetes [57]. Evidence of such diastolic filling abnormalities, even early in the course of diabetes (before the onset of hypertension, renal disease, vasculopathy, or even fasting hyperglycemia), suggests that diastolic dysfunction is an effect of diabetes itself [58]. Finally, sensitive indices of contractile performance such as strain and strain rate are reduced in patients with diabetes, even in the absence of apparent structural heart disease, highlighting that systolic function may also be affected early in the disease [59].

Diabetes and heart failure with preserved ejection fraction

Mechanisms of myocardial dysfunction in diabetes mellitus

Although diabetes is uniformly recognized as an important risk factor for the development of atherosclerosis and its complications, it is perhaps less well understood that diabetes is a powerful and independent risk factor for the development of HF [44]. The Framingham Heart Study found the incidence of HF in men and women with diabetes relative to those without diabetes to be twofold and fivefold greater, respectively, even after controlling for additional risk factors [45]da finding that has been confirmed in several subsequent trials [46,47]. Recognition of the key role that diabetes

The hallmark of type 2 diabetes is insulin resistance with impaired myocardial glucose use and enhanced reliance of the heart on fatty acid metabolism for energy generation [60]. Increased fatty acid turnover enhances myocardial oxygen consumption, impairs glucose and pyruvate use, and promotes accumulation of lactic acid and toxic lipid intermediates that may interfere with mitochondrial adenosine triphosphate (ATP) generation and cellular calcium homeostasis [61]. As well, down-regulation of sarcoplasmic reticulum calcium ATPase (SERCA) expression and activity

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may further impair cellular calcium handling and promote myocardial relaxation abnormalities [62]. Altered membrane Kþ channel function, Naþ/Kþ-ATPase function, and protein kinase C metabolism may also occur as a consequence of impaired insulin signaling [63]. Chronic hyperglycemia leads to nonenzymatic glycation of matrix proteins in the vascular wall and myocardium, producing advanced glycation end products (AGEs) and reactive oxygen species. AGEs promote cross-linkage of adjacent collagen polymers, leading to a loss of collagen elasticity and, subsequently, diminished compliance of the blood vessels and myocardium [64]. Endothelial dysfunction may contribute to diminished availability of nitric oxide, enhanced atherosclerosis progression, diminished collateral formation, worsening arterial stiffness, and associated changes in ventricular load, which together may have important consequences for ventricular remodeling and disease progression [65,66]. Enhanced platelet activity and aggregability, diminished fibrinolysis, and increased expression of procoagulant factors may enhance susceptibility to thrombotic complications of atherosclerosis [66]. Finally, autonomic neuropathy and associated alterations in sympathetic and parasympathetic activity in patients with diabetes have been associated with impaired systolic and diastolic performance, and may play a role in myocardial dysfunction in this population [67]. The prevalence of hypertension is approximately doubled in diabetic patients compared with nondiabetic controls, perhaps as a consequence of hyperinsulinemia, endothelial dysfunction, and renal injury [63]. As well, the development of diabetes is nearly 2.5 times as likely in persons with hypertension than in their normotensive counterparts [68]. Myocardial fibrosis and interstitial collagen deposition are greater in patients with hypertension and diabetes than either entity in isolation [69]. Accordingly, patients with diabetes and hypertension in combination have more severe abnormalities of LV relaxation than those with either condition alone [70]. Synergistic effects on neurohormonal activation and oxidative stress may promote apoptotic myocyte loss, initiating a transition from a subclinical, compensated/hypertrophied state to overt decompensated/dilated cardiomyopathy [71]. Treatment More recent data also support the use of ACE inhibitors in the prevention of HF amongst

patients with diabetes. The Heart Outcomes Prevention Evaluation studied the effects of treatment with ramipril in 9297 patients at high risk for cardiovascular complications, defined as those 55 years of age or older with established vascular disease or diabetes and an additional cardiovascular risk factor. Relative to placebo-treated patients, those treated with ramipril experienced important, statistically significant reductions in death, myocardial infarction, and stroke, as well as a 23% reduction in the risk of new-onset HF; these benefits were robust in separate analyses of the subgroup of 3577 patients with diabetes [72]. Although lower-risk patients with stable coronary artery disease may derive less benefit [73], there is increasing evidence favoring the use of ACE inhibitors in both primary and secondary prevention of cardiovascular events amongst patients with diabetes. With regard to HF prevention, at least two studies support the benefit of ARBs in patients with type 2 diabetes. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study, type 2 diabetic patients with nephropathy and no history of HF were assigned to receive losartan or placebo in addition to conventional antihypertensive therapy. Over 4 years of follow-up, losartan-treated patients experienced a 32% reduction in the incidence of HF (P ¼ .005) and slower progression of renal disease [74]. This result is buttressed by the outcome of the Losartan Intervention for Endpoint reductions in hypertension study, in which 1195 patients with diabetes, hypertension, and LVH were randomized to antihypertensive therapy with losartan or atenolol. In addition to a statistically significant reduction in cardiovascular death, myocardial infarction, or stroke, losartan-treated patients experienced a 41% reduction in HF hospitalizations (P ¼ .013) [75]. ARBs are therefore an alternative to ACE inhibitors for primary prevention of HF in patients with type 2 diabetes. Treatment of heart failure with preserved ejection fraction These observations in both hypertensive and diabetic cohorts have fueled the design of several large, prospective, randomized clinical trials of RAAS blockade in patients with HF-PEF, some of which are ongoing. The Perindopril for Elderly People with Heart Failure trial [76] randomized 850 patients with symptomatic HF, 70 years or older, and preserved LV function to therapy

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with the ACE inhibitor perindopril or placebo. At the end of study follow-up (median 2.1 years), there was no difference in the primary outcome of death or unplanned hospitalization for HF between the two groups (hazard ratio [HR] 0.92 for perindopril versus placebo, P ¼ .55), though fewer perindopril-treated patients experienced the primary outcome at 1 year (10.8% versus 15.3%, HR 0.69, P ¼ .055). It has been argued that some of the benefit to perindopril in this study may have been obscured by a low event rate, limited statistical power, and a high rate of crossover to open-label ACE inhibitor use in the placebo arm [77]. Given statistically important benefits with regard to reduction in HF hospitalizations and improvement in 6-minute walk distance, these results point to at least a modest symptomatic benefit to RAAS inhibition in patients with HF-PEF. Further support for this hypothesis is provided by trials of ARBs in patients with HF-PEF. The Candesartan in Heart FailuredAssessment of Reduction in Mortality and Morbidity (CHARM) Program was a composite of three component trials in patients with symptomatic HF, one of which enrolled 3023 patients with LVEF above 40% (CHARM-Preserved) [78]. Over a median follow-up of 36 months, candesartan treatment did not reduce cardiovascular death but significantly fewer hospitalizations for HF (230 versus 279, P ¼ .017). As well, there was a nonsignificant trend to reduction in the composite primary endpoint of cardiovascular death or HF hospitalization (covariate adjusted HR 0.86 for candesartan versus placebo, P ¼ .051), supporting a modest impact to candesartan treatment in HF-PEF. A mechanistic substudy of conduit vessel function in CHARM suggests that some of the benefit to candesartan in HF may be related to favorable impacts on central aortic stiffness, pulsatile hemodynamic load, and ventriculo-arterial interaction [42]. These results await confirmation in a second ARB trial, the Irbesartan in Heart Failure with Preserved Systolic Function study [79]. Obesity, sleep-disordered breathing, and heart failure with preserved ejection fraction Obesity appears to increase the risk of developing HF. In the Framingham Heart Study, after adjustments for established risk factors, the risk of HF increased by 5% in men and 7% in women for each increment of 1 in the body mass index (BMI) [80]. Obese subjects (BMI 30 or more) had a twofold

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risk for developing HF, and a graded increase occurred over all categories of BMI. Furthermore, in an echocardiographic subgroup, only a minority (43%) of the obese HF cohort had an ejection fraction above 40%; the rest had relatively preserved systolic function (eg, HF-PEF). Yet the relationship between obesity and HF is more complex. For example, it remains controversial as to whether obesity per se is deleterious or protective once HF has been established; some have suggested that obesity is paradoxically associated with improved outcomes [81,82] when compared with those with either normal or underweight (!25) BMI. Furthermore, the establishment of HF in the obese patient may not be straightforward in that HF signs and symptoms, such as exertional dyspnea, orthopnea, and peripheral edema, may have other non-HF etiologies. In fact, biomarkers such as brain natriuretic peptides in this patient population are also not reliably elevated [83]. The complex relationship between obesity and HF is also apparent if the many potential mechanisms that connect obesity to HF are considered. Hypertension, insulin resistance, dyslipidemia, neurohormonal activation, a salt-and-water avid state, increased oxidative stress, and sleep-disordered breathing all have putative mechanistic links that can tie obesity to HF. Sleep-disordered breathing may have particular relevance to HP-PEF because of its prevalence in obese patients. Obesity is the strongest risk factor for obstructive sleep apnea (OSA) [84]. Sleep-disordered breathing, most commonly either OSA or central sleep apnea (CSA; also known as Cheyne-Stokes respirations), has been strongly associated with systolic HF [85]. However, severe OSA (apnea-hypopnea index O40/ hour) has been linked to diastolic abnormalities in the setting of normal systolic ventricular function [86]. Sleep apnea, obstructive or central, likely contributes to the progression of HF through chronic adrenergic stimulation, a critical pathophysiologic pathway in HF. In sleep apnea, wall stress and ventricular afterload are also increased by concomitant hypertension and the exaggerated intrathoracic pleural pressures required to ventilate the lungs when airway obstruction and/or noncompliant lungs are present. Continuous positive airway pressure (CPAP) is the most effective form of therapy for OSA and works by splinting open an obstructed airway. Early studies have suggested that there may be improvements in ventricular function with CPAP support when OSA complicates HF [87], but it

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remains to be determined whether symptoms and/ or prognosis are definitely improved by such therapy [88]. Targeting CSA in HF has not been demonstrated to improve survival [89]. The role of CPAP in HF-PEF remains unexplored. The benefit of significant weight loss by either diet or surgery seems intuitive, but few studies have been prospectively conducted to address this question. ‘‘Primary’’ diastolic heart failure: restrictive cardiomyopathy Although the vast majority of patients with HF-PEF develop diastolic filling abnormalities as a consequence of physiologic stimuli for myocardial hypertrophy or fibrosis, a small proportion do so as a consequence of primary myocardial disorders that directly enhance myocardial stiffness and steepen the pressure-volume relationship in diastole. These patients with primary ‘‘restrictive’’ cardiomyopathies make up a heterogenous group of hypertrophic, infiltrative, and fibrotic disordersdsome inherited and others acquireddwith a prevalence that varies according to the population under study (Table 1). Cardiac amyloidosis, the prototypical disorder, is the most thoroughly studied in Western populations. By contrast, endomyocardial fibrosis is endemic in parts of the tropics and may account for 15% to 25% of deaths due to cardiac disease in equatorial Africa. Although many of these disorders are relatively uncommon in routine clinical practice, they form an important differential for patients presenting with HF-PEF, particularly when the typical comorbidities discussed previously (hypertension, diabetes, obesity, coronary artery disease) are absent. Endomyocardial biopsy may be diagnostic in many cases, but a histopathologic diagnosis is absent in about 50% of cases [90]. As prognosis is often poor for patients with true restrictive cardiomyopathy [91], it is important to differentiate this condition from primary pericardial disease (constrictive pericarditis) where surgical treatment may be curative [92]. Management of the patient with restrictive cardiomyopathy varies widely according to the specific etiology. Patients with heritable metabolic disorders resulting from myocardial accumulation or infiltration of abnormal metabolic products (eg, glycosphingolipids, cerebrosides, glycogen, mucopolysaccharides) may respond to enzyme replacement therapy where it is available (eg, Fabry or Gaucher Disease). Those with cardiac iron overload as a consequence of hereditary

Table 1 Causes of restrictive cardiomyopathy Infiltrative Amyloidosis Sarcoidosis Hemochromatosis Gaucher disease Fabry disease Glycogen storage disease Hurler disease Fatty infiltration Noninfiltrative Hypertrophic cardiomyopathy Scleroderma Pseudoxanthoma elasticum Diabetic cardiomyopathy Idiopathic cardiomyopathy Fibrotic Endomyocardial fibrosis Eosinophilic cardiomyopathy (Lo¨ffler’s endocarditis) Radiation Carcinoid heart disease Toxic (anthracyclines, serotoninergic agents, ergot derivatives, busulfan) Data from Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med 1997;336(4): 267–76.

hemochromatosis can be successfully managed with serial phlebotomy or treatment with chelating agents such as desferrioxamine [90]. Advanced endomyocardial fibrosis with HF typically requires surgical management with endocardiectomy and valve replacement [93]. Unfortunately, general management of restrictive cardiomyopathies remains limited. Careful attention to volume status is essential as modest degrees of either hypovolemia or hypervolemia can lead to hypotension or pulmonary edema, respectively. Chronotropic competence and atrioventricular synchrony are typically critical as stroke volumes are small, fixed, and not augmented during times of stress. Tachycardia must often be tolerated to maintain adequate cardiac output but at the potential expense of decreased diastolic filling times. In fact, little evidence supports the commonly held notion that slowing the heart rate improves diastolic filling to a great enough extent to be clinically relevant. Finally, the use of vasodilator therapy is often complicated by excessive hypotension or orthostasis. Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM) encompasses a spectrum of inherited, autosomal

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dominant disorders of sarcomere gene mutations characterized by LVH in the absence of typical physiologic triggers (pressure or volume overload; eg, due to hypertension or valvular heart disease). Mutations in cardiac b-myosin heavy-chain, myosin-binding protein C, cardiac Troponin T, and cardiac Troponin I account for over 80% of disease, though over 400 individual mutations in 11 different components of the cardiac contractile apparatus have been identified [94]. From the histopathologic standpoint, the disease is uniformly characterized by myocyte hypertrophy with myocyte disarray and fibrosis. The clinical phenotype, however, is diverse, ranging from asymptomatic disease to sudden death and refractory, end-stage HF, with only limited correlation to the specific inherited gene variant [95]. Abnormal diastolic function is a hallmark of HCM, and may be a fundamental consequence of pathologic sarcomere mutations. Early in the course of disease, sarcomere gene mutations produce alterations in intracellular calcium handling that can be restored in part by administration of L-type calcium-channel blockers such as diltiazem [96]. With time, genotype-positive individuals develop progressive abnormalities of diastolic dysfunction that precede typical pathologic changes or gross ventricular hypertrophy [97]. Abnormal diastolic function is thought to account for much of the effort intolerance and HF symptomatology in patients with HCM. In the absence of a substantial evidence base, treatment of patients with symptomatic HCM is focused largely on therapies designed to facilitate diastolic function or on relief of intracavitary obstruction. Beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide may be useful owing to putative lusitropic and/or negative inotropic effects. Where significant LV outflow tract obstruction is present, invasive therapies such as alcohol septal ablation or surgical myomectomy may improve functional capacity. Rare patients that progress to symptomatic HF with LV dysfunction (‘‘burnt-out HCM’’) may benefit from advanced HF therapies, including cardiac transplantation [98]. Amyloidosis In contrast to HCM, in which diastolic dysfunction is a consequence of a primary disorder of the sarcomere, amyloid cardiomyopathy results from the deposition of portions of immunoglobulin light chain within the myocardial interstitium

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without fundamental myocyte pathology. Primary amyloidosis (AL amyloidosis) results from monoclonal expansion of plasma cells in the bone marrow (multiple myeloma) and consequent overproduction of kappa or lambda light chains with deposition in the extracellular tissues of the marrow, kidney, brain, peripheral nerves, gastrointestinal tract, and heart. It should be distinguished from secondary amyloidosis (AA amyloidosis), in which production of amyloid protein is related to an underlying inflammatory or connective tissue disorder, and typically does not result in clinical cardiac disease. Familial amyloid variants associated with cardiomyopathy have also been described, related to overproduction of mutant transthyretin protein in the liver of affected individuals. Elderly patients may also experience age-related transthyretin deposition in the heart (senile amyloidosis) in the absence of a plasma cell dyscrasia or identifiable systemic illness [99]. Regardless of the underlying pathogenesis of amyloid production, cardiac amyloidosis is a myocardial disease characterized by extracellular protein deposition throughout the heart, including ventricles, atria, valves, and the conduction system. Progressive amyloid infiltration results directly in increased chamber stiffness, biventricular wall thickening, and progressive diastolic dysfunction with biatrial enlargement and ultimate progression to HF [100]. The onset of HF symptoms in patients with cardiac amyloidosis invariably portends a poor prognosis, with median survival less than 6 months absent treatment [101]. Early detection and prompt initiation of therapy are therefore critically important. Though echocardiographic imaging and cardiac MRI [102] are useful in the identification of patients with possible amyloidosis, the formal diagnosis rests on demonstration of amyloid deposits on histopathology, which usually requires endomyocardial biopsy. Amyloid deposits characteristically exhibit apple-green birefringence under polarized light or a turquoise green color when stained with sulfated Alcian blue; immunohistochemistry may be useful for identifying the specific amyloid protein responsible, which may be helpful in targeting appropriate therapy [100]. Though treatment options for most patients with cardiac amyloidosis are limited, it may be possible to modify the natural history with chemotherapy, alone or in combination with autologous bone marrow stem cell transplantation [103]. For selected patients with the AL variant, combined heart and autologous bone marrow transplantation can be

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considered [100,104]. Liver transplantation removes the source of transthyretin in patients with familial amyloidosis, and should be considered in those in whom disease is identified early [105]. References [1] He J, Ogden LG, Bazzano LA, et al. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med 2001;161(7):996–1002. [2] Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heart failure. JAMA 1996;275(20):1557–62. [3] Levy D, Anderson KM, Savage DD, et al. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors. The Framingham Heart Study. Ann Intern Med 1988; 108(1):7–13. [4] Haider AW, Larson MG, Franklin SS, et al. Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med 2003;138(1):10–6. [5] Chae CU, Pfeffer MA, Glynn RJ, et al. Increased pulse pressure and risk of heart failure in the elderly. JAMA 1999;281(7):634–9. [6] Verdecchia P, Carini G, Circo A, et al. Left ventricular mass and cardiovascular morbidity in essential hypertension: the MAVI study. J Am Coll Cardiol 2001;38(7):1829–35. [7] Devereux RB. Is the electrocardiogram still useful for detection of left ventricular hypertrophy? Circulation 1990;81(3):1144–6. [8] Eberli FR, Apstein CS, Ngoy S, et al. Exacerbation of left ventricular ischemic diastolic dysfunction by pressure-overload hypertrophy. Modification by specific inhibition of cardiac angiotensin converting enzyme. Circ Res 1992;70(5):931–43. [9] Aurigemma GP, Silver KH, Priest MA, et al. Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy. J Am Coll Cardiol 1995;26(1):195–202. [10] Rosen BD, Edvardsen T, Lai S, et al. Left ventricular concentric remodeling is associated with decreased global and regional systolic function: the Multi-Ethnic Study of Atherosclerosis. Circulation 2005;112(7):984–91. [11] Mitchell GF, Guo CY, Benjamin EJ, et al. Crosssectional correlates of increased aortic stiffness in the community: the Framingham Heart Study. Circulation 2007;115(20):2628–36. [12] Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol 2005;25(5):932–43. [13] Lam CS, Roger VL, Rodeheffer RJ, et al. Cardiac structure and ventricular-vascular function in

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