Sleep Apnea, and Hypertrophic and Infiltrative Cardiomyopathy

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 I...

208KB Sizes 11 Downloads 29 Views

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


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

1551-7136/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.hfc.2007.11.001



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



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



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


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


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



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


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


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



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













persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation 2007;115(15):1982–90. Shapiro BP, Lam CS, Patel JB, et al. Acute and chronic ventricular-arterial coupling in systole and diastole. Insights from an elderly hypertensive model. Hypertension 2007;50(3):503–11. Mitchell GF, Tardif JC, Arnold JM, et al. Pulsatile hemodynamics in congestive heart failure. Hypertension 2001;38(6):1433–9. Tsioufis C, Chatzis D, Dimitriadis K, et al. Left ventricular diastolic dysfunction is accompanied by increased aortic stiffness in the early stages of essential hypertension: a TDI approach. J Hypertens 2005; 23(9):1745–50. Patrianakos AP, Parthenakis FI, Karakitsos D, et al. Relation of proximal aorta stiffness to left ventricular diastolic function in patients with endstage renal disease. J Am Soc Echocardiogr 2007; 20(3):314–23. Mitchell GF, Vasan RS, Keyes MJ, et al. Pulse pressure and risk of new-onset atrial fibrillation. JAMA 2007;297(7):709–15. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006; 113(9):1213–25. Melenovsky V, Borlaug BA, Rosen B, et al. Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community: the role of atrial remodeling/dysfunction. J Am Coll Cardiol 2007;49(2):198–207. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure–abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 2004;350(19):1953–9. Hundley WG, Kitzman DW, Morgan TM, et al. Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001; 38(3):796–802. Kitzman DW, Higginbotham MB, Cobb FR, et al. Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17(5):1065–72. Chen CH, Nakayama M, Talbot M, et al. Verapamil acutely reduces ventricular-vascular stiffening and improves aerobic exercise performance in elderly individuals. J Am Coll Cardiol 1999;33(6):1602–9. Borlaug BA, Melenovsky V, Russell SD, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006; 114(20):2138–47.


[26] Solomon SD, Janardhanan R, Verma A, et al. Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial. Lancet 2007;369:2079–87. [27] Wachtell K, Bella JN, Rokkedal J, et al. Change in diastolic left ventricular filling after one year of antihypertensive treatment: The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Circulation 2002;105(9):1071–6. [28] Kostis JB, Davis BR, Cutler J, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA 1997;278(3):212–6. [29] Gueyffier F, Bulpitt C, Boissel JP, et al. Antihypertensive drugs in very old people: a subgroup metaanalysis of randomised controlled trials. INDANA Group. Lancet 1999;353(9155):793–6. [30] Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA 1996;275(19):1507–13. [31] Koren MJ, Ulin RJ, Koren AT, et al. Left ventricular mass change during treatment and outcome in patients with essential hypertension. Am J Hypertens 2002;15(12):1021–8. [32] Diez J, Querejeta R, Lopez B, et al. Losartandependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 2002;105(21):2512–7. [33] Rocha R, Funder JW. The pathophysiology of aldosterone in the cardiovascular system. Ann N Y Acad Sci 2002;970:89–100. [34] Rocha R, Martin-Berger CL, Yang P, et al. Selective aldosterone blockade prevents angiotensin II/ salt-induced vascular inflammation in the rat heart. Endocrinology 2002;143(12):4828–36. [35] Weber KT. Aldosterone in congestive heart failure. N Engl J Med 2001;345(23):1689–97. [36] Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341(10):709–17. [37] Zannad F, Alla F, Dousset B, et al. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation 2000;102(22):2700–6. [38] Davis BR, Piller LB, Cutler JA, et al. Role of diuretics in the prevention of heart failure: the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation 2006;113(18):2201–10. [39] Warner JG Jr, Metzger DC, Kitzman DW, et al. Losartan improves exercise tolerance in patients













with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999; 33(6):1567–72. Thurmann PA, Kenedi P, Schmidt A, et al. Influence of the angiotensin II antagonist valsartan on left ventricular hypertrophy in patients with essential hypertension. Circulation 1998;98(19):2037–42. Klingbeil AU, Schneider M, Martus P, et al. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med 2003;115(1):41–6. Mitchell GF, Arnold JM, Dunlap ME, et al. Pulsatile hemodynamic effects of candesartan in patients with chronic heart failure: the CHARM Program. Eur J Heart Fail 2006;8(2):191–7. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359(9311):995–1003. Nesto RW. Pharmacological treatment and prevention of heart failure in the diabetic patient. Rev Cardiovasc Med 2004;5(1):1–8. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974;34(1):29–34. Parker AB, Yusuf S, Naylor CD. The relevance of subgroup-specific treatment effects: the Studies Of Left Ventricular Dysfunction (SOLVD) revisited. Am Heart J 2002;144(6):941–7. Gottdiener JS, Arnold AM, Aurigemma GP, et al. Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J Am Coll Cardiol 2000;35(6):1628–37. Hunt SA, Abraham WT, Chin MH, et al. ACC/ AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112(12):e154–235. Yancy CW, Lopatin M, Stevenson LW, et al. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol 2006;47(1):76–84. Aguilar D, Solomon SD, Kober L, et al. Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Circulation 2004; 110(12):1572–8.



[51] Shindler DM, Kostis JB, Yusuf S, et al. Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) Trials and Registry. Am J Cardiol 1996;77(11):1017–20. [52] Waller BF, Palumbo PJ, Lie JT, et al. Status of the coronary arteries at necropsy in diabetes mellitus with onset after age 30 years. Analysis of 229 diabetic patients with and without clinical evidence of coronary heart disease and comparison to 183 control subjects. Am J Med 1980;69(4): 498–506. [53] Malmberg K, Yusuf S, Gerstein HC, et al. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation 2000;102(9):1014–9. [54] Devereux RB, Roman MJ, Paranicas M, et al. Impact of diabetes on cardiac structure and function: the strong heart study. Circulation 2000; 101(19):2271–6. [55] Di Bello V, Talarico L, Picano E, et al. Increased echodensity of myocardial wall in the diabetic heart: an ultrasound tissue characterization study. J Am Coll Cardiol 1995;25(6):1408–15. [56] Hardin NJ. The myocardial and vascular pathology of diabetic cardiomyopathy. Coron Artery Dis 1996;7(2):99–108. [57] Perez JE, McGill JB, Santiago JV, et al. Abnormal myocardial acoustic properties in diabetic patients and their correlation with the severity of disease. J Am Coll Cardiol 1992;19(6):1154–62. [58] Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 2004;25(4):543–67. [59] Fang ZY, Yuda S, Anderson V, et al. Echocardiographic detection of early diabetic myocardial disease. J Am Coll Cardiol 2003;41(4):611–7. [60] Hayat SA, Patel B, Khattar RS, et al. Diabetic cardiomyopathy: mechanisms, diagnosis and treatment. Clin Sci (Lond) 2004;107(6):539–57. [61] Rodrigues B, Cam MC, McNeill JH. Metabolic disturbances in diabetic cardiomyopathy. Mol Cell Biochem 1998;180(1–2):53–7. [62] Golfman L, Dixon IM, Takeda N, et al. Differential changes in cardiac myofibrillar and sarcoplasmic reticular gene expression in alloxan-induced diabetes. Mol Cell Biochem 1999;200(1–2):15–25. [63] Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 2001;37(4):1053–9. [64] Zieman S, Kass D. Advanced glycation end product cross-linking: pathophysiologic role and therapeutic target in cardiovascular disease. Congest Heart Fail 2004;10(3):144–9 [quiz: 150–1]. [65] Cockcroft JR, Webb DJ, Wilkinson IB. Arterial stiffness, hypertension and diabetes mellitus. J Hum Hypertens 2000;14(6):377–80.

[66] Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002;287(19):2570–81. [67] Zola B, Kahn JK, Juni JE, et al. Abnormal cardiac function in diabetic patients with autonomic neuropathy in the absence of ischemic heart disease. J Clin Endocrinol Metab 1986;63(1):208–14. [68] Gress TW, Nieto FJ, Shahar E, et al. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med 2000;342(13): 905–12. [69] van Hoeven KH, Factor SM. A comparison of the pathological spectrum of hypertensive, diabetic, and hypertensive-diabetic heart disease. Circulation 1990;82(3):848–55. [70] Liu JE, Palmieri V, Roman MJ, et al. The impact of diabetes on left ventricular filling pattern in normotensive and hypertensive adults: the Strong Heart Study. J Am Coll Cardiol 2001;37(7):1943–9. [71] Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of the heart in diabetes: Part I: general concepts. Circulation 2002;105(14): 1727–33. [72] Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipiril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. [published erratum appears in Lancet 2000;356:860]. Lancet 2000;355: 253–9. [73] The PEACE Trial Investigators. Angiotensinconverting enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058–68. [74] Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcome in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345(12):861–9. [75] Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359(9311):1004–10. [76] Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27(19):2338–45. [77] McMurray J. Renin angiotensin blockade in heart failure with preserved ejection fraction: the signal gets stronger. Eur Heart J 2006;27(19):2257–9. [78] Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003; 362(9386):777–81. [79] Carson P, Massie BM, McKelvie R, et al. The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and design. J Card Fail 2005;11(8):576–85.


[80] Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med 2002;347(5): 305–13. [81] Horwich TB, Fonarow GC, Hamilton MA, et al. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol 2001;38(3):789–95. [82] Kenchaiah S, Pocock SJ, Wang D, et al. Body mass index and prognosis in patients with chronic heart failure: insights from the Candesartan in Heart failure: assessment of reduction in mortality and morbidity (CHARM) program. Circulation 2007; 116(6):627–36. [83] Taylor JA, Christenson RH, Rao K, et al. B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide are depressed in obesity despite higher left ventricular end diastolic pressures. Am Heart J 2006;152(6):1071–6. [84] Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328(17): 1230–5. [85] Bradley TD, Floras JS. Sleep apnea and heart failure: Part I: obstructive sleep apnea. Circulation 2003;107(12):1671–8. [86] Fung JW, Li TS, Choy DK, et al. Severe obstructive sleep apnea is associated with left ventricular diastolic dysfunction. Chest 2002;121(2):422–9. [87] Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;348(13):1233–41. [88] Sin DD, Logan AG, Fitzgerald FS, et al. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation 2000;102(1):61–6. [89] Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005; 353(19):2025–33. [90] Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med 1997;336(4):267–76. [91] Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342(15):1077–84.


[92] Bertog SC, Thambidorai SK, Parakh K, et al. Constrictive pericarditis: etiology and cause-specific survival after pericardiectomy. J Am Coll Cardiol 2004;43(8):1445–52. [93] Joshi R, Abraham S, Kumar AS. New approach for complete endocardiectomy in left ventricular endomyocardial fibrosis. J Thorac Cardiovasc Surg 2003;125(1):40–2. [94] Ho CY, Seidman CE. A contemporary approach to hypertrophic cardiomyopathy. Circulation 2006; 113(24):e858–62. [95] Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA 2002;287(10):1308–20. [96] Semsarian C, Ahmad I, Giewat M, et al. The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. J Clin Invest 2002;109(8):1013–20. [97] Ho CY, Sweitzer NK, McDonough B, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105(25): 2992–7. [98] Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet 2004;363(9424):1881–91. [99] Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med 1997;337(13):898–909. [100] Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112(13):2047–60. [101] Dubrey SW, Cha K, Anderson J, et al. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM 1998; 91(2):141–57. [102] Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111(2):186–93. [103] Seldin DC, Anderson JJ, Sanchorawala V, et al. Improvement in quality of life of patients with AL amyloidosis treated with high-dose melphalan and autologous stem cell transplantation. Blood 2004;104(6):1888–93. [104] Dubrey SW, Burke MM, Hawkins PN, et al. Cardiac transplantation for amyloid heart disease: the United Kingdom experience. J Heart Lung Transplant 2004;23(10):1142–53. [105] Suhr OB, Herlenius G, Friman S, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver Transpl 2000;6(3):263–76.