HYPERTROPHIC AND RESTRICTIVE CARDIOMYOPATHIES THE ELDERLY

CARDIOVASCULAR DISEASE IN THE ELDERLY

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HYPERTROPHIC AND RESTRICTIVE CARDIOMYOPATHIES IN THE ELDERLY Susan J. Zieman, MD, and Nicholas J. Fortuin, MD

The prevalence of congestive heart failure (CHF) increases tenfold from the sixth to the ninth decade of life, and CHF remains the most common reason for hospital admission and readmission in the elderly.87Approximately 50% of heart failure in older patients is exclusively caused by diastolic dysfunction with preservation of left ventricular systolic function.8,87 Although difficult to distinguish at the the recognition of diastolic from systolic dysfunction has important prognostic and therapeutic implications.10,8y Some degree of diastolic dysfunction results from normal aging changes of the cardiovascular system? 23, 4y, 70 but severe compromise in left ventricular diastolic filling leading to congestive symptoms in older patients may be caused by hypertrophic or restrictive cardiomyopathies.2 HYPERTROPHIC CARDIOMYOPATHIES

Central arterial stiffness creating increased vascular impedance leads to left ventricular hypertrophy in the aging heart of healthy, normotensive volunteers free of cardiovascular disease.23,49 The degree of myocardial hypertrophy, plus increases in left atrial size, left

ventricular mass, and the severity of diastolic dysfunction are all magnified in asymptomatic elderly patients with borderline and isolated systolic hypertension.6s,71 This type of clinically silent hypertrophy, however, differs from the exaggerated and disarrayed cellular hypertrophy that characterizes classic hypertrophic obstructive cardiomyopathy (HOCM). Whether this extreme level of hypertrophy occurs from hemodynamic stress, genetic alterations, or unknown causes, the pathophysiologic result is the same: a left ventricle with thick walls and a small diastolic cavity dimension, hyperdynamic systolic function leading to cavity obliteration, and abnormal diastolic function. The diagnosis of hypertrophic cardiomyopathy in older patients is often overlooked because nonspecific symptoms, such as dyspnea, chest pain, and lightheadedness or syncope, are often attributed to more common conditions, such as pulmonary, coronary artery, or cerebrovascu43, 79, 94 Patients with all types of lar disease.29, hypertrophic disease were likely pooled in earlier reports of this disorder, regardless of the specific cause.8Recent advances in molecular biology, echocardiographic and Doppler techniques have led to an improved understanding of the various distinct causes of hypertrophic heart disease in the elderly.s8 In

From the Department of Medicine and the Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland

CARDIOLOGY CLINICS VOLUME 17 * NUMBER 1 * FEBRUARY 1999

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this article HOCM and hypertensive hypertrophic cardiomyopathy (HHC) in the elderly as examples of hypertrophic disease are discussed. Other causes of hypertrophic cardiomyopathies in older patients such as valvular disease or hyperthyroidism are not addressed. Hypertrophic Obstructive Cardiomyopathy

Prevalence

Once thought to be a familial disorder affecting primarily younger individuals, HOCM or idiopathic hypertrophic subaortic stenosis (IHSS) has been diagnosed in older individuals with increased frequencyz1,29, 50, 52, 69, 72 In two series of newly diagnosed HOCM patients, one conducted in a community hospital and the other in a tertiary referral center, 83% of cases were over 50 years old and 41% of cases were over 60 years old, respectivel ~ .66~ It, has been proposed that there are three age peaks of presentation of HOCM: adolescence, the early forties, and the early 94 There is also a male predominance of this disorder in younger patients that contrasts with an equal to slightly higher prevalence of females in older patients.21,29, 43, 50, 66, 77* 79 Misdiagnosis, less severe symptomatology, and referral bias cloud clinicians' appreciation of the incidence and prevalance of hypertrophic cardiomyopathy in the elderly.21,43 Diagnosis

The constellation of symptoms of dyspnea, chest pain, and lightheadedness or syncope should raise the suspicion of a HOCM in older patients with suggestive physical findings. Several series comparing the clinical features of HOCM presenting in younger versus older patients found no difference in the percentage of patients with angina or syncope> 50*94 but dyspnea was more common in the history of this disorder in e l d e 1 - 1A ~ ~family ~ older patients may not be helpful because there seem to be more sporadic cases of 52, 56, 66, 69 HOCM in the elderl~.~, Physical findings of HOCM include rapid bifid carotid pulsations, a double or triple systolic apical heave, a fourth heart sound, and a systolic ejection murmur at the left lower sternal border that may increase with the Valsalva maneuver.", 95 The clinical conun-

drum of whether a murmur is because of aortic stenosis or mitral regurgitation should prompt the clinician to consider the diagnosis of HOCM. In the elderly, atrial fibrillation and hypertension are more common> 50 but bifid arterial pulsations may be masked by 52, 79 increased arterial ~tiffness.~~, The diagnosis of hypertrophic cardiomyopathy is confirmed by the typical echocardiographic and Doppler findings of left ventricular hypertrophy (LVH) (often asymmetric but may appear concentric)? 69 systolic anterior movement of the anterior leaflet of the mitral valve (SAM), reversal of early and atrial filling waves, and an increase in left ventricular outflow tract (LVOT) velocities. Differences in echocardiographically defined morphologic features between old and young patients with this disorder derived from two series comparing patients ages 65 years or older with patients ages 40 years or younger are summarized in Table l.50-52The most striking difference is an alteration in cardiac shape; 86% of elderly patients have an ovoid left ventricle, whereas 75% of younger patients have reversed septa1 curvature creating a crescentic cavity.2,50* 52 Compared to younger subjects, older patients have the same amount of SAM and LVOT gradients, but the mechanism of gradient development may be different. Posterior movement of the septum may contribute to the high LVOT velocities more than SAM in older patients because of a more anteriorly displaced and often calcified mitral apparatus.&,51, 52 ECG findings in older patients with HOCM include evidence of LVH, left atrial enlargement, and occasional bundle branch block. Q waves in the anterior and lateral leads, often seen in younger HOCM patients, however, are infrequent in the elderly.29,50,94 Pathophysiology-Genetic Considerations

Molecular genetic studies of HOCM reveal an autosomal dominant inheritance pattern of an assortment of missense mutations in the sarcomere apparatus genes.20,92, 95 More than 100 separate mutations have been identified in the genes for four major contractile proteins: cardiac p-myosin heavy chains (chromosome 14ql), cardiac troponin T (chromosome lq3), a-tropomyosin (chromosome 15q2), and cardiac myosin protein C (chromosome 11p11).20,58, 92, 95 These mutations are phenotypically expressed as hypertrophic,

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Table 1. MORPHOLOGIC DIFFERENCES BETWEEN OLD AND YOUNG PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY Findings

Old

Young

Left atrial size Left ventricular shape Septal curvature Septal thickness Mitral annular calcification Left ventricular outflow tract size Right ventricular hypertrophy Major contributor to left ventricular outflow tract Proximal septa1 bulge Left ventricular hypertrophy Mitral annular placement

Larger Ovoid Reversed (concave) Thinner Present Smaller Uncommon Posterior excursion of septum

Smaller Crescentic Normal (convex) Thicker Absent Larger Common Systolic anterior movement of the anterior leaflet of the mitral valve Absent Anterior septum Normal

Present Diffuse Anteriorly displaced

branched, and disarrayed cardiac myocytes, which are frequently interruped by fibrous tissue.13,6y, ys It is unclear whether the altered contractile protein causes the extreme myocyte hypertrophy or whether the hypertrophy is compensatory for the diminished intrinsic 14, 75, ys In contractile ability of the my~cyte.~, addition, despite a common underlying genetic cause of the disease, the hypertrophic expression and clinical course can vary widely, even among family members with y s Some identical mutation^.^, 14, 2 0 , 7 5 * 84, known HOCM mutations (especially those in cardiac troponin T) are associated with sudden death and diastolic dysfunction in the 2n, 7s absence of ventricular hypertr~phy.~, The recognition of HOCM presenting in older patients has led to the realization that specific mutations are associated with characteristic age of onset, clinical course, and incidence of sudden death.14,20, s8, 7s, 92, ys For example, mutations in the gene for cardiac myosin-binding protein C, a less crucial protein in force development, are phenotypically expressed beyond the forties and are associated with a more benign clinical course? In contrast, patients with more malignant mutations in the P-myosin heavy chain (Arg403Gln, A~-g’~”Gln, Arg453Cys,and Arg7lYTrp) and cardiac troponin T genes rarely survive to adulthood.7,75, y2 Although up to 40% of HOCM in the elderly may be due to sporadic mutations, these mutations are often inherited, stressing the importance of screening offspring of older HOCM patients. More recent genetic analysis suggests that late or incomplete disease penetrance may contribute to the delayed presentation. Because hypertension is more common in the elderly, it has also been proposed that hypertension may contribute to late-onset HOCM. No difference in clinical course or y2c

outcome was found when older HOCM patients with and without hypertension were compared.s,lo, 6y In addition, the histology and pattern of myocyte hypertrophy and arrangement in HOCM are distinctly different from the hypertrophy caused by hyperten~ion.’~, Whether certain aspects of the aging process activate the expression of mutated sarcomere protein genes or whether separate modifier genes, such as altered angiotensin-converting enzyme genes, are responsible for the late phenotypic expression of HOCM remains to be an~wered.~, 75 Natural History and Prognosis

Patients diagnosed with HOCM late in life tend to experience more severe symptoms than younger HOCM patients.x,51, s2, sh, 77 Despite this increase in symptoms, elderly HOCM patients tend to have a slower progression of the disease4”x5 and a more favorable prognosis with 1- and 5-year survival rates of 95% and 75%, respectively.2’,23, 51, 52, s6, 77, H5, yo, ys These survival rates do not differ significantly from age- and gender-matched The more favorable prognosis of HOCM in the elderly may be influenced by the inclusion of patients with the more benign condition of HHC in earlier studies of mortality.21As mentioned in the preceding section, genotypes associated with a more favorable prognosis, which are selectively seen in the elderly, may also account for this disparity. McKenna et a1 describe an annual mortality rate of 5.9% in HOCM patients diagnosed as children and 2.6% in patients diagnosed as a finding substantiated by other seThe 1-year mortality rate escalates to 36% in older patients presenting with NYHA class I11 and IV dyspnea.21Cannan et a1 report

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decreased survival with atrial fibrillation, a high NYHA functional class, hypertension, the use of digitalis and diuretics, and ECG evidence of myocardial infarction.8 Sudden death is an uncommon manifestation in those diagnosed in their later years.7,77, 78, yo Retrospective studies have found that syncope and a family history of sudden death are most predictive of sudden death, whereas hemodynamic and ECG abnormalities are not.8,56, 77 These studies did not include sufficient numbers of patients over age 60 to make conclusive statements about the risk factors of sudden death in the elderly; older HOCM patients who experience sudden death had complained of more exertional chest discomfort and dyspnea than older HOCM survivor~.~~ Treatment

Beta-adrenergic receptor blocking agents and nondihydropyridine calcium channel blocking agents remain first-line therapy for elderly HOCM patients. The negative inotropic and chronotropic effects of these medications reduce symptoms,2’, 51, 56, 76, 95 but they have not been shown to affect mortality. Prospective, randomized trials using these drugs are lacking,2I although, in a retrospective series of 120 severely symptomatic patients 65 years of age or older, 41% experienced sustained symptom improvement ( 2 1 NYHA class) while taking either of these medicat i o n ~The . ~ ~negative inotropic effects of disopyramide in oral doses of 600 to 800 mg/day can also alleviate Gentle diuretics may provide symptomatic relief in extreme cases of dyspnea and peripheral edema, but caution must be taken to avoid hypovolemia that may exacerbate symptoms. Agents that cause peripheral vasodilation and decrease preload (nitrates, dihydropyridines) and positive inotropes (digitalis) increase LVOT gradients and are, therefore, harmfuL8,29, 7y Enthusiasm grew for dual-chamber pacing (DDD) as a therapeutic option for severely symptomatic HOCM patients’ refractory medical therapy after several small European and a larger National Institutes of Health cohort study (n = 84, ages 11 to 77) demonstrated that 90% of these patients experienced a decrease in NYHA class symptoms and LVOT gradient with an improvement in exercise tolerance and perceived quality of life 19, When subsequent randomwith pacing.1H* ized, double-blind, crossover trials were per-

formed at the Mayo Clinic (n = 19, ages 25 to 81) and in a multicenter trial in Europe (n = 83, ages 22 to 87), 63% and 84% of HOCM patients, respectively, had symptomatic improvement with DDD pacing with improved exercise tolerance and a decrease in LVOT gradient.5yIn these trails, however, up to 42% of patients also reported symptomatic improvement when the pacer was blindly inactivated (AAI mode), raising the issue of a placebo effect.36, Although the mechanism by which pacing improves symptoms is unclear, the creation of an incoordinate contraction leading to increased chamber volume, less complete emptying, and a delay in proximal septal contraction along with ventricular wall remodeling may be important.27,60, y5 Prolongation of the PR interval by the use of either atrioventricular nodal-slowing medications (P-blockers or calcium channel blockers) or atrioventricular node ablation maximizes the benefit of pacing.19,5y, 6o Trials of dual-chamber pacing have included patients up to 87 years the inclusion of elderly patients in future trials will help to establish its usefulness as a therapeutic option in elderly HOCM patients. Pacing may be considered in older HOCM patients who are considered high risk for surgical options but who remain symptomatic despite aggressive medical therapy. Long-term symptomatic and survival analysis of pacing in hypertrophic disease has not been performed, and pacing does not affect the risk of sudden death. Surgery is reserved for patients debilitated by their symptoms (NYHA class I11 and class IV) and who have high LVOT velocities despite aggressive medical and pacing trials. Several small series of patients 65 years of age or older have shown that 80% to 90% experienced sustained symptomatic improvement following ventricular septal myotomymyectomy42. 51, 52 and demonstrated a signifi77 In these cant reduction in LVOT velocitie~.~~, series, the perioperative mortality of 5% is not significantly different from younger patients undergoing the pera at ion.^^ In a more recent series of 52 HOCM patients over age 65, perioperative mortality was 8%, but escalated to 27% when coronary bypass grafting was performed at the time of septal myotomy-myectomy.” Eighty-five percent of surgical survivors in this National Institutes of Health report had significant symptomatic improvement. Ten-year survival rates of surgical versus medical therapy with verapamil are similar (SOYO)for HOCM, but this comparison has

HYPERTROPHIC AND RESTRICTIVE CARDIOMYOPATHIES IN THE ELDERLY

yet to be established in older patients.76Severe mitral annular calcification and mitral regurgitation may respond to mitral valve replacement or repair at the time of septal m y e ~ t o m y 51 .~~, Elderly patients with HOCM should receive prophylaxis against spontaneous bacterial endocarditis in compliance with the American Heart Association/American Dental Association guidelines because the incidence of infection in this disorder is 3% following high-risk p r o c e d ~ r e s . ~ ~ Hypertensive Hypertrophic Cardiomyopathy Prevalence

HHC, first described by Topol et al, is not uncommon in the elderlyE6Similar to HOCM, however, the true incidence and prevalence of HHC are not known. Earlier descriptions of HOCM likely include a subset of HHC patients,@and controversy still surrounds the distinction of the two condition^.^' In contrast to HOCM, there is a higher female predominance in HHC after adjusting for age-related gender changes in the population.*,E6 In most series, women comprise more than 70% of cases, which may be caused by gender-specific differences in the degree of myocyte hypertrophy to intraventricular pressure-overload previously described in women with aortic sten0sis.I The mechanism of this exaggerated hypertrophic response in women remains unclear. A higher prevalence of HHC in African-American patients has also been described.86 Diagnosis Patients with HHC typically present with episodes of flash pulmonary edema. Although they may have similar chronic symptoms as HOCM patients, including dyspnea, chest pain, syncope, and palpitations, HHC patients more typically have few or no cardiac symptoms before these acute events.*,37, 54, 86 Patients with this disorder often describe a history of long-standing hypertension, either treated or untreated, predominately systolic and with little evidence of end-organ damage. Frequently, the severity of hypertension correlates poorly with the severity of LVH.E6Chronic fluid retention is unusual in HHC and, when present, with suggestive echocardiographic features of this disorder, should raise the question of amyloidosis.

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There is also no apparent familial component to HHC.E6The physical examination reveals normal jugular venous pressure, a left ventricular heave, an often palpable S4, and a systolic ejection murmur.54 The echocardiogram is diagnostic showing left atrial enlargement, severe LVH, hyperdynamic left ventricular systolic function with near cavity obliteration, and delayed mitral valve openingE6In contrast to HOCM, echocardiography in HHC more commonly demonstrates concentric LVH rather than asymmetric septal hypertrophy (Fig. lA,B).*, 37, R6 Systolic anterior movement of the mitral valve occurs in only 29% of patients. Mitral inflow Doppler reveals reduced early (E) filling waves and exaggerated atrial (A) waves indicating reliance on atrial systole (Fig. 2B). The ECG shows LVH, and an enlarged cardiothoracic ratio is present on the chest radiograph.*6 Pathophysiology

Because they share similar gross morphologic and hemodynamic manifestations, HHC and HOCM have often been regarded as similar conditions within a spectrum of hypertrophic disease.37Recent molecular evidence, however, has surfaced in support of unique pathophysiologies of these conditions.**Concentric hypertrophy of the left ventricle is an adaptive response to intraventricular pressure-overload from systemic hypertension.',22, 65, 71 In response to mechanical stretch, adrenergic neurohumoral and growth factors, and local and circulating factors of the renin-angiotensin system, cardiac myocytes undergo hypertrophy and remodelling.', 22 The reduction in left ventricular mass seen with the use of angiotensin-converting enzyme inhibitor therapy in HHC but not in HOCM supports this mechanism.**Cardiac capillary growth may not keep pace with this degree of myocyte hypertrophy and, coupled with the decrease in coronary perfusion caused by an elevated left ventricular end diastolic pressure, may cause myocardial ischemia and the symptom of chest pain.22The prevalence of hypertension in the patients over 65 years old varies from 50% to 70%, yet HHC remains relatively rare, suggesting a unique, poorly understood pathophysiology.2,37 It is unlikely that hypertension alone is the cause of HHC, but may act influentially on a genetically altered s u b ~ t r a t e Most . ~ ~ patients with hypertension do not manifest the severe LVH and hyperdynamic contractile pattern that typifies

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Figure 1. Parasternal long-axis echocardiographic views of hypertensive hypertrophic cardiomyopathy in an 83-year-old woman in A, diastole and B, systole demonstrating concentric hypertrophy and cavity obliteration. Late stage cardiac amyloidosis is shown in C, diastole, and D, systole with characteristic diffuse ground glass infiltrate and pericardial effusion.

HHC. In this regard, HHC is distinctly different from the thickened walls, dilated ventricular cavity, and systolic dysfunction that is the more common result of a prolonged hypertension. Natural History and Prognosis The natural history of HHC has not been clearly defined. Despite the frequent presen-

tation of life-threatening pulmonary edema, these patients often resume a normal and active lifestyle. The frequent lack of coronary artery disease, combined with normal left ventricular systolic function in HHC patients, contributes to a favorable long-term outlook. This is in contrast to the poor prognosis of HOCM patients with long-standing hypertension, who have a 1- and 5-year survival rate

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Figure 2. Two-dimensional Doppler inflow patterns in various conditions. Mitral inflow patterns are represented as the top diagram in each box with early (E) and atrial (A) filling waves. Simultaneous pulmonary venous inflow patterns are shown in the bottom drawing in each box with systolic (S), diastolic (D), and reversed flow waves (shaded). A, Normal. 6, Diastolic dysfunction. C, Pseudonorrnalization. D, Restriction.

of 75% and 43%, respectively, that is lower than elderly HOCM patients without hypertension.8This difference in mortality provides further evidence that HHC and HOCM with hypertension are distinct entities. Another distinction between the two conditions is that sudden death is rare in HHC.86 Treatment

Pharmacologic strategies in HHC are similar to those employed in HOCM, namely, the reduction of chronotropy and inotropy with beta-adrenergic receptor and nondihydropyridine calcium channel antagonists.86These agents may provide additional benefit in HHC by reduction of left ventricular mass 74 and improvement in early diastolic filling.22,

Medications that reduce intravascular volume and ventricular preload or those that promote peripheral vasodilation, such as nitrates, hydralazine, prazosin, angiotensin-converting enzyme inhibitors, and dihydropyridines, can be deleterious.8hBecause of its positive inotropic effect, digitalis should also be avoided unless it is needed for ventricular rate control in atrial fibrillation. Diuretics are often needed to avoid episodic pulmonary edema. Whether dual chamber pacing may provide symptomatic relief in HHC patients is not yet clear. Summary

Hypertrophic cardiomyopathies are often overlooked as a cause of congestive symp-

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toms, chest pain, and syncope in the elderly. Hypertrophic disease represents a broad spectrum of genotypic and phenotypic variations accounting for an equally broad spectrum of so, 9s The prognosis for clinical older patients diagnosed with HOCM is better than for their younger counterparts.21,43 This reduced mortality may be because of a more benign or incompletely expressed phenotypic variant, selection bias for survivors, or the unintentional inclusion of patients with a more benign disease process of HHC in HOCM series. Alterations in cardiac shape and differences in prognosis between older and younger patients with HOCM raises the question of a separate disease en tit^.^^,^^ HHC represents a clinically distinct subgroup of patients with hypertrophic cardiomyopathy, although controversy surrounding the pathophysiologic distinction remains.13,37* 86 Differences in clinical course,", Rh echocardiographic and Doppler findings currently help to distinguish the two forms of hypertrophic disease; molecular biology and genetic studies may help clarify the distinction in the future.88 RESTRICTIVE CARDIOMYOPATHIES

Restrictive cardiomyopathies (RCM) are caused by infiltrative or fibrotic changes in the left ventricular wall creating marked stiffness and a precipitous rise in early diastolic pressure during rapid ventricular filling4 The resultant high diastolic pressures in all cardiac chambers are responsible for systemic and pulmonary congestion. Additionally, systolic function may be compromised contributing to fluid retention and low output manifestation^.^^, 4s Infiltrative disease may also affect the conduction system. The incidence and prevalence of RCM in the elderly are underestimated; advances in molecular genetic techniques have recently shown that these disorders are often the result of an agedependent phenotypic expression of an inherited mutation.34 Etiology

Amyloidosis is the most common cause of an RCM in the elderly and is discussed in 68, 91 Other infiltrative processes detail 1ater.'7,34, creating restrictive hemodynamics include sarcoidosis, carcinoid syndrome, scleroderma, hemochromatosis, and malignancies.2,4s Im-

provements in cancer therapy survival have led to an increasing number of older patients with restrictive cardiac disease caused by postirradiation and anthracycline-induced myocardial fibrosis.45 Idiopathic RCM is rarely seen in the elderly, but carries a better prognosis than in either younger patients or those with infiltrative disorders.38,45, Ro, 87 Diagnosis

RCM should be suspected in older patients who present with marked fluid retention and a normal or minimally enlarged heart.2,17, 45 Atrial fibrillation and heart block are common manifestations, and one third of patients with restrictive disorders present with thromboemb01ism.~~ Chest discomfort is rare, but patients with amyloidosis may have angina-like symptoms caused by infiltration of small vessels, thickened walls, and a high left ventricular end diastolic pressure.6,45, R3 Although no physical examination finding is specific for RCM, a distinct nondisplaced apical impulse, a third heart sound, a low volume peripheral pulse, a rapid y descent of the jugular pulse, Kussmaul's sign, an enlarged pulsatile liver, pleural effusions, and ascites point toward the diagnosis.2,4s Low voltage, anterior Q wave, left atrial enlargement and conduction delays on the ECG suggest an infiltrative process such as a m y l ~ i d 30, . ~ ~ 83 , The diagnosis of RCM is made by combining the clinical presentation with echocardiographic and Doppler findings. Markedly thickened walls with a sparkling or groundglass appearance, left atrial enlargement, interatrial septa1 and valve thickening, and a small pericardial effusion typify the echocardiographic findings in amyloidosis but are nonspecific for the diagnosis (see Fig. 1C and O).l2,lS* R1 Early in the course of amyloidosis, systolic function may seem normal, but inevitably, systolic indices decline as the disease p r o g r e s ~ e s .When ~~ thickened ventricular walls with a small diastolic cavity are seen with abnormal systolic function, the clinician should consider amyloidosis (see Fig. 1D). Other restrictive disorders may show only a normal to small left ventricular cavity with normal systolic function. Classic pulsed wave Doppler mitral inflow patterns reflect the abnormal diastolic pressure-volume relationship created by increased ventricular stiffness (see Fig. 20).40Rapid early diastolic relaxation causes a steep, high velocity E filling wave.

HYPERTROPHIC AND RESTRICTIVE CARDIOMYOPATHIES IN THE ELDERLY

The precipitous rise in intraventricular pressure abruptly ceases filling and is manifest by a rapid E wave deceleration time. Atrial systole contributes little against the high late diastolic ventricular pressure and produces only a small or absent A wave (see Fig. 2D).45 Atrial waves are normally higher than E waves in elderly subjects (see Fig. 2B).3, 7o The dominant E and small A waves of RCM are referred to as pseudonormalization in the elderly2,40, 8y An increase in velocity and amplitude of retrograde flow in the pulmonary vein during atrial systole can help to identify restrictive disorders as the cause of a pseudonormalization pattern (see Fig. 2C).2,64 Invasive hemodynamic features characteristic of restrictive disease are similarly elevated filling pressures in all cardiac chambers, a rapid y greater than x descent on atrial pressure tracings, and a dip and plateau or square root sign on ventricular diastolic filling created by the abrupt cessation of a rapid early rise in 45 Constrictive pericarditis, another pres~ure.~, cause of CHF with normal systolic function and cardiac size, can be difficult to differentiate from RCM because of many similar clinical, echocardiographic, and hemodynamic par a m e t e r ~ x9 .~~, When an RCM has been diagnosed by these clinical and hemodynamic findings, the etiologic agent must be determined. Amyloidosis is diagnosed by demonstrating amyloid deposits on biopsy of an affected organ, subcutaneous fat pad or bone marrow aspiration, or rectal biopsy. Myocardial biopsy is defini-

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tive, but amyloid may be recovered in 90% of aspirates from subcutaneous fat pad or rectal biopsy specimens in patients with this disorder.25

Amy loidosis Over 300 years ago, Virchow first used the term amyloid to describe amorphous, insoluble, proteinaceous fibrils found in various organs that were found more commonly in h8, y6 Amyloidosis now refers to older people.17, a diffuse systemic process characterized by the multiorgan system infiltration and destruction of normal tissue by extracellular amyloid fibrils.I7 Advances in immunohistochemistry and molecular genetics have established that there are distinctly different types of amyloid protein despite their similar appearance under light microscopy. The proteins that make up amyloid fibrils may consist of monoclonal immunoglobulin light chains, prealbumin (transthyretin), serum protein A, P,-microglobulin, or polypeptide the specific type of amyloid protein determines the clinical presentation and natural history of the disease.l7.4h In recognition of its differing protein-based causes, amyloidosis is now classified into three major types: (1) primary amyloidosis associated with immunoglobulin deposition, (2) familial amyloidosis, and (3) reactive (secondary) amyloidosis (Table ,)., In addition to these formal classifications, the term senile cardiac amy-

Table 2. SUMMARY OF THE THREE MAJOR TYPES OF AMYLOIDOSIS* Primarv

Protein precursor Pathophysiology

Immunoglobulin light chains Monoclonal plasma cell dyscrasia

Gender Mean age onset Percent of amyloidoses

Male>female

Primary organs infiltrated Diagnosis

Renal>cardiac>neural

Treatment Prognosis Other “World Health Organization

62 Y

85%

Immunoelectrophoresis Immunofixation (urine,’ serum) Supportive/stem cell Transplant 2 chemotherapy Poor (1-2 y) Macroglossia

Familial

Secondarv

Transthyretin

Serum protein A

Missense mutation in hepatically synthesized protein Male>female 64 Y 10% (higher in AfricanAmericans) Neurabcardiac

Reactive protein to underlying chronic illness (rheumatic)

Isoelectric focusing Immunostaining of serum

Male = female <5‘% Renal> >gastrointestinal Immunohistochemical staining tissue for protein A

Supportive Treat underlying chronic Orthotopic liver transplant illness Mean 5.8 y 2Y Rare renal Rare in Western world

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loidosis has been used widely in the literature as a general term to describe amyloidosis in older individuals, regardless of the subtype. Originally coined in the nineteenth century to describe an increase in cardiac amyloid deposits with age, senile cardiac amyloidosis now lends to confusion over the specific cause of amyloidosis in older patients.2,33, 55, 57, 63, 83, y6 To further the confusion, the term senile cardiac arnyloidosis was refined to systemic senile amyloidosis once the systemic nature of the deposits was appreciated, but the two expressions are often used interchangeab l ~ . ~h7 *The , most recent World Health Organization-IUIS Nomenclature Subcommittee recognizes three separate age-related protein precursors of systemic senile amyloidosis: isolated atrial amyloid, normal, and genetically altered transthyretin.hzAutopsy studies on subjects over 60 years old confirm the increase in amyloid with age reporting deposits in 50% to 91% of hearts.31,3y, 53 At least two thirds of these hearts contained isolated atrial amyloid, which does not seem to bear any clinical significance, in contrast to the diffuse ventricular infiltrates of primary and familial 73, y6, y7 The presence of an aamyloid~sis.~~, atrial natriuretic peptide-derived protein subunit in isolated atrial amyloid suggests an association with chronic hypertension or CHF.", 5 3 Molecular studies identifying the protein precursor of systemic senile amyloidosis as genetically altered transthyretin has led to its reclassification as a subset of familial amyloidosis.28,30.33. 34.55. 57.62.83 Alternatively, Westermark et a1 have shown that the protein precursor in systemic senile amyloidosis is normal tran~thyretin.~~ Differentiating between the types of amyloidosis has important prognostic and therapeutic implication^.'^, 2s, 4x Primary and familial amyloidoses are discussed in detail later. Reactive (secondary) amyloidosis is derived from serum amyloid protein A, an acute phase reactant that is elevated in chronic infectious and inflammatory disorders such as tuberculosis, syphilis, rheumatoid arthritis, 46 With the deosteomyelitis, and lepr~sy.'~, cline of these disorders in industrialized countries, the incidence of secondary amyloidosis has dropped.24 Primary Amyloidosis Primary amyloidosis (AL) is by far the most prevalent subtype of amyloidosis. It commonly presents later in life with a median

age at presentation of 62 years with a slight male predominance.'*,25, 47, *3 Similar to multiple myeloma, this is a plasma cell dyscrasia causing an overproduction of monoclonal immunoglobulin light chains (A:K ratio of 3:l). The ratio of A to K light chains, however, is reversed from that seen in multiple mye10ma.l~Amino acid substitutions in the variable regions of these light chains may be responsible for the increased fibrill~genesis.'~ The clinical features of primary amyloidosis reflect organ involvement. Renal disease ranging from proteinuria to overt nephrotic syndrome is the most common initial 46*47 Approximately one quarpresentati~n.~~, ter of patients present with CHF symptoms and one sixth with orthostatic hypotension or 47 Macperipheral sensorimotor ne~ropathy.'~, roglossia, soft tissue masses, firm hepatomegaly, and easy bruisability support the diagnosis of primary amyloid~sis.'~ Although low ECG voltage, a pseudoinfarction pattern, and the echocardiographic features listed earlier suggest amyloidosis, their sensitivity and 16, 83 Mitral inflow patspecificity are terns may show only the classic restrictive pattern late in the disease; 10% to 20% of patients present with normal echocardiograms.I2 Normal Doppler studies in the elderly may actually represent the transition from a predominant A wave of diastolic dysfunction to a predominant E wave of a restrictive pathologic condition (see Fig. 2C).4"Amyloid is seen by light microscopy on 85% of abdominal subcutaneous aspiration, 50% of bone marrow specimens, and 80% of rectal biopsies.l7,47 Monoclonal immunoglobulin A or K light chains are present by immunoelectrophoresis and immunofixation in 90% of serum and urine of primary amyloid patients.15,17.46 The prognosis for primary amyloidosis is poor with a median survival of 1 to 2 years that plummets to 6 months in those patients presenting with CHF.12,15, l7 In contrast, patients with primarily renal or neural involvement can have a life span ranging from 21 to 52 months.I7Thirty percent to 50% of primary amyloid patients die from cardiac causes, including 33% from sudden death.41,83 Survival has been inversely associated with left ventricular thickness (2.4 years for mean wall thickness 5 12 mm versus 0.4 year for mean wall thickness 2 15 mm) and fractional shortening on echocardiogram.lZAn increased restrictive filling pattern, characterized by a shortened deceleration time and augmented

HYPERTROPHIC AND RESTRICTIVE CARDIOMYOPATHIES IN THE ELDERLY

early diastolic to atrial filling velocity ratio, reduces the probability of 1-year survival to 49% from 92% in patients without these Doppler changes.41 Symptomatic and supportive treatments are the mainstay of therapy for older patients with primary amyloidosis. Although diuretics can provide significant symptomatic improvement, they must be used with caution to avoid hypotension from diminished preload and forward flow. Electronic pacing of bradycardia may improve symptoms but does not alter prognosis.25Skinner et als2demonstrated an increase in survival from 6.7 months with colchicine alone to 12.2 months using alkylating agents (melphalan), prednisone, and colchicine (mean subject age, 62.7 years). Autologous stem cell infusion after alkylating agents has been shown to reduce the monoclonal gammopathy, but has little effect on existing infiltrative amy10id.l~Stem cell and bone marrow transplant data are lacking in the elderly.

169

loidosis depend on the specific mutation, but most patients present with a progressive, ascending peripheral sensorimotor neuropathy and autonomic compromise, such as orthostatic hypotension and gastrointestinal motility problems.5, 17, 25 In a series of 52 familial amyloidosis patients at the Mayo Clinic, 83% presented with peripheral neuropathy, 33% with autonomic insufficiency, and 26% with cardiac symptoms.25In contrast to primary amyloidosis, less than 10% of familial amyloidosis patients have renal manifestations, and macroglossia is not seen.25It is not possible to differentiate primary from familial amyloidosis based on echocardiographic and Doppler features.ls The ECG findings in familial amyloidosis are nonspecific and similar to those in primary amyloidosis with the exception of higher voltage in familial cases.15,2s, 30, 81 Once the diagnosis of amyloidosis has been made by biopsy, monoclonal immunoglobulins suggesting primary amyloidosis must be ruled out. In addition to a family history of the disorder, the specific diagnosis of familial amyloidosis is Familial Amyloidosis made by the identification of variant transAlthough the familial form of amyloidosis thyretin (or other altered protein) by isoelecaccounts for 10% of all amyloidosis, the imtric focusing and immunostaining the seportance of this autosomal dominant disorder rum.15. 17. 30 in older patients has recently been recogIt is important for the clinician to distinnized.h, 25, 34 Familial amyloidosis is caused guish familial from primary amyloidosis beby various mutations in genes altering their cause the former carries a more favorable protein expression to a fibrillogenic form. prognosis with a median survival of 5.8 Over 50 separate mutations have been discovyears.15,17, 25 Mortality is greatly increased in ered that lead to a spectrum of clinical disease patients presenting with signs of a cardiomywith varying morbidity and mortality5,6, 17, 25 opathy who have a mean survival of 3.4 years The most common familial amyloidogenic compared to 7 years in those without cardiac protein is the hepatically produced thyroxine compromise at diagnosis.2s Although the and retinol-binding protein, transthyretin. prognosis varies with the specific mutation, Despite a lifelong amino acid substitution, patients diagnosed in their later years have a there is a delay in phenotypic expression of better prognosis than younger patients. The amyloidosis with a median age at diagnosis best predictors of survival are age greater of 64 years; 44% of patients are diagnosed at than 60 years and isolated neural involve65 years of age or older.25,30 It has been proment.2s The most common cause of death in posed that some facet of the aging process familial amyloidosis is cardiac failure or ar”turns on” the pathologic expression of this rhythmias followed by i n a n i t i ~ n . ~ ~ There is a higher male prevalence Orthotopic liver transplantation has been of familial amyloidosis and fourfold increase in prevalence in older African-American~.~~shown to eradicate completely the hepatically synthesized abnormal transthyretin protein The specific transthyretin gene amino acid from the serum and improve the peripheral substitution isoleucine to valine at position neuropathy.15,17, 32 Older patients have not 122 is common in the African-American popbeen included in these trials to date; therapy ulation (3.9%carrier rate) and has been found remains supportive. The use of alkylating to be the most common cause of late-onset agents in these patients can be leukemogenic, restrictive cardiomyopathy in elderly AfricanAmerican patients.l7!33, 34, 57 underscoring the importance of differentiatThe clinical manifestations of familial amying primary from familial amyloidosis.25

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Summary

RCM should be considered in older patients with marked fluid retention, conduction abnormalities, and a normal to small left ventricular cavity with usually normal systolic function. In contrast to early diastolic relaxation impairment seen in hypertrophic disease, signs and symptoms of RCM are caused by compromise in late diastole. Although amyloid is a frequent finding in older hearts at autopsy, most deposits are confined to the atria and are of little clinical significance.3,y, 53 Of the pathologic types of amyloidosis, immunoglobulin light chain amyloid most commonly infiltrates the heart and carries the worst prognosis (although survival is slightly better in older than younger patients). Familial amyloidosis is an example of a genetic disease of late-onset phenotypic expression with growing importance in the elderly.17 Familial amyloidosis carries a more favorable prognosis stressing the significance of accurately diagnosing the type of amyloid by serum immunohistochemistry. The terms systemic senile amyloidosis and senile cardiac amyloidosis have been broadly used to describe the age-related increase in amyloid deposits, regardless of the protein subtype. Normal and genetically altered transthyretin have been identified as the protein precursors of these disorders, reclassifying them as a subset of familial amyloidosis. Symptomatic treatment with diuretics remains the goal of therapy with careful titration to avoid hypotension. Unresolved Issues

With the increased recognition of hypertrophic and restrictive cardiomyopathies as a cause of CHF in the elderly, many unanswered questions have surfaced. Specifically, the pathophysiology of HHC remains unclear as does its distinction from HOCM. Therapeutic options for HHC are currently anecdotal; treatment trials may reduce the frequency of flash pulmonary edema in patients with this disorder and thus improve quality of life and decrease recurrent hospitalizations. The newly recognized molecular basis for familial amyloidosis provides insight into screening, early recognition, and genetic therapy for this disease. In a broader sense, both HOCM and familial amyloidosis are paradigms of genetic conditions with delayed

phenotypic expression. These late penetrance disorders may help our understanding of the role of the aging process in gene regulation. References 1. Aurigemma GO, Gaasch WH: Gender differences in older patients with pressure-overload hypertrophy of the left ventricle. Cardiology 86:310-317, 1995 2. Backes RJ, Gersh BJ: Cardiomyopathies in the elderly. In Lowenthal DT (ed): Geriatric Cardiology. Philadelphia, FA Davis, 1992, p 105 3. Benjamin EJ, Levy D, Anderson KM, et al: Determinants of doppler indexes of left ventricular diastolic function in normal subjects (the Framingham Heart Study). Am J Cardiol 70:508-515, 1992 4. Benotti JR, Grossman W, Cohn P F Clinical profile of restrictive cardiomyopathy. Circulation 61:12061212, 1980 5. Benson MD: Familial amyloidosis. J Int Med 232:525527, 1992 6. Booth DR, Tan SY, Hawkins PN, et al: A novel variant of transthyretin, 59Thr'Ly', associated with autosomal dominant cardiac amyloidosis in an Italian family. Circulation 91:962-967, 1995 7. Brugada R, Roberts R The molecular genetics of arrhythmias and sudden death. Clin Cardiol 21:553560, 1998 8. Cannan CR, Reeder GS, Bailey KR, et al: Natural history of hypertrophic cardiomyopathy: A population-based study, 1976 through 1990. Circulation 92~2488-2495,1995 9. Chikamori T, Doi YL, Dickie S, et al: Comparison of clinical features in patients 2 60 years of age to those 5 40 years of age with hypertrophic cardiomyopathy. Am J Cardiol 66:875-878, 1990 10. Cohn JN, Johnson G: Heart failure with normal ejection fraction: the V-HeFT study. Circulation Rl(supp1 III):48-53, 1990 11. Cooper MM, McIntosh CL, Tucker E, et al: Operation for hypertrophic subaortic stenosis in the aged. Ann Thorac Surg 44:370, 1987 12. Cueto-Garcia L, Reeder GS, Kyle RA: Echocardiographic findings in systemic amyloidosis: Spectrum of cardiac involvement and relation to survival. J Am Coll Cardiol 6:737-743, 1985 13. Davies MJ: Hypertrophic cardiomyopathy: One disease or several? Br Heart J 63:263-264, 1990 14. Davies MJ, McKenna WJ: Hypertrophic cardiomyopathy: An introduction to pathology and pathogenesis. Br Heart J 72(suppl):S2-3, 1994 15. Dubrey SW, Cha K, Skinner M, et al: Familial and primary (AL) cardiac amyloidosis: Echocardiographically similar diseases with distinctly different clinical outcomes. Heart 78:74-82, 1997 16. Falk RH, Plehn JF, Deering T Sensitivity and specificity of the echocardiographic features of cardiac amyloidosis. Am J Cardiol 59:418422, 1987 17. Falk RH, Comenzo RL, Skinner M: The systemic amyloidoses. N Engl J Med 337898-909, 1997 18. Fananapazir L, Cannon RO, Tripodi D, et al: Impact of dual-chamber permanent pacing in patients with obstructive hypertrophic cardiomyopathy and symptoms refractory to verapamil and P-adrenergic blocker therapy. Circulation 85:2149-2161, 1992 19. Fananapazir L, Epstein ND, Curie1 RV, et al: Longterm results of dual-chamber (DDD) pacing in ob-

HYPERTROPHIC AND RESTRICTIVE CARDIOMYOPATHIES IN THE ELDERLY

20. 21.

22. 23. 24. 25.

26.

27. 28.

29. 30. 31. 32.

33.

34.

35. 36.

37.

38.

structive hypertrophic cardiomyopathy: Evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy. Circulation 90:2731-2742, 1994 Fananapazir L, Epstein ND: Prevalence of hypertrophic cardiomyopathy and limitations of screening methods. Circulation 92:700-704, 1995 Fay WP, Taliercio CP, Ilstrup DM, et a1 Natural history of hypertrophic cardiomyopathy in the elderly. J Am Coll Cardiol 16:821-826, 1990 Frohlich ED, Chobanian AV, Devereux RB, et al: The heart in hypertension. N Engl J Med 327:998-1008, 1992 Gerstenblith G, Fredericksen J, Yin FCP, et al: Echocardiographic assessment of a normal aging population. Circulation 56273-278, 1977 Gertz MA: Secondary amyloidosis (AA). J Int Med 232517-518, 1992 Gertz MA, Kyle RA, Thibodeau SN. Familial amyloidosis: Study of 52 North American-born patients examined during a 30-year period. Mayo Clin Proc 67428440,1992 Ghali JK, Kadakia S, Cooper RS, et al: Bedside diagnosis of preserved versus impaired left ventricular systolic function in heart failure. Am J Cardiol 67~1002-1006,1991 Glikson M, Hayes DL, Nishimura RA: Newer clinical applications of pacing. J Cardiovasc Electrophysiol 8:1190-1203, 1997 Gorevic I'D, Prelli FC, Wright J, et al: Systemic senile amyloidosis: Identification of a new prealbumin (tranthyretin) variant in cardiac tissue-immunologic and biochemical similarity to one form of familial amyloidotic polyneuropathy. J Clin Invest 83:836843, 1989 Hamby RI, Aintablian A: Hypertrophic subaortic stenosis is not rare in the eighth decade. Geriatrics 31~71-74,1976 Heese A, Altland K, Linke RP, et al: Cardiac amyloidosis: A review and report of a new transthyretin (prealbumin) variant. Br Heart J 70:111-115, 1993 Hodkinson HM, Pomerance A The clinical significance of senile cardiac amyloidosis: A prospective clinico-pathological study. QJM 77:381-387, 1977 Holmgren G, Ericzon BG, Groth CG: Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 341:1113-1116, 1993 Jacobson DR, Gorevic PD, Buxbaum JN: A homozygous transthyretin variant associated with senile systemic amyloidosis: Evidence for a late-onset disease of genetic etiology. Am J Hum Genet 47127-136,1990 Jacobson DR, Pastore RD, Yaghoubian R Variantsequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in Black Americans. N Engl J Med 336:466-473, 1997 Jeanrenaud X, Goy JJ, Kappenberger L: Effects of dual chamber pacing in hypertrophic obstructive cardiomyopathy. Lancet 339:1318-1323, 1992 Kappenberger L, Linde C, Daubert C, et al: Pacing in hypertrophic obstructive cardiomyopathy: A randomized crossover study. Eur Heart J 18:1249-1256, 1997 Karam R, Lever HM, Healy BP: Hypertensive hypertrophic cardiomyopathy or hypertrophic cardiomyopathy with hypertension? A study of 78 patients. J Am Coll Cardiol 13:580-584, 1989 Katritsis D, Wilmshurst PT, Wendon JA: Primary restrictive cardiomyopathy: Clinical and pathological characteristics. J Am Coll Cardiol 18:1230-1235, 1991

171

39. Kawamura S, Takahashi M, Ishihara T Incidence and distribution of isolated atrial amyloid: Histologic and immunohistochemical studies of 100 aging hearts. Pathol Int 45:335-342, 1995 40. Klein AL, Hatle LK, Burstow DJ: Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 13:1017-1026, 1989 41. Klein AL, Hatle LK, Taliercio CP: Prognostic significance of doppler measures of diastolic function in cardiac amyloid: A doppler echocardiographic study. Circulation 83:808-816, 1991 42. Koch JP, Maron BJ, Epstein SE, et al: Results of operation for obstructive hypertrophic cardiomyopathy in the elderly: Septa1 myotomy and myectomy in 20 patients 65 years of age or older. Am J Cardiol 46:963-966, 1980 43. Krasnow N, Stein RA: Hypertrophic cardiomyopathy in the aged. N Engl J Med 96:326-336, 1978 44. Krasnow N: An acquired disease component in hypertrophic cardiomyopathy: New clinical clarifications. J Am Coll Cardiol 13:4647, 1989 45. Kushwaha SS, Fallon JT, Fluster V Restrictive cardiomyopathy. N Engl J Med 336967-276, 1997 46. Kyle RA: Amyloidosis: minisymposium. J Int Med 232~507-508,1992 47. Kyle RA: Primary systemic amyloidosis. J Int Med 232~523-524, 1992 48. Kyle RA, Spitell PC, Gertz MA, et al: The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med 101:395400, 1996 49. Lakatta EG: Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 73:413467, 1993 50. Lever HM, Karam RF, Currie PJ, et al: Hypertrophic cardiomyopathy in the elderly: Distinctions from the young based on cardiac shape. Circulation 79:580589, 1989 51. Lewis JF, Maron BJ: Elderly patients with hypertrophic cardiomyopathy: A subset with distinctive left ventricular morphology and progressive clinical course late in life. J Am Coll Cardiol 13:36-45, 1989 52. Lewis JF, Maron BJ: Clinical and morphological expression of hypertrophic cardiomyopathy in patients 2 65 years of age. Am J Cardiol 73:1105-1111, 1994 53. Lie JT, Hammond PI: Pathology of the senescent heart: Anatomic observations on 237 autopsies of patients 90 to 105 years old. Mayo Clin Proc 63:552564, 1988 54. Longworth DL, Stoller J K An 81-year-old woman with dyspnea on exertion. Cleve Clin J Med 63209212, 1996 55. McCarthy RE, Kasper EK: A review of the amyloidosis that infiltrates the heart. Clin Cardiol21:547552, 1998 56. McKenna W, Deanfield J, Faruqui A, et al: Prognosis in hypertrophic cardiomyopathy: Role of age and clinical, electrocardiographic and hemodynamic features. Am J Cardiol47:532-538, 1981 57. Nichols WC, Liepnieks JJ, Snyder EL, et al: Senile cardiac amyloidosis associated with homozygosity for a transthyretin variant (ILE-122).J Lab Clin Med 117:175-180, 1990 58. Niimura H, Bachinski LL, Sangwatanaroj S, et al: Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 338:1248-1257, 1998 59. Nishimura RA, Hayes DL, Ilstrup DM, et al: Effect of dual-chamber pacing on systolic and diastolic function in patients with hypertrophic cardiomyopathy: Acute doppler echocardiography and catheter-

172

ZIEMAN & FORTUIN

ization hemodynamic study. J Am Coll Cardiol 27:421430, 1996 60. Nishimura RA, Symanski JD, Hurrell DG, et al: Dualchamber pacing for cardiomyopathies: A 1996 clinical perspective. Mayo Clin Proc 71:1077-1087, 1996 61. Nishimura RA, Trusty JM, Hayes DL, et al: Dualchamber pacing for hypertrophic cardiomyopathy: A randomized, double-blind, crossover trial. J Am Coll Cardiol 29:435441, 1997 62. Nomenclature of amyloid and amyloidosis. WHOIUIS Nomenclature Sub-Committee. Bull WHO 71:105-108, 1993 63. Olson LJ, Gertz MA, Edwards WD, et al: Senile cardiac amyloidosis with myocardial dysfunction: Diagnosis by endomyocardial biopsy and immunohistochemistry. N Engl J Med 317738-742, 1987 64. Pai RG, Shah I'M: Echo-Doppler evaluation of left ventricular diastolic function. ACC Curr J Rev 3033, 1994 65. Pearson AC, Gudipati C, Nagelhout D, et al: Echocardiographic evaluation of cardiac structure and function in elderly subjects with isolated systolic hypertension. J Am Coll Cardiol 17422430, 1991 66. Petrin TJ, Tavel ME: Idiopathic hypertrophic subaortic stenosis as observed in a large community hospital: Relation to age and history of hypertension. J Am Geriatr SOC274346, 1979 67. Pitkanen P, Westermark P, Corneill GG: Senile systemic amyloidosis. Am J Pathol 117391-399, 1984 68. Pomerance A: Pathology of the heart with and without cardiac failure in the aged. Br Heart J 27697710, 1965 69. Pomerance A, Davies MJ: Pathological features of hypertrophic obstructive cardiomyopathy (HOCM) in the elderly. Br Heart J 37305-312, 1975 70. Rich MW: Congestive heart failure in older adults. J Am Geriatr SOC45:968-974, 1997 71. Sagie A, Benjamin EJ, Galderisi M, et al: Echocardiographic assessment of left ventricular structure and diastolic filling in elderly subjects with borderline isolated systolic hypertension (the Framingham Heart Study). Am J Cardiol 726624365, 1993 72. Sanders CA, Austen WG, Jordan JC: Idiopathic hypertrophic subaortic stenosis in two elderly siblings. N Engl J Med 274:1254-1256,1966 73. Saraiva MJM, Almeida MdR, Sherman W, et al: A new transthyretin mutation associated with amyloid cardiomyopathy. Am J Hum Genet 50:1027-1030, 1992 74. Schulman SP, Weiss JL, Becker LC, et al: The effects of antihypertensive therapy on left ventricular mass in elderly patients. N Engl J Med 322:1350-1356, 1990 75. Schwartz K, Carrier L, Guicheney P, et al: Molecular basis of familial cardiomyopathies. Circulation 91~532-540,1995 76. Seiler C, Hess OM, Schoenbeck M, et al: Long-term follow-up of medical versus surgical therapy for hypertrophic cardiomyopathy: A retrospective study. J Am Coll Cardiol 17634-642, 1991 77. Shah PM, Adelman AG, Wigle ED, et al: The natural (and unnatural) history of hypertrophic obstructive cardiomyopathy: A multicenter trial. Circ Res ~ ~ ( S U PII):179-195, P~ 1974

78. Shapiro LM: Hypertrophic cardiomyopathy in the elderly. Br Heart J 63265-266, 1990 79. Shenoy MM, Khanna A, Nejat M, et al: Hypertrophic cardiomyopathy in the elderly: A frequently misdiagnosed disease. Arch Intern Med 146:6584561, 1986 80. Siege1 RJ, Shah PK, Fishbein MD: Idiopathic restrictive cardiomyopathy. Circulation 70:165-169, 1984 81. Simons M, Isner JM: Assessment of relative sensitivities of noninvasive tests for cardiac amyloidosis in documented cardiac amyloidosis. Am J Cardiol 69:425427, 1992 82. Skinner M, Anderson JJ, Simms R: Treatment of 100 patients with primary amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med 100:290-297, 1996 83. Smith TJ, Lie J T Clinical significance of histopathological patterns of cardiac amyloidosis. Mayo Clin Proc 59:547-555, 1984 84. Spirito P, Bellone P: Natural history of hypertrophic cardiomyopathy. Br Heart J 72(suppl):S10-12, 1994 85. Spirito P, Maron BJ: Absence of progression of left ventricular hypertrophy in adult patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 9:10131017, 1987 86. Topol EJ, Trail1 TA, Fortuin NJ: Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 312~277-283,1985 87. Tresch DD, McGough MF: Heart failure with normal systolic function: A common disorder in older people. J Am Geriatr SOC43:1035-1042, 1995 88. Tskeda A, Takeda N Different pathophysiology of cardiac hypertrophy in hypertension and hypertrophic cardiomyopathy. J Mol Cell Cardiol 2999612965, 1997 89. Vasan RS, Benjamin EJ, Levy D. Congestive heart failure with normal left ventricular systolic function. Arch Intern Med 156:146-157, 1996 90. Wadehra D, Gunnar RM, Scanlon PJ: Prognosis in hypertrophic cardiomyopathy with asymmetric septal hypertrophy. Postgrad Med J 61:1107-1109, 1985 91. Waller BF, Roberts WC: Cardiovascular disease in the very elderly: Analysis of 40 necropsy patients aged 90 years or over. Am J Cardiol 51:403-421, 1983 92. Watkins H: Multiple disease genes cause hypertrophic cardiomyopathy. Br Heart J 72(suppl):S4-9,1994 93. Westermark P, Sletten K, Johansson 8, et al: Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci U S A 8728432845, 1990 94. Whiting RB, Powell WJ, Dinsmore RE, et al: Idiopathic hypertrophic subaortic stenosis in the elderly. N Engl J Med 285:196-200, 1971 95. Wigle ED, Rakowski H, Kimball BP, et al: Hypertrophic cardiomyopathy: Clinical spectrum and treatment. Circulation 92:1680-1692, 1995 96. Wright JR, Calkins E, Breen WJ: Relationship of amyloid to aging; Review of the literature and systematic study of 83 patients derived from a general hospital population. Medicine 48:39450, 1969 97. Wright JR, Calkins E: Amyloid in the aged heart: Frequency and clinical significance. Am J Geriatr 23~97-103, 1975 Address reprint requests to Nicholas J. Fortuin, MD Johns Hopkins at Greenspring Station 10755 Falls Road, Suite 320 Lutherville, MD 21093