Improvement in hypertrophic cardiomyopathy after significant weight loss: case report. (Case Report).

Abstract

A 17-year-old obese boy found to have familial apical hypertrophic cardiomyopathy on routine screening was enrolled in a weight loss program on the basis of the hypothesis that significant weight loss would improve his cardiac status. He was followed with serial dual-energy x-ray absorptiometry, electrocardiography, echocardiography, and blood pressure and pulse rate measurements. Within 1 year, he lost 49 kg, with a body mass index reduction from 43.6 to 28.1 kg/[m.sup.2] and associated reductions in systolic blood pressure, diastolic blood pressure, pulse pressure, mean heart rate, rate pressure product, and echocardiographic indices of left ventricular mass that resulted in a change from the initial geometric finding of eccentric left ventricular hypertrophy to a "normal" left ventricular mass with minimal asymmetric apical left ventricular thickening. Significant weight loss in an obese adolescent with presumed familial apical hypertrophic cardiomyopathy was associated with striking improvement in cardiac functional indices, which could have profound implications for long-term cardiovascular risk.

Key Words: cardiac hypertrophy, hypertrophic cardiomyopathy, hypertension, obesity, weight loss

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Obesity has become the most prevalent chronic medical condition in developed countries. Among the known comorbidities associated with obesity are hypertensive heart disease, cor pulmonale associated with the pickwickian syndrome, coronary heart disease, and obesity-associated cardiomyopathy. (1,2) These are associated with increased cardiac morbidity and mortality, which may be attributable to heart failure, myocardial infarction, sudden cardiac death, and/or malignant arrhythmia. (1) Obesity may also exacerbate other forms of cardiomyopathy, including the familial hypertrophic cardiomyopathies. The familial hypertrophic cardiomyopathies were previously thought to be uncommon but are now known to be more prevalent, particularly in black male patients such as our patient. (3) This cardiomyopathy has a significant association with sudden cardiac death, especially in younger patients. (3) Some reports suggest a prevalence of up to 0.2% in young adults screened using echocardiography. (4,5)

The hypertrophic variants may be obstructive or nonobstructive. (Even the so-called nonobstructive variants can have obstructive physiology in settings such as Valsalva maneuver and dehydration, and with posture changes, isometric exercise, and/or sympathomimetic medications.) Treatment modalities include [beta]-blockade and/or calcium channel blockade, pacemaker use, surgical treatment, and other experimental methods. (6) We present the case of a 17-year-old, obese, asymptomatic adolescent who was found, during an evaluation for inclusion in a weight loss program, to have findings consistent with familial apical hypertrophic cardiomyopathy (FAHCM). His physiologic and hemodynamic findings were most consistent with the midcavity obstructive variant because of observed apposition of the interventricular septum with the free wall and papillary muscles during systole. The significant improvement observed in left ventricular mass and other cardiac functional indices during a 1-year period in which this patient lo st 49 kg highlights the importance of obesity's contribution to cardiomyopathy severity, even in familial variants, and also the central role that weight loss may play in the management of such patients.

Results

The patient lost a large amount of weight (49 kg) (Table 1), with concomitant reductions in body mass index and body fat measured on dual-energy x-ray absorptiometric scans (Hologic QDR 4500A; Hologic, Inc., Bedford, MA) obtained during the study period. Cardiovascular vital signs obtained during the first month of treatment were also significantly improved compared with those obtained 1 year later (Table 1). The patient had Stage 1 isolated systolic hypertension according to Joint National Committee VI criteria at the start of the program, but this condition resolved by the end of the study period.

The baseline echocardiogram showed a nondilated hyperdynamic left ventricle with asymmetric left ventricular hypertrophy, no systolic anterior motion of the mitral valve, hypertrophy restricted to the left ventricular apex, and mid-ventricular apposition of the septum with papillary muscles and free wall. There was also color Doppler sonographic evidence of mild mitral and tricuspid regurgitation. These findings were noted to be virtually pathognomonic of familial hypertrophic cardiomyopathy. (10) The echocardiogram obtained at the 1-year follow-up examination showed essentially similar observations, with changed dimensions. The cardiac dimensions, echocardiographic derived mass, volume and functional indices, and color Doppler flow measurements obtained from both studies are shown in Table 2. Whether computed on the basis of the thin model or the thick model, and whether indexed by body surface area (LVMI) or by height (LVMIH), there was a clinically significant reduction in the LVM. In addition, the left ve ntricular internal and external volumes and the left ventricular myocardial volume were reduced significantly. The ratio of left ventricular internal to external volumes was found to be reduced significantly compared with established norms for hypertensive patients (0.85 [+ or -] 0.02), consistent with the patient's hypertrophic cardiomyopathy and an associated restrictive cardiopathic pattern.

Discussion

This case suggests that even for patients with FAHCM, which is a primarily genetic disease, weight reduction in the obese adolescent can be associated with profound improvement in cardiac functional indices. The patient's clinical, electrocardiographic, and echocardiographic findings were virtually pathognomonic of familial hypertrophic cardiomyopathy, (10) with features most consistent with the midcavity obstructive variant. (6) There also are reports of a distinct apical variant more common in Japanese patients that bears similarity to the findings in our index case. (10,11)

Although poorly characterized, there is evidence distinct obesity-associated cardiomyopathy characterized left ventricular restrictive dysfunction that improves marked weight loss associated with bariatric surgery or effective weight loss strategies. (2,9,12) Unlike the findings our patient, however, most reports of this entity suggest that it is associated most typically with eccentric left ventricular hypertrophy and consequent diastolic (12-15) Obesity-associated cardiomyopathy is described as having a greater effect on the interventricular septum than on the left ventricular apex. (16) Concentric hypertrophy has been observed almost exclusively in the setting of coexisting hypertension. (17) Obesity-associated cardiomyopathy may rarely present as dilated cardiomyopathy with a worse prognosis. (16) Obesity-associated cardiomyopathy could coexist with FAHCM in patients such as ours and thus might explain some of the observed improvements in our patient. (18)

Although the exact pathophysiology of obesity-related cardiomyopathy is unclear, the increased epicardial fat and associated fatty infiltration into myocardial cells often found in these patients suggest the possibility of a "lipotoxic" phenomenon possibly related to excess ceramide production with secondary parenchymal cell apoptosis, as described in other tissues, including the pancreatic [beta] cell and muscle. (19)

Our patient had isolated systolic hypertension before weight loss initiation and thus could have had a component of hypertensive heart disease superimposed on FAHCM. Black patients such as ours with hypertension have an even higher prevalence of hypertension-related left ventricular hypertrophy. (20) The recognition of the potential for this coexisting condition in such patients is vital, because left ventricular hypertrophy secondary to hypertension is treatable with antihypertensive medication and/or with weight loss in a patient with comorbid obesity. (21)

Rarely, fatty infiltration of the cardiac myofibers may result in cardiac dysfunction. This condition, called adipositas cordis, most commonly presents as a restrictive or hypertrophic cardiomyopathy with selective interventricular septal thickening, but occasionally it may be associated with dilated cardiomyopathy as well. (22-24) Without performing endomyocardial biopsy, making a definitive premortem diagnosis of this entity is impossible.

The marked weight loss that our patient achieved had the expected multisystemic effects reported to be associated with marked weight loss, including significant improvement in both systolic and diastolic blood pressure. Furthermore, pulse pressure, which has been identified as a distinct cardiac risk factor, was significantly reduced, (25) as was the rate pressure product (i.e., an index of sympathetic cardiac activity and a surrogate of myocardial oxygen demand). (26) The cardiac dynamics required to achieve a static estimated ejection fraction changed during the study period, even though the ejection fraction remained similar throughout that time. The heart rate and midventricular peak gradient decreased, as did the left ventricular mass, left ventricular volume, and left ventricular fractional shortening. Consonant with the patient's weight and fat mass losses, his overall cardiac function improved, with maintenance of normal systolic function at a lower myocardial mass, lower myocardial oxygen demand, and more efficient muscle contractility.

Although obesity is common, reports of its association or coexistence with familial hypertrophic cardiomyopathies are scant in the literature. Smahel and Gregor's (27) cohort is probably the largest reported group in which the findings of obesity and increased abdominal girth are mentioned. There is an isolated report in the literature of an obese patient with pickwickian syndrome and hypertrophic cardiomopathy. (28) This paucity of information, however, probably does not mean that the association is uncommon, because the prevalence of obesity is great. The benefits associated with weight loss in our patient suggest that in evaluating patients with this rare familial cardiomyopathy, physicians should not lose sight of this potentially modifiable cardiac risk factor, the amelioration of which can have salutary effects on cardiac structure, physiologic function, and possibly long-term cardiac risk. (18,29)

Limitations

Although the cardiac findings observed in our patient are compelling, it is important to be aware that the models used to estimate cardiac mass on the basis of the echocardiographic data are derived from mathematical geometric models that are limited, particularly in scenarios of asymmetric cardiac enlargement observed in FAHCM. (7) Model-based echocardiographic measures have been shown to underestimate significantly the prevalence of left ventricular hypertrophy, particularly among patients with hypertension (30) Furthermore, the functional indices derived from color Doppler and echocardiographic studies are also potentially error-prone and not as accurate as radionuclide or right heart catheterization studies. Although the epidemiologic and echocardiographic findings were typical and virtually diagnostic of FAHCM, the absence of a significant family history of sudden cardiac death and the absence of a definitive genetic diagnosis does raise the possibility of the findings' being entirely attributable to ob esity rather than to a primary familial cardiomyopathy.

Conclusions

On the basis of our findings, it seems that in patients with familial hypertrophic cardiomyopathy who are obese, weight loss can have significant beneficial anatomic and physiologic effects that result in improved cardiac contractility, reduction in cardiac hypertrophy, and reduction in myocardial oxygen demand. This benefit could potentially result in significant long-term improvement in cardiac risk in this subgroup of patients. We think that significant, sustained weight loss should be included as one of the multimodal initial management strategies in this subgroup of patients.

Table 1

Vital signs and characteristics of an obese patient with familial
hypertrophic cardiomyopathy (a)

Parameter                             Baseline (b)

Weight (kg)                        137.9 [+ or -] 5.4
Height (m)                          1.78 [+ or -] 0.6
Body mass index (kg/[m.sup.2])      43.6 [+ or -] 3.1
DXA fat mass (kg)                         46.3
DXA lean mass (kg)                        87.8
Mean heart rate (beats/min)          87 [+ or -] 2.6
Mean SBP (mm Hg)                    147 [+ or -] 8.3
Mean DBP (mm Hg)                    68.2 [+ or -] 8.7
Pulse pressure (mm Hg)              80.8 [+ or -] 7.8
Mean arterial pressure (mm Hg)      93.1 [+ or -] 7.7
Mean blood pressure (mm Hg)        115.2 [+ or -] 10.5
Rate pressure product (mm Hg/min)  12,800 [+ or -] 942

Parameter                                 1 yr

Weight (kg)                         88.9 [+ or -] 14
Height (m)                         1.79 [+ or -] 1.3
Body mass index (kg/[m.sup.2])     28.1 [+ or -] 5.4
DXA fat mass (kg)                         11.6
DXA lean mass (kg)                        75.1
Mean heart rate (beats/min)         63 [+ or -] 1.7
Mean SBP (mm Hg)                   118 [+ or -] 13.9
Mean DBP (mm Hg)                     65 [+ or -] 3
Pulse pressure (mm Hg)             56.3 [+ or -] 14.6
Mean arterial pressure (mm Hg)      80.4 [+ or -] 5
Mean blood pressure (mm Hg)         101 [+ or -] 5.6
Rate pressure product (mm Hg/min)  7,426 [+ or -] 462

(a)DXA, dual-energy x-ray absorptiometry.

(b)Mean values at baseline are averages of data obtained during first 4
weeks of weight reduction program and values obtained at 1 year are
averages of data obtained during the last 4 weeks of the program.

Table 2

Echocardiographic cardiac dimensions, Doppler flow indices, and mass,
volume, and functional indices (a)

Parameter                                Baseline      1 yr

Aortic diameter (mm) (20-37)               29          29
Left atrium diameter (mm) (19-40)          42          39
Left ventricle internal diastolic          50          46
 diameter (mm) (37-56)
Left ventricle internal systolic           29          30
 diameter (mm)
Diastolic ventricular septal thickness     11           9
 (mm) (6-11)
Diastolic left ventricular posterior       11          11
 wall thickness (mm) (6-11)
Midventricular Doppler flow velocity       3            2
 (m/s)
Midventricular peak gradient (mm Hg)      36           16
LVM (thick-wall model) (g)               244.5        157
LVMI (thick-wall model) (g)               98           76
LVM indexed for height, thick wall       137.5         88.2
 model (g/m)
LvIV (ml)                                130.9        101.9
LvEV (ml)                                390.8        274.5
LvMV (ml)                                259.9        172.6
P (LvIV/LvEV)                              0.34         0.37
Lvfs (%)                                  42           34.8
Left ventricular hypertrophy              Yes           No
Left ventricular geometry                Eccentric   "Normal"
                                        hypertrophy
Cardiac output (L/min)                    11.4          6.4
Cardiac index (L/min/[m.sup.2])            4.56         3.09
Total peripheral resistance                0.66         1.03
 (dynes * s * [cm.sup.-5])

(a)LVM, left ventricular mass; LVMI, LVM index; LvIV, left ventricular
internal volume; LvEV. left ventricular external volume; Lvfs. left
ventricular fractional shortening; LvMV. left ventricular myocardial
volume.

Acknowledgments

We thank the nursing staff of both Ward 9 West and the 9 West Day Hospital for assistance in inpatient care and outpatient follow-up of our patient.

Accepted August 13, 2002.

References

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(18.) Alpert MA. Management of obesity cardiomyopathy. Am J Med Sci 2001;321:237--241.

(19.) Unger RH. Lipotoxic diseases. Annu Rev Med 2002;53:319--336.

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RELATED ARTICLE: Key Points

* Obesity (particularly marked obesity with body mass index >40 kg/[m.sup.2]) is associated with increased risk for various comorbidities associated with increased cardiac morbidity and mortality.

* Obesity is associated with a distinct "cardiomyopathy" distinct from the effects related to its well-known and more common comorbidities, such as essential hypertension, diabetes mellitus type 2, and cor pulmonale.

* The presentation of even primarily genetic diseases such as the familial hypertrophic cardiomyopathies is modulated and modified by secondary diseases such as obesity and essential hypertension.

* Effective management of coexisting comorbidities such as essential hypertension and obesity may have a positive clinical effect and might improve the clinical course of patients with familial hypertrophic cardiomyopathy.

Case Report

A 17-year-old, otherwise healthy black male was evaluated for possible inclusion in a randomized, double-blind, placebo-controlled trial in which a weight loss program was being conducted to evaluate the safety and efficacy of orlistat (Xenical; Roche Laboratories, Inc., Nutley, NJ). The Institutional Review Board of the National Institute of Child Health and Human Development approved the protocol, and both parental and patient consent were obtained before enrollment. The patient's medical history was significant for obesity in both parents and a half-sister. His mother had diabetes mellitus type 2 and hypertension, but there was no family history of sudden cardiac death or other cardiac problems. The patient's vital signs at the initial evaluation were within normal limits, with the exception of mild systolic hypertension (blood pressure, 147/68 mm Hg). The clinical examination was significant for widespread acanthosis nigricans and mild lipomas, as was the cardiac examination. The patient's heart sounds we re normal, with a physiologic split of the second heart sound but no murmurs or other added sounds. The electrocardiogram (Fig. 1) revealed abnormalities that were diagnosed as FAHCM on the basis of further transthoracic echocardiography.

In consultation with cardiologists, it was decided to allow the patient to commence the weight loss program with strict advice to avoid competitive, exhausting, isometric, and/or isotonic exercise. The patient was treated according to the study protocol and was administered randomized medication for 6 months, followed by 6 months of open-label orlistat. Roche Pharmaceuticals, Inc., supplied orlistat and placebo under a materials transfer agreement. Echocardiography was performed with the use of the Acuson 2D Sequoia probe (Siemens AG, Mountain View, CA), and color Doppler sonography was performed in the left lateral decubitus position from the left parastemal window. Estimates of left ventricular mass (LVM) were made according to the American Society of Echocardiography standard thin-wall (after Devereux and Alonso) and thick-wall (after Devereux and Reichek) models. The various wall thicknesses were measured according to the Penn measurement conventions. (7) The LVM index (LVMI) was derived from body surface area and height indexation. (8) The left ventricular internal, external, and myocardial volume, (7) as well as cardiac output and total peripheral resistance, (9) also were estimated. The P value was computed as the ratio of left ventricular internal and external volumes and is an index of left ventricular compliance. (7) Left ventricular fractional shortening was also estimated as described previously. (9)

From the Developmental Endocrinology Branch and the Pharmacy Department, National Institute of Child Health and Human Development, and the Department of Rehabilitation Medicine, National Institutes of Health, Bethesda, MD.

Reprint requests to Gabriel I. Uwaifo, MD, MedStar Research institute, Suite 50, 650 Pennsylvania Avenue, SE, Washington, DC 20003. Email: [e-mail]

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