Cardiac transplantation is a treatment option for patients with hypertrophic cardiomyopathy (HC) who developed refractory heart failure and/or intractable arrhythmia. However, the pretransplant characteristics and post-transplant prognosis for patients with nondilated idiopathic HC has not yet fully elucidated. Therefore, we retrospectively reviewed 813 consecutive transplant recipients undergoing cardiac transplantation at Columbia University Medical Center from 1999 to 2010 and compared the clinical course of 41 patients with idiopathic HC with that of 373 patients with ischemic heart disease and 398 patients with other heart disease. The patients with HC were younger than those with ischemic heart disease (47.8 ± 14.0 vs 57.1 ± 9.4 years; p <0.0001). The proportion of patients undergoing ventricular assist devise surgery for bridge-to-transplant was lower in patients with HC than in those with ischemic heart disease or other heart disease (14.6% vs 31.1% vs 35.7%, all p <0.01). The post-transplant survival of those with HC was better than that for those with ischemic heart disease (90.1% vs 85.8% and 83.9% vs 67.1% at 1 and 5 years, respectively; p = 0.0359), although it was not significantly different from those with other heart disease. Proportional hazards analysis revealed that the subjects with HC had reduced post-transplant mortality (hazard ratio 0.4760, 95% confidential interval 0.1889 to 0.9762; p = 0.042) on univariate, but not multivariate, analysis. Most patients with HC had nondilated left ventricles (left ventricular end-diastolic dimension ≤55 mm; n = 27), and post-transplant survival did not differ from that for those with dilated left ventricles (left ventricular end-diastolic dimension >55 mm; n = 14). In conclusion, the post-transplant survival of those with HC did not differ from those of the subjects who underwent transplant for other non-HC indications.
Heart transplantation is a treatment option for patients with hypertrophic cardiomyopathy (HC) who have developed refractory heart failure and/or life-threatening arrhythmia unresponsive to medical therapy. Several reports have been published regarding cardiac transplantation in patients with HC; however, most of the reports were restricted to a small number of patients at a single transplant center or had included only pediatric cases. Recently, Maron et al reported on survival after heart transplantation using the United Network of Organ Sharing (UNOS) Thoracic Registry database. The diagnosis of HC in their study was according to the pretransplant diagnostic code listed in the Heart Transplant Recipient Registration Form of the UNOS database; therefore, detailed pretransplant clinical information was not available. The definition of HC is a disease state characterized by unexplained left ventricular (LV) hypertrophy associated with nondilated ventricular chambers in the absence of another cardiac or systemic disease that itself would be capable of producing the magnitude of hypertrophy. The differential diagnosis of HC included hypertensive heart disease and the physiologic remodeling associated with athletic training and metabolic or infiltrative storage disorders causing LV hypertrophy. It is difficult to differentiate nonobstructive HC from hypertensive LV hypertrophy in some patients, because the phenotypes of each condition can overlap. Therefore, detailed pretransplant information is essential to definitively establish the diagnosis of HC. Accordingly, we retrospectively evaluated the clinical outcome of transplant recipients with nondilated idiopathic HC, whose diagnosis of HC had been determined by from the clinical and histologic findings of the explanted hear. These patients had undergone cardiac transplantation at Columbia University Medical Center (New York, New York). We compared their findings with those from patients with ischemic heart disease or other reasons for heart failure.
Methods
The institutional review board of Columbia University approved the data collection protocol. The protocol complied with the Health Insurance Portability and Accountability Act and all ethical guidelines outlined by the 1975 Declaration of Helsinki.
We retrospectively reviewed 813 patients (629 men and 184 women) who had undergone de novo heart-only transplantation at Columbia University Medical Center from 1999 to 2010. The patients who had undergone repeat transplantation or multiple organ transplantation were excluded from the present analysis. The patients were classified into 3 groups: those with nondilated idiopathic HC, those with ischemic heart disease, and those with another cause of heart failure as the reason for transplantation. The diagnosis of nondilated idiopathic HC was determined by conventional echocardiographic demonstration of a hypertrophic left ventricle in the absence of other cardiac or systemic diseases that might lead to LV hypertrophy. It was confirmed by the histologic findings of myocyte disarray on the explanted heart with exclusion of any storage diseases that can mimic HC in the explanted heart at transplantation. A nondilated hypertrophic left ventricle in the present study was defined as echocardiographic measurements of the LV end-diastolic dimension (LVEDD) <55 mm and LV wall thickness >15 mm at their initial echocardiogram performed at our institution. Myocyte disarray was defined as bundles of myocytes that were oriented perpendicularly or obliquely to each other or were interspersed in different directions. Patients with a long-term history of hypertension (systolic blood pressure >150 mm Hg or diastolic blood pressure >90 mm Hg, or both, for ≥3 years as determined from the medical chart) or aortic stenosis were not categorized as having HC in the present study. The pretransplant clinical characteristics of the patients and laboratory examination findings were obtained from a clinical database. For patients with multiple laboratory measurements before transplantation, the results obtained closest to the date of transplantation were used for the present study. The pretransplant clinical characteristics reviewed in the present study included age, gender, UNOS status, race, body mass index, blood type, with or without an LV assist device, a history of diabetes, renal dysfunction, stroke and peripheral vascular disease, smoking history, and serology of cytomegalovirus (CMV) at transplantation. Donor-related/perioperative information, including donor age, gender, CMV mismatch (serology-positive donor to serology-negative recipient), and ischemic time, was also obtained. Pre-transplant and donor-related characteristics and post-transplant survival were compared among the groups. For patients with HC, the presence or absence of the recurrence of myocyte hypertrophy in their transplanted heart was evaluated using the most recent endomyocardial biopsy specimens obtained for the purpose of rejection surveillance or using the specimen obtained from autopsy for patients who died after transplantation. The post-transplant rejection profiles of those with HC were also investigated. Acute rejection was graded according to the revised International Society of Heart and Lung Transplantation criteria. Antibody-mediated rejection was defined as positive attainment of C4d at the capillary in the biopsy specimen with or without hemodynamic deterioration. As a subanalysis, patients with HC were divided into 2 groups: those with a dilated left ventricle (LVEDD >55 mm) and those with a nondilated left ventricle (LVEDD ≤55 mm) on the echocardiogram at the time of listing. The echocardiographic data within 1 month before transplantation were also obtained for both subgroups.
The data are presented as the mean ± SD and frequency (percentages). Normality was evaluated for each variable on the basis of the normal distribution plots and histograms and using the Kolmogorov-Smirnov test. Analysis of variance, with a post hoc test for multiple comparisons, was used to assess the differences among the groups. Student’s unpaired t test was used to compare the variables between those with HC with preserved ejection fraction and those with decreased ejection fraction. Categorical variables are compared using chi-square test. A p value of <0.05 was considered statistically significant. A Cox proportional hazards models was used to assess the impact of pre- and peri-operative factors on mortality after transplant. Variables that achieved statistical significance in the univariate analysis were subsequently included in a multivariate analysis. Survival after transplant was compared using Kaplan-Meier methods with log-rank test. All statistical analyses were performed using JMP, version 7.0, software (SAS Institute, Cary, North Carolina).
Results
Of the 812 patients, 41 (5.0%) underwent transplantation for HC, 373 (45.9%) for ischemic heart disease, and 398 (49.0%) for another cause of heart failure. The pretransplant clinical characteristics, laboratory variables, and donor-related information are summarized in Table 1 . Of the 41 patients with HC, 10 (24.4%) had a family history of HC and 19 (46.3%) had an implantable cardioverter defibrillator. The indication for transplantation for those with HC was refractory heart failure in 39 patients (95.1%) and recurrent malignant arrhythmias associated with continuous implantable cardioverter defibrillator firing in 2 patients (4.9%).
| Variable | HC (n = 41) | IHD (n = 373) | Other-HD (n = 398) | p Value |
|---|---|---|---|---|
| Preoperative information | ||||
| Age at transplant (years) | 47.8 ± 14.0 | 57.1 ± 9.4 ⁎ | 49.7 ± 13.2 | <0.0001 |
| Men | 22 (54%) | 324 (86.9%) ⁎ | 282 (70.9%) † | <0.0001 |
| White | 33 (81%) | 249 (66.7%) | 219 (55.0%) ‡ | 0.0001 |
| Body mass index (kg/m 2 ) | 25.7 ± 4.5 | 26.0 ± 4.6 | 26.2 ± 5.2 | 0.7486 |
| United Network of Organ Sharing Status (1A) | 17 (42%) | 147 (39.4%) | 148 (37.3%) | 0.7411 |
| Left ventricular assist device | 6 (15%) | 116 (31.1%) † | 142 (35.7%) ‡ | 0.0088 |
| Diabetes | 4 (10%) | 127 (34.1%) § | 98 (24.6%) † | 0.0002 |
| Chronic kidney disease (stage 3 or worse) | 3 (7%) | 57 (15.3%) | 75 (18.8%) † | 0.0828 |
| Stroke | 6 (15%) | 40 (10.7%) | 49 (12.3%) | 0.6387 |
| Peripheral vascular disease | 3 (7%) | 25 (6.7%) | 16 (4.1%) | 0.2808 |
| Smoking | 5 (12%) | 169 (45.4%) ⁎ | 108 (27.2%) † | <0.0001 |
| Cytomegalovirus serology (positive) | 16 (39%) | 238 (64.7%) ‡ | 229 (60.1%) † | 0.0239 |
| Waiting time (days) | 282.6 ± 324.6 | 179.8 ± 171.6 † | 196.4 ± 294.7 | 0.0146 |
| Albumin (mg/dl) | 4.0 ± 0.6 | 3.9 ± 0.6 | 3.9 ± 0.6 | 0.7324 |
| Sodium (mEq/L) | 137.1 ± 6.9 | 137.3 ± 7.6 | 137.7 ± 7.0 | 0.7431 |
| Potassium (mEq/L) | 4.1 ± 0.6 | 4.3 ± 0.5 | 4.3 ± 0.5 | 0.1168 |
| Blood urea nitrogen (mg/dl) | 27.4 ± 14.0 | 31.1 ± 17.0 | 27.7 ± 14.3 | 0.0077 |
| Creatinine (mg/dl) | 1.2 ± 0.4 | 1.5 ± 0.7 † | 1.3 ± 0.8 | 0.0318 |
| Total bilirubin (mg/dl) | 1.3 ± 0.8 | 1.2 ± 1.0 | 1.2 ± 1.1 | 0.5315 |
| Direct bilirubin (mg/dl) | 0.4 ± 0.4 | 0.4 ± 0.4 | 0.4 ± 0.5 | 0.3263 |
| Aspartate aminotransferase (IU/L) | 36.7 ± 20.0 | 30.6 ± 23.8 | 38.7 ± 77.5 | 0.1347 |
| Alanine aminotransferase (IU/L) | 31.1 ± 27.6 | 30.9 ± 37.1 | 34.3 ± 66.1 | 0.6668 |
| Total cholesterol (mg/dl) | 147.3 ± 40.7 | 143.5 ± 45.8 | 147.2 ± 50.3 | 0.555 43 |
| Triglyceride (mg/dl) | 107.2 ± 41.3 | 125.7 ± 65.7 | 124.5 ± 65.7 | 0.2211 |
| Hematocrit (%) | 37.6 ± 5.3 | 35.6 ± 5.7 † | 36.7 ± 6.1 | 0.0062 |
| Mean pulmonary artery pressure (mm Hg) | 28.8 ± 9.1 | 29.4 ± 8.8 | 26.4 ± 7.9 | 0.735 |
| Pulmonary artery wedge pressure (mm Hg) | 20.3 ± 6.9 | 21.1 ± 5.9 | 20.1 ± 4.8 | 0.621 |
| Cardiac index (L/min/m 2 ) | 1.7 ± 0.6 | 1.6 ± 0.6 | 1.6 ± 0.7 | 0.7112 |
| Perioperative and donor-related information | ||||
| Ischemic time (minutes) | 194.8 ± 48.5 | 188.7 ± 56.3 | 198.1 ± 56.6 | 0.0906 |
| Donor age at transplant (years) | 28.6 ± 12.8 | 35.2 ± 13.2 ‡ | 33.7 ± 13.3 † | 0.0086 |
| Male donors (n) | 22 (54%) | 216 (57.9%) | 208 (52.3%) | 0.5292 |
| Blood type | 0.0925 | |||
| A | 17 (44%) | 166 (44.5%) | 145 (36.2%) | |
| B | 7 (17%) | 78 (20.9%) | 74 (18.6%) | |
| O | 14 (34%) | 109 (29.2%) | 149 (37.4%) | |
| AB | 3 (7%) | 20 (5.4%) | 30 (7.5%) | |
| Cytomegalovirus serology mismatch positive donor to negative recipient | 15 (37%) | 74 (20.1%) † | 86 (21.2%) † | 0.0713 |
The Kaplan-Meier survival curves revealed that patients with HC showed better survival than those with ischemic heart disease (90.1% vs 85.8% and 83.9% vs 67.1% at 1 and 5 years, respectively; p = 0.0359; Figure 1 ). However, survival was not significantly different between those with HC and those with other heart disease (p = 0.1771). Proportional hazards analysis revealed that HC was associated with better post-transplant survival on univariate analysis ( Table 2 ) but not on multivariate analysis.
| Variable | HR (95% CI) | p Value |
|---|---|---|
| Clinical characteristics | ||
| Hypertrophic cardiomyopathy (yes = 1, no = 0) | 0.4760 (0.1889–0.9762) | 0.0420 |
| Age (years) | 1.0116 (1.0012–1.0226) | 0.0289 |
| Gender (male = 1, female = 0) | 1.1780 (0.8766–1.6131) | 0.2833 |
| Race (white = 1, others = 0) | 0.8915 (0.6951–1.1493) | 0.3723 |
| Body mass index (kg/m 2 ) | 0.9790 (0.9537–1.0047) | 0.1094 |
| Blood type O (yes = 1, no = 0) | 1.0167 (0.7775–1.3191) | 0.9024 |
| United Network of Organ Sharing Status 1A (yes = 1, no = 0) | 1.1149 (0.8689–1.4525) | 0.3989 |
| Left ventricular assist device requirement (yes = 1, no = 0) | 1.0926 (0.8345–1.4176) | 0.5140 |
| Diabetes (yes = 1, no = 0) | 1.2377 (0.9507–1.5982) | 0.1119 |
| Stroke (yes = 1, no = 0) | 0.9952 (0.6747–1.4181) | 0.9797 |
| Peripheral vascular disease (yes = 1, no = 0) | 0.9263 (0.5154–1.5265) | 0.7782 |
| Smoking (%) | 1.0319 (0.8010–1.3223) | 0.8062 |
| Cytomegalovirus serology positive (yes = 1, no = 0) | 0.8079 (0.6316–1.0369) | 0.0934 |
| Waiting time (days) | 1.3421(0.9984–1,8,423) | 0.1018 |
| Laboratory findings | ||
| Albumin (mg/dl) | 0.6170 (0.5091–0.7500) | <0.0001 |
| Sodium (mEq/L) | 0.9748 (0.9601–0.9902) | 0.0015 |
| Creatinine (mg/dl) | 1.1601 (1.0119–1.2930) | 0.0348 |
| Total bilirubin (mg/dl) | 1.2267 (1.0972–1.3474) | 0.0007 |
| Total cholesterol (mg/dl) | 0.9999 (0.0063–1.0016) | 0.4401 |
| Triglycerides (mg/dl) | 1.0004 (0.9985–1.0022) | 0.6660 |
| Hematocrit (%) | 0.9959 (0.9754–1.0166) | 0.6942 |
| Perioperative and donor-related information | ||
| Ischemic time (minutes) | 0.9990 (0.0060–1.0020) | 0.5192 |
| Donor age (years) | 1.0131 (1.0035–1.0229) | 0.0073 |
| Donor gender (male = 1, female = 0)) | 0.8599 (0.7254–1.2141) | 0.2417 |
| Cytomegalovirus serology mismatch (positive donor to negative recipient = 1, other = 0) | 1.3669 (1.0291–1.7942) | 0.0313 |
Histologic evaluation of the biopsy specimen obtained from the transplanted heart or explanted heart at autopsy revealed that none of the patients with HC had had a recurrence of myocyte hypertrophy or more than minor disarray after transplantation. Of the 41 patients with HC, 33 (80.5%) were treated with a cyclosporine-based immunosuppressive regimen and 8 patients (19.5%) with a tacrolimus-based immunosuppressive regimen. Of the 41 patients, 7 (17.1%) experienced grade 2R or greater rejection at 53 to 2,701 days after transplantation, 11 patients (26.8%) experienced grade 1R or conventional International Society of Heart and Lung Transplantation grade 1B rejection at 6 to 2,789 days after transplant, and 1 patient (2.4%) had an antibody-mediated rejection. The incidence of treatment-requiring rejection within 1 and 5 years after transplant in our patients with HC was 9.8% and 17.1%, respectively. All the rejections occurring in our patients with HC were successfully treated.
The results of the subanalysis of patients with HC with a dilated left ventricle versus a nondilated left ventricle at transplant listing are listed in Table 3 . Of the 41 patients with HC, 14 had a dilated left ventricle and 27 a nondilated left ventricle. At the initial visit, the ventricular diameter was already larger and the LV ejection fraction lower in the patients who developed subsequent LV dilation. In both groups, none of patients showed either LV outflow or midventricular obstruction >20 mm Hg, as measured by continuous flow Doppler echocardiography.
| Variable | Dilated Left Ventricle | p Value | |
|---|---|---|---|
| Yes (n = 14) | No (n = 27) | ||
| Clinical characteristics | |||
| Age (years) | 52.4 ± 3.7 | 45.4 ± 2.6 | 0.1273 |
| Men | 7 (50%) | 15 (57%) | 0.7353 |
| White | 9 (64%) | 24 (89%) | 0.0657 |
| Body mass index (kg/m 2 ) | 26.8 ± 4.3 | 25.1 ± 4.6 | 0.2576 |
| Blood type | 0.2084 | ||
| A | 5 (36%) | 12 (44%) | |
| B | 4 (29%) | 4 (15%) | |
| O | 4 (29%) | 9 (33%) | |
| AB | 1 (7%) | 2 (7%) | |
| United Network of Organ Sharing Status at listing | 0.3471 | ||
| 1A | 2 (15%) | 2 (7%) | |
| 1B | 7 (50%) | 9 (33%) | |
| 2 | 5 (36%) | 16 (59%) | |
| United Network of Organ Sharing Status at transplantation | 0.4896 | ||
| 1A | 4 (29%) | 12 (44%) | |
| 1B | 6 (43%) | 7 (26%) | |
| 2 | 4 (29%) | 8 (30%) | |
| Left ventricular assist device | 3 (21%) | 3 (11%) | 0.3858 |
| Waiting time (days) | 331.9 ± 250.3 | 177.1 ± 151.2 | 0.0484 |
| Hemodynamic findings | |||
| Mean pulmonary artery pressure (mm Hg) | 26.8 ± 9.2 | 30.1 ± 9.1 | 0.4024 |
| Pulmonary artery wedge pressure (mm Hg) | 21.0 ± 8.9 | 19.8 ± 5.7 | 0.6902 |
| Mean right atrial pressure (mm Hg) | 13.0 ± 8.1 | 12.6 ± 7.0 | 0.8994 |
| Cardiac index (L/min/m 2 ) | 1.5 ± 0.8 | 1.8 ± 0.5 | 0.2821 |
| Pulmonary exercise test | 10 | 21 | |
| Peak oxygen consumption (ml/kg/min) | 9.1 ± 1.3 | 8.9 ± 1.6 | 0.5811 |
| Laboratory findings | |||
| Albumin (mg/dl) | 4.0 ± 0.6 | 4.0 ± 0.6 | 0.8466 |
| Sodium (mEq/L) | 137.5 ± 6.0 | 136.8 ± 7.4 | 0.7727 |
| Potassium (mEq/L) | 4.2 ± 0.4 | 4.1 ± 0.5 | 0.4034 |
| Blood urea nitrogen (mg/dl) | 27.4 ± 8.7 | 27.4 ± 16.3 | 0.9973 |
| Creatinine (mg/dl) | 1.3 ± 0.4 | 1.2 ± 0.4 | 0.7359 |
| Total bilirubin (mg/dl) | 1.5 ± 1.0 | 1.2 ± 0.8 | 0.4293 |
| Direct bilirubin (mg/dl) | 0.5 ± 0.5 | 0.4 ± 0.4 | 0.5270 |
| Aspartate amino transferase (IU/L) | 36.9 ± 23.2 | 36.6 ± 18.6 | 0.9645 |
| Alanine aminotransferase (IU/L) | 27.8 ± 12.9 | 32.8 ± 23.5 | 0.5868 |
| Total cholesterol (mg/dl) | 148.2 ± 41.3 | 146.8 ± 41.1 | 0.9162 |
| Triglyceride (mg/dl) | 102.1 ± 34.9 | 109.9 ± 44.7 | 0.5695 |
| Hematocrit (%) | 38.9 ± 5.2 | 37.0 ± 5.3 | 0.2945 |
| Echocardiographic findings at the initial visit | |||
| Left ventricular end-diastolic internal dimension (mm) | 53.6 ± 2.6 | 44.0 ± 7.1 | <0.0001 |
| Left ventricular end-systolic internal dimension (mm) | 41.1 ± 6.2 | 30.5 ± 7.9 | 0.0001 |
| End-diastolic interventricular septum thickness (mm) | 15.4 ± 1.9 | 17.7 ± 4.9 | 0.0853 |
| End-diastolic posterior wall thickness (mm) | 13.9 ± 3.4 | 15.5 ± 3.4 | 0.1605 |
| Left ventricular ejection fraction (%) | 41.4 ± 15.0 | 55.7 ± 16.0 | 0.0367 |
| Echocardiographic findings at listing | |||
| Left ventricular end-diastolic internal dimension (mm) | 54.6 ± 5.5 | 44.3 ± 7.3 | <0.0001 |
| Left ventricular end-systolic internal dimension (mm) | 51.9 ± 8.6 | 30.2 ± 8.0 | <0.0001 |
| End-diastolic interventricular septum thickness (mm) | 12.2 ± 2.4 | 15.3 ± 5.2 | 0.0435 |
| End-diastolic posterior wall thickness (mm) | 12.3 ± 2.5 | 14.2 ± 3.8 | 0.0940 |
| Left ventricular ejection fraction (%) | 29.2 ± 14.7 | 54.3 ± 15.2 | <0.0001 |
| Left atrial dimension (mm) | 47.1 ± 11.2 | 50.1 ± 8.2 | 0.3596 |
| Echocardiographic findings within 1 month before surgery | 13 | 21 | |
| Left ventricular end-diastolic internal dimension (mm) | 60.2 ± 7.3 | 45.3 ± 7.0 | <0.0001 |
| Left ventricular end-systolic internal dimension (mm) | 56.6 ± 9.3 | 33.3 ± 9.0 | <0.0001 |
| End-diastolic interventricular septum thickness (mm) | 12.1 ± 2.4 | 14.7 ± 5.7 | 0.1163 |
| End-diastolic posterior wall thickness (mm) | 12.3 ± 2.6 | 13.8 ± 4.0 | 0.2195 |
| Left ventricular ejection fraction (%) | 28.4 ± 14.3 | 46.7 ± 19.1 | 0.0051 |
| Left atrial dimension (mm) | 47.6 ± 11.4 | 49.4 ± 7.6 | 0.6007 |
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