Sudden cardiac death (SCD) is a common cause of death in the general population, occurring in 300,000 to 350,000 people in the United States alone. Currently, there are no data supporting implantable cardioverter-defibrillator therapy in patients who underwent orthotopic heart transplant (OHT) with low left ventricular ejection fraction (LVEF). In this retrospective study, we included all patients who underwent primary OHT at our institution from 2007 to 2013. We compared the cause of death in patients who underwent OHT and evaluated the correlation of the cause of death and the patients’ LVEF. Our objectives were to determine whether patients who underwent OHT with LVEF <35% are at increased risk for SCD compared with those who underwent OHT with normal LVEF. To summarize our results, a total of 345 patients were included in our study (mean age 50 ± 14 years, 68% men). The mean follow-up was 1,260 ± 698 days. Forty patients (11.5%) died >6 months after OHT. Surviving patients had higher LVEF compared with deceased patients (64 ± 7% and 50 ± 24%, respectively, p ≤0.001). In all, 10 (25%) of the deceased patients died suddenly, 9 (23%) from sepsis, and 8 (20%) from malignancy. Of the 11 deceased patients with LVEF ≤35%, 2 patients (18%) died suddenly compared with 9 SCDs among the 29 deceased patients (31%) with LVEF >35% (p = 0.54). In conclusion, patients who underwent OHT who died were more likely to have LVEF <35%, and a quarter of the deceased patients who underwent OHT died suddenly. A reduced LVEF was not associated with an increased risk of SCD.
Sudden cardiac death (SCD) is a frequent cause of death in the general population, occurring in 300,000 to 350,000 people in the United States alone. Most SCD occur in the setting of ischemic heart disease and is a result of ventricular fibrillation. It is thought that the autonomic nervous system plays a key role in the development of this arrhythmia because of acute ischemia. Orthotopic heart transplantation (OHT) results in denervation of the autonomic nervous system, with partial and nonuniform sympathetic reinnervation occurring with time in some patients. However, the presence of parasympathetic reinnervation is debated. These heterogeneous reinnervations may be associated with ventricular arrhythmias as well. Practice guidelines recommend implantable cardioverter-defibrillator (ICD) use as primary prevention for both ischemic and nonischemic cardiomyopathy patients with left ventricular ejection fraction (LVEF) ≤30% to 35%. However, currently, there are no data supporting ICD therapy in patients who underwent OHT with low LVEF. We hypothesized that, unlike the general population, patients who underwent OHT with low LVEF would not be at increased risk of SCD because of autonomic nerve denervation in the transplanted heart.
Methods
In this retrospective, single-center study, we included all patients who underwent primary OHT at the hospital of the University of Pennsylvania from 2007 to 2013. We reviewed the patients’ medical file and ascribed the cause of death after careful evaluation of the terminal events for each patient. The last available echocardiogram or nuclear stress study performed before death was recorded as the preterminal LVEF. To prevent confounders associated with primary graft dysfunction and transplant surgery–related complications, we excluded patients who died within the first 6 months after the transplant. The study was approved by the University of Pennsylvania Institutional Review Board.
As described in previous studies, the mode of death was determined based on the clinical circumstances. SCD was defined as unexpected sudden death occurring within 24 hours after onset of any new symptoms. Death from infection, cerebrovascular accident, rejection, etc., was determined based on hospital summary and the course of hospitalization. Rejection was defined in accordance with the definitions of International Society for Heart and Lung Transplantation nomenclature adopted in 1990 and revised in 2004.
Continuous variables were expressed as mean ± SD, and statistical differences between means were assessed using the unpaired Student’s t test for normal distributions or Mann-Whitney test for non-normal distributions. A univariate analysis of variance was used to compare the means of continuous variables across 3 groups representing the 3 most frequent mechanisms of death. Categorical variables, expressed as numbers or percentages, were compared with the chi-square test and confirmed with Fisher’s exact test. Cumulative event rates (mortality) were calculated according to the Kaplan-Meier method in the overall population. All tests were 2 tailed and a p value <0.05 was considered statistically significant.
Results
A total of 345 patients, with a mean age of 50 ± 14 years (range 16 to 70 years, 67% men) were included in our study; the mean follow-up time after transplantation was 1,260 ± 698 days. During this time, 60 patients (17%) of the study cohort died. Forty patients (11.5%) died >6 months after OHT and served as our deceased population. The mean LVEF of the 285 surviving patients was 64 ± 7% (range 25% to 75%) and the mean LVEF among the deceased patients was significantly lower at 50 ± 24% (range 5% to 75%, p ≤0.001). The baseline characteristics of the deceased patients are summarized in Table 1 . Eleven patients (28%) of the deceased cohort and only 2 patients (0.7%) of the surviving subset had LVEF ≤35% (p <0.001). Figure 1 details the causes of death in our cohort. Briefly, 10 patients (25%) of the 40 deceased patients died from SCD, 9 (23%) from sepsis, and 8 (20%) from malignancy. Of the 11 deceased patients with LVEF ≤35%, only 2 patients (18%) died suddenly, compared with 9 SCD deaths (31%) among the 29 deceased patients with LVEF >35% (p = 0.54). Using an LVEF cutoff of 30% did not alter the results.
| Overall (N=40) | LVEF≤35% (N=11) | LVEF>35% (N=29) | P value | |
|---|---|---|---|---|
| Men | 67% | 72% | 65% | 0.67 |
| Age at transplantation (years) | 49±15 | 44±5 | 50±4 | 0.19 |
| Hypertension | 71% | 64% | 74% | 0.53 |
| Type 2 diabetes mellitus | 55% | 45% | 59% | 0.45 |
| Chronic renal failure | 18% | 0 | 26% | 0.06 |
| Etiology for transplant | 0.70 | |||
| Ischemic cardiomyopathy | 25% | 9% | 31% | |
| Idiopathic cardiomyopathy | 45% | 63% | 38% | |
| Valvular cardiomyopathy | 2.5% | 0 | 3% | |
| Congenital cardiomyopathy | 2.5% | 0 | 3% | |
| Other | 25% | 27% | 24% | |
| History of Acute Cellular Rejection (mean #) | 1.1±1.1 | 1.4±1.3 | 1.0±1.0 | 0.32 |
| History of Antibody Mediated Rejection (mean #) | 0.4±0.9 | 0.6±1.0 | 0.3±0.8 | 0.27 |
| Cardiac allograft vasculopathy | 13% | 9% | 15% | 0.64 |
| Left ventricle ejection fraction prior to death | 50%±22 | 19%±8 | 63%±11 | <0.001 |
| Medical Therapy | ||||
| Ace Inhibitors or Angiotensin II receptor blocker | 23% | 36% | 18% | 0.25 |
| Beta blockers | 34% | 18% | 41% | 0.19 |
| Statins | 66% | 55% | 70% | 0.36 |
| Tacrolimus | 84% | 72% | 88% | 0.22 |
| Rapamune | 8% | 0 | 11% | 0.26 |
| Azathioprine | 24% | 36% | 19% | 0.25 |
| Mycophenolate Mofetil | 45% | 36% | 48% | 0.52 |
| Prednisone | 82% | 81% | 85% | 0.80 |
We evaluated the risk of SCD in patients suffering from cardiac allograft vasculopathy (CAV), finding no difference in the prevalence of CAV in patients with reduced or preserved LVEF (p = 0.63). In addition, a composite variable of CAV or reduced LVEF and a composite variable of CAV or presence of acute rejection were not associated with SCD (p = 0.85 and 0.27, respectively).
Among the patients who died beyond 3 years post-transplant, 2 of the 4 patients (50%) with LVEF ≤35% died from SCD versus 1 of 12 patients (8%) with LVEF >35% (p = 0.064); among those who died beyond 5 years, 1 of 2 with LVEF ≤35% and 0 of 5 with LVEF >35% died from SCD ( Figure 2 ) (p = 0.088).
Results
A total of 345 patients, with a mean age of 50 ± 14 years (range 16 to 70 years, 67% men) were included in our study; the mean follow-up time after transplantation was 1,260 ± 698 days. During this time, 60 patients (17%) of the study cohort died. Forty patients (11.5%) died >6 months after OHT and served as our deceased population. The mean LVEF of the 285 surviving patients was 64 ± 7% (range 25% to 75%) and the mean LVEF among the deceased patients was significantly lower at 50 ± 24% (range 5% to 75%, p ≤0.001). The baseline characteristics of the deceased patients are summarized in Table 1 . Eleven patients (28%) of the deceased cohort and only 2 patients (0.7%) of the surviving subset had LVEF ≤35% (p <0.001). Figure 1 details the causes of death in our cohort. Briefly, 10 patients (25%) of the 40 deceased patients died from SCD, 9 (23%) from sepsis, and 8 (20%) from malignancy. Of the 11 deceased patients with LVEF ≤35%, only 2 patients (18%) died suddenly, compared with 9 SCD deaths (31%) among the 29 deceased patients with LVEF >35% (p = 0.54). Using an LVEF cutoff of 30% did not alter the results.
