Ethnic disparity in Israel impacts long-term results after heart transplantation

Between 1991 and 2017, 285 patients who underwent HTx were enrolled and prospectively followed-up in the tertiary center Sheba HTx Registry. Excluded from further analysis were children (n = 11), patients who underwent HTx in China and whose donors might have been executed prisoners (n = 13), in accordance with current ethical guidelines of transplantation societies [13], and additional patients whose ethnic origin was unknown (n = 7). Thus, the present study population comprised 254 patients.

Among the study population 89% were Jews (n = 226) and 11% were Arabs (n = 28). The baseline characteristics of recipients by ethnic origin are summarized in Table 1. Arabs recipients were significantly younger than Jewish recipients (42 ± 14 vs. 50 ± 12, respectively, p = 0.01). The mean age of the donors did not differ between the ethnic groups. Donor ethnicity data were available only for 166 HTx patients of the total cohort. Of the 139 Jewish recipients, 109 had Jewish and 30 had Arab donors. Of the 27 Arab recipients, 25 had Jewish and 2 had Arab donors. The rate of organ donations among Israeli Arabs and Jews in the current study was found to be proportional to their representation in the general population.

In both groups, the percentage of men was higher than that of women, but this difference was more pronounced among Jewish recipients than among the Arabs. Ischemic heart disease was a more common cause for HTx among Jews than among Arabs. No differences were found between the two groups relating to donors’ characteristics. Pre-transplant donor-specific antibodies (DSAs) were negative for all patients. Crossmatch in our series was negative for all patients.

Operative and post-operative data are summarized in Table 2. Length of hospitalization was longer among Jews compared to Arabs recipients (80 ± 120 vs. 43 ± 45 days, respectively; p = 0.007), due to longer pre-HTx waiting time. In addition, rates of statin therapy after HTx were higher among Jews compared to Arabs (91% vs. 68%, respectively; p < 0.001). Consistently, LDL levels following HTx were higher among Arabs. Immunosuppression protocol did not differ between the ethnic groups.

HTx is the treatment of choice for patients suffering from end stage heart failure despite maximum medical therapy, with survival continuing to improve over time [2]. However, reports confirm that the benefit and improved results of HTx are not uniform since certain racial/ethnic minorities have inferior outcomes [3, 4, 6, 7]. Of the HTx recipients, Israeli Arabs have a trend toward greater prevalence of non-ischemic cardiomyopathy, which seems to be a more aggressive form of cardiomyopathy. While most of the recipients are male, the proportion of females is higher, with younger age at transplantation. These findings are in line with a recent study suggesting a higher prevalence of non-ischemic cardiomyopathy characterized by early onset and rapid deterioration among Jewish and Arab patients with heart failure who have ICD/CRTD implantations [17].

Life expectancy in Israel is higher in the Jewish population than among Arabs. In 2014, average life expectancy at birth was 81.1 years for Jewish men, 84.5 years for Jewish women, 76.9 years for Arab men and 81.2 years for Arab women [8]. Mortality differentials between Arabs and Jews declined at ages below 45 years and increased among older people in whom heart disease, diabetes and cancer are the major contributors for the increasing inequality among the elderly [2, 18]. In the present study, although age at HTx was younger for the Arab recipients with a tendency toward more female recipients among this population, CV mortality was higher among the overall Arabs recipients with a > 4-fold increase in the risk for CV mortality after adjusting for covariates. No differences were found in overall mortality between these two ethnic groups.

A recent study of cystic fibrosis patients who underwent lung transplantation showed better correlated survival among the ethnic Jewish population [19]. This study also showed that bronchiolitis obliterans syndrome was more common and appeared earlier in the Arab compared with the Jewish population.

Ethnic related differences in mortality among patients following HTx have been previously reported, albeit in other ethnic groups. A more than two-decade follow-up study of > 39, 000 HTx patients found that black recipients had an increased risk of death when compared with white recipients after multivariable adjustment for recipient, transplant, and socioeconomic factors [20]. Although overall survival of HTx patients has improved during the last decade, Singh et al. showed that among 36,784 HTx recipients, long-term survival had improved in white but not in black or Hispanic recipients, resulting in a more marked disparity in outcomes in the current era [4]. The disparity in outcomes in minority populations is not unique to HTx, as ethnic minorities have been associated with reduced survival also after other solid organ transplantations [21].

CAV remains a leading cause of graft loss and mortality among late survivors of HTx. A novel finding of our study is that the ethnic origin of Arab recipients is independently associated with a significant > 2-fold increase in the risk for CAV.

It has been previously reported that African American HTx recipients have increased risk for CAV, and shorter time to the development of CAV compared with Hispanic-Latino and Caucasian recipients [6, 22]. Similarly, a study including 5211 pediatric HTx recipients included in the OPTN/UNOS Database showed that the African American race was highly associated with shorter CAV-free survival [23].

Differences in CV mortality and cerebral events have been reported in the Israel National Survey, suggesting higher rates of mortality from all heart disease in Arab men and women compared with their Jewish counterparts (15% vs. 27%, respectively) [8, 24]. While the higher risk of CAV in African Americans is likely related to the increased burden of acute cellular rejection, a known risk factor for earlier development of CAV, no differences in rejection rates related to a patient’s ethnic group were found in our study [6, 15]. To the best of our knowledge, the present study is the first to address the impact of these ethnicities on outcomes after HTx.

Because CAV is a major cause of graft loss and mortality, prevention of CAV is critical in order to improve graft survival. The present findings suggest that more aggressive attempts should be adopted. Transplant recipients with known risk factors for CAV should be monitored closely and receive early intervention to reduce CAV risk. These interventions should focus on education of patients, strengthening the professional relationship between community medicine and the tertiary center. Implementation of prevention programs to reduce risk factors, particularly diabetes and obesity. Individualizing the cardiovascular follow up protocol emphasizing on early vasculopathy assessment including frequent oriented visits and more frequent use of non-invasive modalities. Primary prevention treatment with aspirin should also be considered [25].

Suggested explanations contributing to ethnic disparities in Israel include socioeconomic, environmental and genetic factors [6, 26, 27]. The Jewish and Arab populations differ in social, cultural, economic and genetic characteristics, as well as in health characteristics. Arabs in Israel have lower socioeconomic status and poorer health awareness [28, 29], that have previously been shown to be related to increased mortality and CV morbidity.

Dietary patterns might also play a role. Jews and Arabs from the same region in Israel exhibit major differences in food consumption. A high intake of the foods historically produced by the rural Arab population, now demonstrate modifications that have reduced the healthy properties of the traditional Arab diet (e.g. replacement of whole grains with refined grains, increased consumption of meat dishes/animal fat) [30]. These dietary differences contribute to the disparity seen in the current LDL levels between ethnic groups. Katler et al. have consistently shown that levels of HDL and triglycerides were significantly worse among Arabs compared with Jews in a study cohort of > 30,000 patients [28].

Hence, one of the explanations for the differences in outcomes between the two ethnic groups is the contribution of LDL levels. Despite the fact that Arabs had higher mean LDL levels, they were treated less aggressively with statin therapy. This is supported by the findings of our study showing that higher LDL levels were independently associated with a greater risk of CV mortality (HR 1.031, p = 0.037). The contribution of high LDL levels to the disparities in outcomes is further reinforced because, although the recommendations for treatment was similar in both ethnic groups, Arab recipients demonstrated a lower use of statins than Jews (68% vs. 92% for Arabs and Jews, respectively; p < 0.001).

Differences in healthy life-styles are also evident between the two populations and contribute to higher CV morbidity and mortality. Physical activity in accordance with the WHO recommendations has been reported to be significantly lower in the Arab population (43.7% vs. 28.7% of Jewish and Arabs men respectively; 31.9% vs. 18.1% of Jewish and Arab women respectively) as reported in the National Health Survey [30]. Hence, controlling risk factors with an emphasis on LDL levels and statin therapy is of utmost importance [31, 32].

All multivariate models were extended to include wider combinations of different variables (Supplemental Table), ethnicity remained significantly associated with outcomes, with some reduction in the ethnicity coefficient. It is possible that they are simply confounders, yet, as not all possible confounders were recorded or adjusted for, the contribution of the above-mentioned risk factors (i.e., healthy lifestyles, physical activity, nutritional elements) cannot be eliminated.

Another explanation for the differences in outcomes between the two ethnic groups, could be related to the fact that Arabs are more likely than Jews to receive a heart from an ethnic mismatched donor and hence perhaps less genetically match.

The data presented in this paper will help to design treatment protocols and regimens unique to our patients, emphasizing on frequency of biopsies, immunosuppressive protocols, medication adherence assessment, and subsequent close monitoring.

Further identifying the causes of Arabs excess cardiovascular risk may help provide enhanced surveillance and culturally sensitive care. Future, prospectively designed trials, are required in order to define additional factors that may explain these differences (focusing on social, ethnic, medication adherence and nutritional variables). This should be prioritized by public health systems and by organ transplant programs. These data call for the establishment of a National Heart Transplant Registry.

Increased awareness and early intervention by the Israeli healthcare system, such as the responsible national authorities and public health providers, and cooperation with the Arab community is of paramount importance. Efforts should target dedicated and individualized education of patients; families; primary care medical staff; religious leaders such as Imams and heads of families, with consideration of the unique family fabric in Arab society. Implementation of prevention programs to reduce cardiovascular risk factors, particularly diabetes and obesity, may help reduce the disparity between Arabs and Jews. Individualizing the cardiovascular follow up protocol emphasizing on early vasculopathy assessment including frequent oriented visits and more intense use of non-invasive cardiovascular screening modalities (i.e., donor-specific antibodies screening, ergometry, stress echocardiography, myocardial perfusion imaging) for early detection of cardiac vasculopathy.

The major limitation of our study lies in its observational nature. The relevance of the various social determinants of health (i.e., socioeconomic status, health awareness) and modifiable risk factors for CAV and CV mortality (i.e., BMI, physical activity, dietary details) were not assessed in this study and therefore deserve further investigation. Compliance was only indirectly evaluated based on patient adherence with recommended follow up protocols. However, pill count and other formal methods for adherence assessment were not available. Our current practice does not include routine intravascular ultrasound (IVUS) assessment which might be associated with underestimation of CAV. While the sample size might be too small to draw definitive conclusions, our study provides the most current data and the largest report on ethnic disparities between Arabs and Jews undergoing HTx in Israel.