Trends and Outcomes in Heart Transplantation over the Past Three Decades: A Single Tertiary Center Experience in Israel.

BACKGROUND: Heart transplantation (HT) is the treatment of choice for patients with end-stage heart failure. The HT unit at the Sheba Medical Center is the largest of its kind in Israel. OBJECTIVES: To evaluate the experience of HT at a single center, assess trends over 3 decades, and correlate with worldwide data. METHODS: Between 1990 and 2017, we reviewed all 285  adult HT patients. Patients were grouped by year of HT: 1990-1999 (decade 1), 2000-2009 (decade 2), and 2010-2017 (decade 3). RESULTS: The percentage of women undergoing HT has increased and etiology has shifted from ischemic to non-ischemic cardiomyopathy (10% vs. 25%, P = 0.033; 70% vs. 40% ischemic, for decades 1 vs. 3, respectively). Implantation of left ventricular assist device as a bridge to HT has increased. Metabolic profile has improved over the years with lower low-density lipoprotein, diabetes, and hypertension after HT (101 mg/dl, 27%, and 41% at decade 3, respectively). There has been a prominent change in immunosuppressive treatments, currently more than 90% are treated with tacrolimus, compared with 2.7% and 30.9% in decades 1 and 2, respectively (P < 0.001). Cardiac allograft vasculopathy (CAV) rates have declined significantly (47% vs. 17.5% for decades 1 and 2, P < 0.001) as have the combined endpoint of CAV/death. Similarly, the current incidence of acute rejections is significantly lower. CONCLUSIONS: Our analysis of over 25 years of a single-center experience with HT shows encouraging improved results, which are in line with worldwide standards and experience.

Risk of early, intermediate, and late rejection following heart transplantation: Trends over the past 25 years and relation to changes in medical management. Tertiary center experience: The Sheba Heart Transplantation Registry.

AIM: To explore the trends in the risk for rejection following heart transplantation (HT) over the past 25 years, and their relation to changes in medical management. METHODS: The study population comprised 216 HT patients. Rejection periods were defined as follows: 0-3 months (early), 3-12 months (intermediate), and 12+ months (late). HT era was dichotomized as follows: 1991-1999 (remote era) and 2000-2016 (recent era). Medication combination was categorized as newer (TAC, MMF, and everolimus) vs older therapies (AZA, CSA). RESULTS: Multivariate analysis showed that patients who underwent HT during the recent era experienced a significant reduction in the risk for major rejection. These findings were consistent for early (OR = 0.44 [95% CI 0.22-0.88]), intermediate (OR = 0.02 [95% CI 0.003-0.11]), and late rejections (OR = 0.18 [95% CI 0.05-0.52]). Using the year of HT as a continuous measure showed that each 1-year increment was independently associated with a significant reduction in the risk for early, intermediate, and late rejections (5%, 21%, 18%, respectively). In contrast, the risk reduction associated with newer types of immunosuppressive therapies was not statistically significant after adjustment for the treatment period. CONCLUSIONS: Major rejection rates following HT have significantly declined over the past 2 decades even after adjustment for changes in immunosuppressive therapies, suggesting that other factors may also play a role in the improved outcomes of HT recipients.

Early aspirin initiation following heart transplantation is associated with reduced risk of allograft vasculopathy during long-term follow-up.

AIM: Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality after heart transplantation (HT). Enhanced platelet reactivity is a contributing factor. We aimed to investigate the association between early initiation of aspirin therapy post-HT and the 15-year risk of the development of CAV. METHODS: We studied 206 patients who underwent HT between 1991 and 2016. Multivariate Cox proportional hazards regression modeling was employed to evaluate the association between early aspirin initiation and the long-term risk of CAV. RESULTS: Ninety-seven patients (47%) received aspirin therapy. At 15 years of follow-up, the rate of CAV was lowered by sixfold in patients treated with aspirin compared with the non-treated patients: 7% vs 37% (log-rank P-value<.001). The corresponding rates of the combined end-point of CAV or death were also lower in patients treated with aspirin, compared with the non-treated patients: 42% vs 78% (log-rank P < .001). Consistently, multivariate analysis showed that early aspirin therapy was associated with a significant 84% (P < .001) reduction in CAV risk, and with a corresponding 68% (P < .0001) reduction in the risk of the combined end-point of CAV or death. We further validated these results using a propensity score-adjusted Cox model. CONCLUSIONS: Early aspirin initiation is independently associated with a significant reduction in the risk of CAV.

Thrombus aspiration during primary percutaneous coronary intervention in acute ST-elevation myocardial infarction.

BACKGROUND AND OBJECTIVES: The main limitation of primary PCI in acute MI is lack of tissue reperfusion due to distal embolization. We sought to examine the safety and feasibility of a manual thrombus aspiration device in patients undergoing primary PCI. METHODS: Seventy-eight consecutive patients with ST-elevation MI eligible for primary PCI were included. The device was used immediately after guidewire crossing only if a total occlusion (thrombolysis in myocardial infarction [TIMI] flow 0) existed or if a large filling defect was observed. End points were TIMI flow immediately after thrombus aspiration and at the end of procedure and ST resolution of more than 70%. RESULTS: Mean age was 59+/-12 years, and 79% of patients were males. Risk factor profile included smoking in 62%, diabetes in 21%, hypertension in 46%, and hyperlipidemia in 45%. The infarct-related artery was LAD in 42%, RCA in 36%, and LCX in 22%. Initial TIMI flow was 0 in 71%, I in 10%, and II/III in 19%. Immediately after aspiration, TIMI flow was II/III in 89% of patients and I in 9%. Direct stenting was performed in 73%. Final TIMI flow was III in 90%, II in 9%, and 0 in 1%. ST-segment resolution of more than 70% was observed in 76% of patients. No major device-related complications occurred. CONCLUSIONS: Based on this preliminary data, manual thrombus aspiration using the Export device during primary PCI appears to be feasible and safe. The advantages over routine primary PCI should be further evaluated in randomized trials.

[Ventricular assist devices as bridge to heart transplantation in cardiogenic shock or terminal heart failure--12 years experience at the Sheba Medical Center].

BACKGROUND: Patients in cardiogenic shock (CS) or with terminal heart failure (THF) are at imminent risk of death while waiting for heart transplantation (HTx). Implantation of left or bi-ventricular assist device (LVAD/BiVAD) as a bridge to HTx may save many of these doomed patients' lives. PATIENTS AND METHODS: Between March 1994 and December 2006, 29 terminally ill patients (age 2.5-65 years, mean 48 years) underwent VADs implantation as bridge to HTx. The HeartMate VE LVAD was used in 18 patients, Thoratec pneumatic BiVAD in 7, Berlin Heart Excor BiVAD in one, and HeartMate II axial flow, Thoratec pneumatic and Biomedicus centrifugal LVADs in one each. Indications for VADs implantation were CS in 16 patients (55%) and intractable THF in 13 pts (45%). Etiologies were ischemic in 20 patients, idiopathic dilated, myocarditis and congenital in 2 patients each, and valvular, post partum and HTx graft vasculopathy in one patient each. RESULTS: Seventeen patients (59%) survived VADs implantation and underwent HTx or are ongoing. Mean survival on VADs was 72 days (range 1-353 days, total 5.2 patient years). Seven patients (24%) were discharged home while on LVAD support for a mean of 146 days. Nine of the transplanted patients (64%) were discharged home. In 4 LVAD patients the cause of death was RV failure necessitating later implantation of RVAD. CONCLUSIONS: VADs implantation as bridge to HTx in CS or THF saves many of these doomed patients, sometimes providing quality out-of-hospital life while waiting for HTx. Early recognition of RV failure and liberal use of BiVAD is important.

The impact of gender mismatching on early and late outcomes following heart transplantation.

AIMS: The role of donor/recipient gender matching on the long-term rejection process and clinical outcomes following heart transplantation (HT) outcomes is still controversial. We aim to investigate the impact of gender matching on early and long-term outcome HT. METHODS AND RESULTS: The study population comprised 166 patients who underwent HT between 1991 and 2013 and were prospectively followed up in a tertiary referral centre. Early and late outcomes were assessed by the type of donor-recipient gender match (primary analysis: female donor-male recipient [FD-MR, n = 36] vs. male donor-male recipient [MD-MR, n = 109]). Early mortality, need for inotropic support, length of hospital stay, and major perioperative adverse events did not differ between the FD-MR and MD-MR groups. However, the FD-MR group experienced significantly higher rates of early major rejections per patient as compared with the MD-MR group (1.2 ± 1.6 vs. 0.4 ± 0.8; P = 0.001), higher rates of overall major rejections (16 vs. 5.5 per 100 person years; P < 0.05), and higher rate of cardiac allograft vasculopathy (43% vs. 20%; P = 0.01). Kaplan-Meier survival analysis showed that the cumulative probabilities of survival free of rejections and major adverse events were significantly higher in MD-MR group (P = 0.002 and 0.001, respectively). Multivariate analysis showed that FD-MR status was associated with >2.5-fold (P = 0.03) increase in the risk for rejections and with a >3-fold (P = 0.01) increase in the risk for major adverse events during follow-up. CONCLUSIONS: Donor-recipient gender mismatch is a powerful independent predictor of early and late rejections and long-term major adverse events following HT.

Metformin therapy reduces the risk of malignancy after heart transplantation.

BACKGROUND: Malignancy and diabetes mellitus (DM) cause significant morbidity and mortality after heart transplantation (HTx). Metformin, one of the most commonly used anti-diabetic drugs worldwide, has also been shown to exhibit anti-tumor activity. We therefore investigated the association between metformin therapy and malignancy after HTx. METHODS: The study population comprised 237 patients who underwent HTx between 1991 and 2016 and were prospectively followed-up. Clinical data were recorded on prospectively designed forms. The primary outcome was any cancer recorded during 15 years of follow-up. Treatment with metformin and the development of DM after HTx were assessed as time-dependent factors in the analyses. RESULTS: Of the 237 study patients, 85 (36%) had diabetes. Of the DM patients, 48 (56%) were treated with metformin. Kaplan-Meier survival analysis showed that, at 15 years after HTx, malignancy rate was 4% for DM patients treated with metformin, 62% for those who did not receive metformin and 27% for non-DM patients (log-rank test, p < 0.0001). Consistently, multivariate analysis showed that for DM patients, metformin therapy was independently associated with a significant 90% reduction (hazard ratio = 0.10; 95% confidence interval 0.02 to 0.40; p = 0.001) in the risk of the development of a malignancy. DM patients who were treated with metformin had a markedly lower risk (65%; p = 0.001) for the development of a malignancy or death after HTx as compared with non-DM patients. CONCLUSIONS: Our findings suggest that metformin therapy is independently associated with a significant reduction in the risk of malignancy after HTx.

Primary angioplasty with routine stenting compared with thrombolytic therapy in elderly patients with acute myocardial infarction.

BACKGROUND: Prior studies have yielded conflicting data on the advantage of primary angioplasty compared with thrombolysis in elderly patients with acute myocardial infarction (AMI). These studies, however, were performed before the contemporary widespread use of intracoronary stents and glycoprotien IIb/IIIa antagonists. METHODS: We prospectively compared the outcome of 130 consecutive elderly patients (aged > or =70 years) with ST-elevation AMI who were admitted to 2 similar neighboring medical centers. Patients were assigned to receive either thrombolytic therapy with accelerated tissue-type plasminogen activator (center I) or primary angioplasty with routine stenting (center II). RESULTS: Of the patients assigned to receive primary angioplasty, 91% underwent stenting. At 6 months, patients treated with primary angioplasty, compared with those treated with thrombolytic therapy, had a lower incidence of reinfarction (2% vs 14%, P =.053) and revascularization for recurrent ischemia (9% vs 61%, P <.001) and a significant reduction in the prespecified combined end point of death, reinfarction, or revascularization for recurrent ischemia (29% vs 93%, P <.01). Primary angioplasty remained an independent predictor of the triple combined end point after controlling for potential covariables (relative risk 0.63, 95% CI 0.38-0.84). Major bleeding complications were also significantly reduced in the primary angioplasty group (0% vs 17%, P =.03). CONCLUSIONS: Compared with thrombolysis, primary angioplasty with routine stenting in elderly patients with AMI is associated with better clinical outcomes and a lower risk of bleeding complications.

Left main coronary artery atresia: extremely rare coronary anomaly in an asymptomatic adult and an adolescent soccer player.

Left main coronary artery atresia is a very rare coronary anomaly with only 33 cases reported in the literature, of whom only 1 patient is asymptomatic. Pediatric patients are usually very symptomatic early in life (dyspnea, syncope, failure to thrive, ventricular tachycardia, and sudden death), whereas adult patients begin showing symptoms (angina or sudden death) only at an advanced age. Given the high risk related to the presence of left main coronary artery atresia, and in view of the good results obtained by coronary artery bypass surgery, coronary artery revascularization should always be considered as the possible treatment of choice for establishing adequate myocardial blood flow.

Tricuspid valve regurgitation after orthotopic heart transplantation: prevalence and etiology.

Background. Tricuspid valve regurgitation (TR) after orthotopic heart transplantation (OHT) is common. The aims of this study were to determine the prevalence of TR after OHT, to examine the correlation between its development and various variables, and to determine its outcomes. Methods. All 163 OHT patients who were followed up between 1988 and 2009 for a minimal period of 12 months were divided into those with no TR/mild TR and those with at least mild-moderate TR, as assessed by doppler echocardiography. These groups were compared regarding preoperative hemodynamic variables, surgical technique employed, number of endomyocardial biopsies, number of acute cellular rejections, incidence of graft vasculopathy, and clinical outcomes. Results. At the end of the followup (average 8.2 years) significant TR was evident in 14.1% of the patients. The development of late TR was found by univariate, but not multivariate, analysis to be significantly correlated with the biatrial surgical technique (P < 0.01) and the presence of graft vasculopathy (P < 0.001). TR development was found to be correlated with the need for tricuspid valve surgery but not with an increased mortality. Conclusions. The development of TR after OHT may be related to the biatrial anastomosis technique and to graft vasculopathy.

In-stent restenosis and remote coronary lesion progression are coupled in cardiac transplant vasculopathy but not in native coronary artery disease.

OBJECTIVES: The purpose of this study was to describe the clinical, angiographic, and histological features of concomitant in-stent restenosis (ISR) and cardiac allograft vasculopathy (CAV) progression. BACKGROUND: Cardiac allograft vasculopathy is a major challenge to long-term success of heart transplantation. Coronary stenting for CAV is hampered by ISR. METHODS: Quantitative coronary angiography compared late lumen loss (LL) at stented and reference, non-stented segments during 1-year follow-up in post-heart transplant and control atherosclerosis patients. Stented and non-stented arteries with CAV were also obtained post-mortem for immunohistochemical analysis. RESULTS: In 37 stented lesions (25 patients), 1-year binary restenosis occurred in 37.8%. Patients with ISR had higher long-term cardiac death/myocardial infarction rates than patients without ISR (53.8% vs. 9.1%, p = 0.03). In the same 25 patients, 34 CAV lesions with non-significant obstructions were identified as reference controls. After 1 year, patients who developed ISR also had more control lesion LL (0.78 +/- 0.38 mm vs. 0.39 +/- 0.27 mm, p < 0.006) compared to patients without ISR. In the post-transplant patients, in-stent LL was closely coupled to control segment LL (R(2) = 0.63, p < 0.05). Conversely, in native atherosclerosis patients, ISR and remote disease progression were not correlated. Histological staining of stented and control arteries from CAV patients revealed similar pathologies common to ISR and non-intervened CAV segments. CONCLUSIONS: Progression of CAV at non-intervened segments and ISR correlate strongly and share common histopathology. Optimized treatment for patients with aggressive CAV needs to address the widespread nature of this disease, even when it presents as an initially focal lesion.

Subclavian coronary steal syndrome: an obligatory common fate between subclavian artery, internal mammary graft and coronary circulation.

The long-term patency of the left internal mammary artery (IMA) has made it the preferred conduit for myocardial revascularization. The proximal segment of the subclavian artery becomes functionally connected to the coronary circulation as a result of IMA implantation during coronary artery bypass surgery. The subclavian coronary steal syndrome results from stenosis in the left subclavian artery proximal to the IMA, compromising blood flow to the myocardium. We describe 7 patients, aged 55-75 years, 1.7-10.5 years after coronary bypass who presented with recurrent angina due to subclavian artery stenosis. The IMA graft was found open in each patient. A true steal mechanism was not demonstrated, casting doubt on the syndrome's traditional name. Angioplasty and stenting of the subclavian artery resulted in the immediate disappearance of angina and continuous benefit at a follow-up of 3-32 months. The subclavian coronary steal syndrome, although rare, is a severe condition readily treated by angioplasty and stenting.