Weight gain post-heart transplantation is associated with an increased risk for allograft vasculopathy and rejection.

OBJECTIVE: Obesity and overweight are associated with an increased risk for cardiovascular disease. Since fat mass (FM) and fat-free mass (FFM) both contribute to total body weight (TBW), we characterized the post-heart transplantation (HT) change in TBW and its implications for outcomes. METHODS: Post-HT changes in TBW, FM, and FFM were reviewed for 211 HT patients assessed during 1997-2017. Endpoints included cardiac allograft vasculopathy (CAV) and rejection. RESULTS: Median TBW increased by 7.3% at 1 year, with a significant rise in the obese category (28% vs. 13%, p < 0.001) and with FM versus FFM making the main contribution (23% vs. 3%, p < 0.001). When patients were divided according to median TBW change ("high" vs. "low"), Kaplan-Meier analysis showed that 10-year freedom from CAV (log-rank p < 0.005) and rejection (log-rank p < 0.01) was significantly higher for the "low" TBW change group. Consistently, multivariable analyses showed that the "high" group was independently associated with significant 3.5-fold and 4.2-fold increased risks for CAV (95% CI 1.4-8.7, p = 0.01) and rejection (95% CI 1.2-15.4, p = 0.03), respectively. CONCLUSIONS: Weight gain, contributed mostly by FM, is independently associated with an increased risk for CAV and rejection. Follow-up emphasis should be placed on weight gain and preventative measures.

Donor thyroid hormone therapy is associated with an increased risk of graft dysfunction after heart transplantation.

OBJECTIVE: Heart transplantation (HT) is uniquely associated with the potential impact of thyroid hormone therapy at three intersecting levels-donor, operation, and recipient. We aimed to study the effect of thyroid hormone therapy of the donor on primary graft dysfunction (PGD). METHODS: A retrospective cohort study was conducted on 209 HT recipients assessed from 1997 to 2018; for 33 of the recipients, the donors had received T4 (DT4 group), and for 176, the donors had not (NoDT4 group). The primary endpoint was PGD defined according to the International Society for Heart and Lung consensus statement. RESULTS: Both the incidence (58% vs 35%, P = .022) and the severity of PGD (42% vs 25% moderate/severe, P = .007) were significantly higher in the DT4 recipients. Multivariable analysis showed donor T4 therapy to be independently associated with a ~3.5-fold increased risk for PGD (OR = 3.44, 95% CI 1.26-9.86). These results remained consistent after propensity score analysis. CONCLUSIONS: Donor thyroid hormone therapy is independently associated with an increased risk of PGD. Hypothesizing a "withdrawal effect" as the cause, we suggest that administration of thyroid hormone to the recipient at time of reperfusion could counter this negative effect. Prospective studies are needed to validate this hypothesis-generating study.

Recurrent acute cellular rejection graded ISHLT 1R early after heart transplantation negatively affects long-term outcomes: The prognostic significance of 1990 ISHLT grades 1B and 2.

PURPOSE: We investigated the implications of early recurrent 1R rejections for long-term outcomes after heart transplantation (HT) and evaluated the prognostic significance of 1990 ISHLT grading 1B/2 versus 1A. METHODS: Data on all patients who underwent HT between 1992 and 2017 were reviewed. Patients with ≥2 endomyocardial biopsies graded 1R in the first 3 months were classified as "recurrent 1R." Those patients were further categorized according to 1A vs. 1B/2. Outcomes (>3 months) were long-term rejections and the combined endpoint of cardiac allograft vasculopathy (CAV) and cardiovascular (CV) mortality. RESULTS: Sixty-nine out of 228 patients were classified as recurrent grade 1R. In the recurrent 1R group, 2R rejection rate was significantly higher (2.6 ±â€¯0.6 vs 1.2 ±â€¯0.4, p = 0.03), while survival free of rejections was lower (5-year: 57.1% vs. 72.3%, p = 0.022). Multivariate analysis showed that early recurrent 1R rejection was associated with a 30% increased risk for subsequent major rejection. Among 28 patients classified as 1B/2 of the recurrent group, rejection scores were higher, while survival free of rejections was lower, compared to 37 patients of the recurrent group classified as 1A (5-year: 57.1% vs. 72.7%, p = 0.013). Kaplan-Meier analysis showed that CAV/CV mortality at 10 years of follow-up was significantly higher among the recurrent 1R group (38% vs. 18% p < 0.05). Multivariate analysis showed that early recurrent 1R rejections were associated with a 2.5-fold increased risk for CAV/CV mortality. CONCLUSION: Early recurrent grade 1R rejections negatively affect long-term outcomes. The adverse outcomes are experienced mainly by 1R patients subcategorized as1B/2 and not 1A.

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.

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.

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.

Quality of life and long-term mortality in patients with advanced chronic heart failure treated with intermittent low-dose intravenous inotropes in an outpatient setting.

AIMS: There are limited data on the effect of low-dose, intermittent inotropic therapy in an outpatient setting on the quality of life (QOL) in patients with advanced refractory heart failure (HF) symptoms. We aimed to analyse the effect of this treatment modality on QOL and subsequent survival. METHODS AND RESULTS: The study population comprised 287 consecutive patients with advanced refractory HF symptoms who were treated with low-dose, intravenous intermittent inotropic therapy in the HF Day Care Service at Sheba Medical Centre between September 2000 and September 2012. All patients completed a baseline Minnesota Living with Heart Failure Questionnaire (MLWHFQ), and 137 (48%) completed a 1 year follow-up questionnaire. MLWHFQ scores' means ranged from 0 (better QOL) to 5 (worse QOL). Mean age was 68 ± 12, 86% were men, 77% had ischaemic cardiomyopathy, and the mean left ventricle ejection fraction (LVEF) was 26% ± 13. The mean baseline MLWHFQ score was 3.1 (±1), while the mean at 1 year of treatment was of 2.7 (±1.1), indicating an overall improvement in QOL associated with intermittent low-dose inotrope therapy (p < 0.01). Multivariate analysis showed that younger age, non-ischaemic cardiomyopathy, and worse renal function were independently associated with improvement in QOL at 1 year. Improvement in QOL was not associated with a significant survival benefit during subsequent follow-up. CONCLUSIONS: In patients with advanced refractory HF symptoms, treatment with low-dose, intermittent intravenous inotropes in an outpatient setting is associated with significant improvement in QOL. However, improvement in QOL in this population does not appear to affect subsequent long-term survival.

Heat acclimation and performance in hypoxic conditions.

INTRODUCTION: Hypoxia is known to reduce performance. Adaptation is limited and requires special conditions. Heat and hypoxia have been shown to share some adaptive mechanisms. The purpose of this study was to test the possibility that prior heat acclimation may preserve performance under hypoxia. METHODS: Eight young healthy men participated in this study. They went through two cognitive tests: Visual Vigilance Task (VVT) and Four Choice Reaction Time (FCRT); through a Dynamic Posture Test (DPT); and through an exercise onset of blood lactate accumulation rate (OBLA) test under moderate hypoxia (O2 = 15.6%) before and after 12 d of heat acclimation. RESULTS: Maximal heart rate and core temperature were lower during the last day of heat acclimation compared to baseline (103 +/- 14 compared to 115 +/- 13 bpm and 37.59 +/- 0.20 compared to 37.83 +/- 0.28 degrees C, respectively). OBLA was higher after heat acclimation under both normoxic and hypoxic conditions. Blood oxygen saturation during walking at a pace of 7 km/h in hypoxic conditions was higher after heat acclimation compared to baseline (88 +/- 2% and 86.5 +/- 2%, respectively). Average steps during DPT in hypoxic conditions increased from 4.083 +/- 0.044 to 4.75 +/- 0.326 after heat acclimation. The VVT results under hypoxia did not change after heat acclimation, but false positive results were lower. The FCRT test results improved after heat acclimation (475 +/- 30 ms compared to 500 +/- 24 ms). CONCLUSIONS: Prior heat acclimation may reduce physiological strain and improve cognitive performance in moderate hypoxia. Further studies are required in order to evaluate the possibility of implementing this method as an operational preconditioning tool.

Hand immersion in cold water alleviating physiological strain and increasing tolerance to uncompensable heat stress.

The current study examines the use of hand immersion in cold water to alleviate physiological strain caused by exercising in a hot climate while wearing NBC protective garments. Seventeen heat acclimated subjects wearing a semi-permeable NBC protective garment and a light bulletproof vest were exposed to a 125 min exercise-heat stress (35 degrees C, 50% RH; 5 km/h, 5% incline). The heat stress exposure routine included 5 min rest in the chamber followed by two 50:10 min work-rest cycles. During the control trial (CO), there was no intervention, whilst in the intervention condition the subjects immersed their hands and forearms in a 10 degrees C water bath (HI). The results demonstrated that hand immersion in cold water significantly reduced physiological strain. In the CO exposure during the first and second resting periods, the average rectal temperature (T (re)) practically did not decrease. With hand immersion, the mean (SD) T (re) decreased by 0.45 (0.05 degrees C) and 0.48 degrees C (0.06 degrees C) during the first and second rest periods respectively (P < 0.005). Significant decreases in skin temperature, sweat rate, heart rate, and heat storage was also noted in the HI vs. the CO trials. Tolerance time in the HI exposure were longer than in the CO exposure (only 12 subjects in the CO trial endured the entire heat exposure session, as opposed to all 17 subjects in the HI group). It is concluded that hand immersion in cold water for 10 min is an effective method for decreasing the physiological strain caused by exercising under heat stress while wearing NBC protective garments. The method is convenient, simple, and allows longer working periods in hot or contaminated areas with shorter resting periods.