Malignancy following heart transplantation: differences in incidence and prognosis between sexes - a multicenter cohort study.

Male patients are at increased risk for developing malignancy postheart transplantation (HT); however, real incidence and prognosis in both genders remain unknown. The aim of this study was to assess differences in incidence and mortality related to malignancy between genders in a large cohort of HT patients. Incidence and mortality rates were calculated for all tumors, skin cancers (SCs), lymphoma, and nonskin solid cancers (NSSCs) as well as survival since first diagnosis of neoplasia. 5865 patients (81.6% male) were included. Total incidence rates for all tumors, SCs, and NSSCs were lower in females [all tumors: 25.7 vs. 44.8 per 1000 person-years; rate ratio (RR) 0.68, (0.60-0.78), P < 0.001]. Mortality rates were also lower in females for all tumors [94.0 (77.3-114.3) vs. 129.6 (120.9-138.9) per 1000 person-years; RR 0.76, (0.62-0.94), P = 0.01] and for NSSCs [125.0 (95.2-164.0) vs 234.7 (214.0-257.5) per 1000 person-years; RR 0.60 (0.44-0.80), P = 0.001], albeit not for SCs or lymphoma. Female sex was associated with a better survival after diagnosis of malignancy [log-rank p test = 0.0037; HR 0.74 (0.60-0.91), P = 0.004]. In conclusion, incidence of malignancies post-HT is higher in males than in females, especially for SCs and NSSCs. Prognosis after cancer diagnosis is also worse in males.

Incidence of vasoplegic syndrome after cardiac transplantation in patients treated with sacubitril/valsartan.

Vasoplegic syndrome (VS) is associated with poor outcomes after heart transplantation (HT). Our aim was to determine whether SAC/VALS is associated with VS after HT. We retrospectively analyzed all consecutive HT performed in three centers between January 2017 and August 2018. VS was defined as vasopressor need (norepinephrine or epinephrine >.5 mcg/kg/min or vasopressin) for more than 24 hours to maintain a mean arterial pressure >70 mm Hg. Ninety-six recipients underwent HT in the study period: 60 elective HT with no LVAD, 5 elective HT on long term LVAD, and 31 emergent HT: 3 on long-term LVAD and 28 on temporary mechanical circulatory support. Fourteen patients were on SAC/VALS treatment at the time of transplant, and 82 were not. The global incidence of VS was 15.6%, with no significant differences between the groups (7.14% in with SAC/VALS vs 17.07% in no-SAC/VALS). In conclusion, in our small cohort SAC/VALS was not associated with VS development.

Gender differences in heart transplantation: Twenty-five year trends in the nationwide Spanish heart transplant registry.

The study of gender differences may lead into improvement in patient care. We have aimed to identify the gender differences in heart transplantation (HT) of adult HT recipients in Spain and their evolution in a study covering the years 1993-2017 in which 6740 HT (20.6% in women) were performed. HT indication rate per million inhabitants was lower in women, remaining basically unchanged during the 25-year study period. HT rate was higher in men, although this decreased over the 25-year study period. Type of heart disease differed in men versus women (p < .001): ischemic heart disease 47.6% versus 22.5%, dilated cardiomyopathy 41.3% versus 34.6%, or other 36% versus 17.8%, respectively. Men were more frequently diabetics (18% vs. 13.1% p < .001), hypertensives (33.1% vs. 24% p < .001), and smokers (21.7% vs. 12.9% p < .001), respectively. Women had more pre-HT malignancies (7.1% vs. 2.8% p < .001), and their clinical status was worse at HT due to renal function and mechanical ventilation. Adjusted survival (p = .198) and most of the mortality-related variables were similar in men and women. Death occurred more frequently in women due to rejection (7.9% vs. 5.1% p < .001) and primary failure (18.2% vs. 12.5% p < .001) and in men due to malignancies (15.1% vs. 6.6% p < .001).

Impact of mechanical circulatory support on survival in pediatric heart transplantation.

Evidence on the impact of MCS on pediatric heart transplant survival is still scarce related to congenital heart disease patients including univentricular physiology as well as the risk factors for complications. We performed a retrospective review of all urgent pediatric (aged ≤16 years) HT from 2004 to 2014 in the Spanish Pediatric Heart Transplant Registry Group. Patients were stratified into two groups: urgent 0 (MCS at HT) and urgent 1 (non-MCS at HT). The primary outcome measure was post-transplant survival; secondary outcome measures were complications and absence of infections and rejection during the first post-transplant year. One hundred twenty-one pediatric patients underwent urgent HT, 58 (47.9%) urgent 0 and 63 (52%) urgent 1. There were 30 (24.8%) deaths: 12 in the urgent 0 group and 18 in the urgent 1 group, P = n.s. Regarding the type of MCS, patients on ECMO had the highest rate of complications (80%) and mortality (40%). Patients in the urgent 1 group showed a higher risk of hospital re-admission for infection during the first year after transplantation (OR 2.31 [1.1-4.82]), P = .025. We did not identify a risk factor for mortality. MCS does not impact negatively on survival after HT. However, there is a significant increase in 30-day and 1-year mortality and complications in ECMO patients compared with VAD patients. Infants, congenital heart disease, and PediMACS were not found to be risk factors for mortality.

Elective or emergency heart transplantation: Cost comparison in a single center.

BACKGROUND AND AIMS: Heart transplantation (HT) is the treatment of choice for selected cases of advanced heart failure. There is an increasing rate of emergency HT in our country. The aim of this study was to determine the cost of HT in our hospital according to emergent vs. elective transplantation status. METHODS: The costs of all consecutive HTs performed in our center between January 2010 and May 2015 were analyzed. The cost of elective and emergent HT was compared. RESULTS: HT mean cost at our institution was €62 203 ± 47 976. Elective HT mean cost was €47 540 ± 25 140, whereas emergent HT cost was €102 733 ± 68 050 (emergency status 1, as regional priority, was €66 077 ± 28 067 and emergency status 0, as the highest national priority, was €136 056 ± 77 080; P < 0.001). Increased emergent HT cost was mainly related to a longer admission (32 ± 24 days vs. 69 ± 53 days; P = 0.006; accounting for a cost of €14 517 ± 12 475 vs. €37 846 ± 31 702; P < 0.001) and increased drug-related expenses (€6622 ± 7465 vs. €15,171 ± 15,758; P < 0.02). Elective HT survival rate was 96%, compared to 68% for emergent HT; P = 0.002. CONCLUSIONS: Elective HT showed a high survival rate with a relatively low and less variable cost, leading to a favorable economic balance in today's public health reimbursement system. In contrast, emergent HT showed a higher cost and a lower survival rate. New treatment strategies should be identified for heart failure patients at risk of requiring emergency HT.

Initial experience with bosentan for the management of pulmonary hypertension after heart transplantation.

BACKGROUND: Pulmonary hypertension (PH) after heart transplantation (HT) is associated to right ventricular (RV) dysfunction and increased morbidity and mortality. We present our experience with bosentan for the treatment of PH after HT. METHODS: A retrospective evaluation of patients with PH receiving bosentan post-transplant was performed. Pulmonary hemodynamics before and after bosentan (BG) and clinical outcomes were assessed and compared to a historical control group (CG) not receiving bosentan. RESULTS: Between 2013 and 2016, 21 patients were treated post-transplant with bosentan. Twenty-four hours after bosentan initiation, there were significant decreases in systolic (42.5 ± 8 to 38.1 ± 8 mm Hg, P = 0.015), diastolic (21.4 ± 4 to 17.8 ± 6 mm Hg, P = 0.008) and mean (29.6 ± 5 to 25 ± 6 mm Hg, P = 0.001) pulmonary artery pressures (PAP), transpulmonary gradient (13.1 ± 3 to 9.7 ± 4 mm Hg, P < 0.001), diastolic gradient (5.2 ± 4 to 2.3 ± 3 mm Hg, P = 0.001) and pulmonary vascular resistance (PVR) (2.2 ± 1 to 1.6 ± 1WU, P = 0.015). This effect was maintained at day 3. Compared with CG, BG showed significantly more decrease in PVR (0.7 ± 0.9 vs 0.3 ± 1.7WU, P = 0.025) and mean PAP (4.6 ± 5.2 vs 1.5 ± 4.4 mm Hg, P = 0.040). RV function 7 days post-transplant was significantly better in BG compared to CG, P = 0.004. There were not clinically significant interactions between bosentan and immunosuppressive treatment. CONCLUSIONS: Bosentan, initiated early post-transplant, was associated with a significant decrease in PVR. Bosentan was well tolerated and did not interact with immunosuppressive treatment.

Predictors of renal replacement therapy after heart transplantation and its impact on long-term survival.

BACKGROUND: Renal replacement therapy (RRT) after heart transplant (HT) is associated with worse prognosis. We aimed to identify predictors of RRT and the impact of this complication on long-term survival. METHODS: Cohort study of HT patients. Univariate and multivariate competing-risk regression was performed to identify independent predictors of RRT. The cumulative incidence function was plotted for RRT. The Kaplan-Meier method was used to compare long-term survival. RESULTS: We included 103 patients. At multivariate analysis, only the emergency status of HT (short-term mechanical circulatory support as a bridge to transplant), chronic kidney disease, and low oxygen delivery were independent predictors of RRT (subhazard ratio [SHR] 4.11, 95% CI 1.84-9.14; SHR 3.17, 95% CI 1.29-7.77; SHR 2.86, 95% CI 1.14-7.19, respectively). Elective HT patients that required RRT showed a significantly reduced survival comparable to patients with emergency HT and RRT (75% ± 13% vs. 67% ± 16%). The absence of RRT implied an excellent survival in patients with an emergency status of HT and elective HT (100% vs. 93% ± 4%). CONCLUSION: The emergency status of HT, chronic kidney disease, and low oxygen delivery were independent predictors of RRT. The occurrence of RRT increases the risk of death in elective HT as much as in patients with an emergency status.

Transcriptional regulation of the sodium channel gene (SCN5A) by GATA4 in human heart.

Aberrant expression of the sodium channel gene (SCN5A) has been proposed to disrupt cardiac action potential and cause human cardiac arrhythmias, but the mechanisms of SCN5A gene regulation and dysregulation still remain largely unexplored. To gain insight into the transcriptional regulatory networks of SCN5A, we surveyed the promoter and first intronic regions of the SCN5A gene, predicting the presence of several binding sites for GATA transcription factors (TFs). Consistent with this prediction, chromatin immunoprecipitation (ChIP) and sequential ChIP (Re-ChIP) assays show co-occupancy of cardiac GATA TFs GATA4 and GATA5 on promoter and intron 1 SCN5A regions in fresh-frozen human left ventricle samples. Gene reporter experiments show GATA4 and GATA5 synergism in the activation of the SCN5A promoter, and its dependence on predicted GATA binding sites. GATA4 and GATA6 mRNAs are robustly expressed in fresh-frozen human left ventricle samples as measured by highly sensitive droplet digital PCR (ddPCR). GATA5 mRNA is marginally but still clearly detected in the same samples. Importantly, GATA4 mRNA levels are strongly and positively correlated with SCN5A transcript levels in the human heart. Together, our findings uncover a novel mechanism of GATA TFs in the regulation of the SCN5A gene in human heart tissue. Our studies suggest that GATA5 but especially GATA4 are main contributors to SCN5A gene expression, thus providing a new paradigm of SCN5A expression regulation that may shed new light into the understanding of cardiac disease.

Benefits of chronic total coronary occlusion percutaneous intervention in patients with heart failure and reduced ejection fraction: insights from a cardiovascular magnetic resonance study.

BACKGROUND: Chronic total occlusion percutaneous coronary intervention (CTO-PCI) can improve angina and left ventricular ejection fraction (LVEF). These benefits were not assessed in populations with heart failure with reduced ejection fraction (HFrEF). We studied the effect of CTO-PCI on left ventricular function and clinical parameters in patients with HFrEF. METHODS: Using cardiovascular magnetic resonance (CMR), we studied 29 patients with HFrEF and evidence of viability and/or ischemia in the territory supplied by a CTO who were successfully treated with CTO-PCI. In patients with multi-vessel disease, non-CTO PCI was also performed. Imaging parameters, clinical status, and brain natriuretic peptide (BNP) levels were evaluated before and 6 months after CTO-PCI. RESULTS: A decrease in left ventricular end-systolic volume (160 ± 54 ml vs. 143 ± 58 ml; p = 0.029) and an increase in LVEF (31.3 ± 7.4 % vs. 37.7 ± 8 %; p < 0.001) were observed. There were no differences in LVEF improvement between patients who underwent non-CTO PCI (n = 11) and those without this intervention (n = 18); (p = 0.73). The number of segments showing perfusion defects was significantly reduced (0.5 ± 1 vs. 0.2 ± 0.5; p = 0.043). Angina (p = 0.002) and NYHA functional class (p = 0.004) improved, and BNP levels decreased (p = 0.004) after CTO-PCI. CONCLUSIONS: In this group of patients with HFrEF showing CMR evidence of viability and/or ischemia within the territory supplied by the CTO, an improvement in ejection fraction, left ventricular end-systolic volume and ischemia burden was observed after CTO-PCI. Clinical and laboratory parameters also improved. TRIAL REGISTRATION: ClinicalTrials.gov NCT02570087 . Registered 6 October 2015.

Prognosis of new-onset heart failure outpatients and collagen biomarkers.

BACKGROUND: Prognosis of heart failure patients has been defined in hospital-based or retrospective studies. This study aimed to characterize prognosis of outpatients with new-onset preserved or reduced ejection fraction heart failure; to explore the role of collagen turnover biomarkers (MMP2, MMP9, TIMP1) in predicting prognosis; and to analyse their relationship with echocardiographic parameters and final diagnosis. METHODS: This is an observational, prospective, longitudinal study. Outpatients with new-onset heart failure symptoms referred to a one-stop clinic were included. Echocardiography and biomarkers plasma levels determination were performed at the inclusion. A prospective follow-up was conducted to report cardiovascular events. The discriminant analysis was applied to identify the parameters related to cardiovascular outcomes. RESULTS: A total of 172 patients (75 ± 9 years) were included, 67% with heart failure (64% preserved and 36% with reduced ejection fraction). During follow-up (median 34.5 months), 32.6% had at least one cardiovascular event and 9.9% died. Heart failure groups showed no differences in cardiovascular outcomes with a higher rate of events than nonheart failure patients. MMP2 and TIMP1 were correlated with diastolic dysfunction (Rho 0.349 and 0.294, P < 0.001). In the discriminant analysis, the combination of biomarkers with clinical, biochemical and echocardiographic parameters was useful to predict cardiovascular outcomes (AUC ROC 0.806, Wilks lambda 0.7688, P < 0.001). CONCLUSIONS: Prognosis of outpatients with new-onset heart failure symptoms is comparable between heart failure with preserved or reduced subgroups. The addition of biomarkers specially MMP2 and high sensitive troponin I to other clinical, biochemical and echocardiographic variables can predict cardiovascular prognosis at the time of diagnosis.