Outcomes in recipients who have undergone combined heart and kidney transplantation have mainly been addressed in small, single-center studies. We studied long-term results of combined heart and ...kidney transplantation in a large multicenter cohort.
Between 1984 and 2007, 67 consecutive patients (61 men and 6 women) from 3 French centers underwent combined heart and kidney transplantation. At transplantation, 38 (57%) were receiving dialysis. All patients received immediate triple immunosuppression therapy (anti-calcineurin, steroids, azathioprine, or mycophenolate).
Overall actuarial survival rates were 62.0%, 60.3%, 53.3%, and 46.5% at 1, 3, 5, and 10 years, respectively. These rates were similar to those observed in 2981 isolated heart recipients at the 3 participating centers during the same period (respectively, 71.0%, 65.2%, 60.1%, and 47.2%, p = 0.6). Survival tended to improve during the last decade (1996 to 2007) and reached 71.1%, 67.5%, and 60% at 1, 3, and 5 years. Cardiac allograft rejection requiring treatment occurred in 12 (17.9%). Coronary artery vasculopathy developed in 3 (9.3%). Kidney allograft rejection occurred in 9 (13.4%). Kidney graft survival was 95.9% at 1, 3, 5, and 10 years.
Long-term survival rates in a large cohort of combined heart and kidney recipients are similar to those of isolated heart recipients in France. The rates of acute heart and kidney rejection and angiographic coronary artery vasculopathy were low in this patient population.
In 2018, an algorithm-based allocation system for heart transplantation (HT) was implemented in France. Its effect on access to HT of patients with rare causes of heart failure (HF) has not been ...assessed.
In this national study, including adults listed for HT between 2018 and 2020, we analyzed waitlist and posttransplant outcomes of candidates with rare causes of HF (restrictive cardiomyopathy RCM, hypertrophic cardiomyopathy, and congenital heart disease). The primary end point was death on the waitlist or delisting for clinical deterioration. Secondary end points included access to HT and posttransplant mortality. The cumulative incidence of waitlist mortality estimated with competing risk analysis and incidence of transplantation were compared between diagnosis groups. The association of HF cause with outcomes was determined by Fine-Gray or Cox models.
Overall, 1604 candidates were listed for HT. At 1 year postlisting, 175 patients met the primary end point and 1040 underwent HT. Candidates listed for rare causes of HF significantly differed in baseline characteristics and had more frequent score exceptions compared with other cardiomyopathies (31.3%, 32.0%, 36.4%, and 16.7% for patients with hypertrophic cardiomyopathy, RCM, congenital heart disease, and other cardiomyopathies). The cumulative incidence of death on the waitlist and probability of HT were similar between diagnosis groups (
=0.17 and 0.40, respectively). The adjusted risk of death or delisting for clinical deterioration did not significantly differ between candidates with rare and common causes of HF (subdistribution hazard ratio (HR): hypertrophic cardiomyopathy, 0.51 95% CI, 0.19-1.38;
=0.18; RCM, 1.04 95% CI, 0.42-2.58;
=0.94; congenital heart disease, 1.82 95% CI, 0.78-4.26;
=0.17). Similarly, the access to HT did not significantly differ between causes of HF (hypertrophic cardiomyopathy: HR, 1.18 95% CI, 0.92-1.51;
=0.19; RCM: HR, 1.19 95% CI, 0.90-1.58;
=0.23; congenital heart disease: HR, 0.76 95% CI, 0.53-1.09;
=0.14). RCM was an independent risk factor for 1-year posttransplant mortality (HR, 2.12 95% CI, 1.06-4.24;
=0.03).
Our study shows equitable waitlist outcomes among HT candidates whatever the indication for transplantation with the new French allocation scheme.
Using reduced doses of Cyclosporine A immediately after heart transplantation in clinical trials may suggest benefits for renal function by reducing serum creatinine levels without a significant ...change in clinical endpoints. However, these trials were not sufficiently powered to prove clinical outcomes.
In a prospective, multicentre, open-label, parallel-group controlled trial, 95 patients aged 18 to 65 years old, undergoing de novo heart transplantation were centrally randomised to receive either a low (130 < trough CsA concentrations <200 μg/L, n = 47) or a standard dose of Cyclosporine A (200 < trough CsA concentrations <300 μg/L, n = 48) for the three first post-transplant months along with mycophenolate mofetil and corticosteroids. Participants had a stable haemodynamic status, a serum creatinine level <250 μmol/L and the donors' cold ischemia time was under six hours; multiorgan transplants were excluded. The change in serum creatinine level over 12 months was used as the main criterion for renal function. Intention-to-treat analysis was performed on the 95 randomised patients and a mixed generalised linear model of covariance was applied.
At 12 months, the mean (± SD) creatinine value was 120.7 μmol/L (± 35.8) in the low-dose group and 132.3 μmol/L (± 49.1) in the standard-dose group (P = 0.162). Post hoc analyses suggested that patients with higher creatinine levels at baseline benefited significantly from the lower Cyclosporine A target. The number of patients with at least one rejection episode was not significantly different but one patient in the low-dose group and six in the standard-dose group required dialysis.
In patients with de novo cardiac transplantation, early Cyclosporine A dose reduction was not associated with renal benefit at 12 months. However, the strategy may benefit patients with high creatinine levels before transplantation.
ClinicalTrials.gov NCT00159159.
Trichilemmal carcinoma is a rare cutaneous adnexal malignant tumor deriving from the outer root sheath of hair follicles. It is only rarely reported in recipients of solid (renal) organ transplants. ...We describe the first case of trichilemmal carcinoma presenting with a misleading clinical aspect in a heart transplant recipient. We then briefly outline the salient clinicopathologic features of this malignancy.
Congestion is one of the main predictors of poor patient outcome in patients with heart failure. However, congestion is difficult to assess, especially when symptoms are mild. Although numerous ...clinical scores, imaging tools, and biological tests are available to assist physicians in ascertaining and quantifying congestion, not all are appropriate for use in all stages of patient management. In recent years, multidisciplinary management in the community has become increasingly important to prevent heart failure hospitalizations. Electronic alert systems and communication platforms are emerging that could be used to facilitate patient home monitoring that identifies congestion from heart failure decompensation at an earlier stage. This paper describes the role of congestion detection methods at key stages of patient care: pre-admission, admission to the emergency department, in-hospital management, and lastly, discharge and continued monitoring in the community. The multidisciplinary working group, which consisted of cardiologists, emergency physicians, and a nephrologist with both clinical and research backgrounds, reviewed the current literature regarding the various scores, tools, and tests to detect and quantify congestion. This paper describes the role of each tool at key stages of patient care and discusses the advantages of telemedicine as a means of providing true integrated patient care.
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End stage kidney disease increase the risk of COVID-19 related death but how the kidney replacement strategy should be adapted during the pandemic is unknown. Chronic hemodialysis makes social ...distancing difficult to achieve. Alternatively, kidney transplantation could increase the severity of COVID-19 due to therapeutic immunosuppression and contribute to saturation of intensive care units. For these reasons, kidney transplantation was suspended in France during the first epidemic wave. Here, we retrospectively evaluated this strategy by comparing the overall and COVID-19 related mortality in kidney transplant recipients and candidates over the last three years. Cross-interrogation of two national registries for the period 1 March and 1 June 2020, identified 275 deaths among the 42812 kidney transplant recipients and 144 deaths among the 16210 candidates. This represents an excess of deaths for both populations, as compared with the same period the two previous years (mean of two previous years: 253 in recipients and 112 in candidates). This difference was integrally explained by COVID-19, which accounted for 44% (122) and 42% (60) of the deaths in recipients and candidates, respectively. Taking into account the size of the two populations and the geographical heterogeneity of virus circulation, we found that the excess of risk of death due to COVID-19 was similar for recipients and candidates in high viral risk area but four-fold higher for candidates in the low viral risk area. Thus, in case of a second epidemic wave, kidney transplantation should be suspended in high viral risk areas but maintained outside those areas, both to reduce the excess of deaths of candidates and avoid wasting precious resources.
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Despite promising preclinical results targeting sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA2), clinical trials application remains limited, highlighting the urgency to develop suitable ...model reflecting clinical physiopathology. Recently, we discovered a new regulatory mechanism of SERCA2 based on serine 663-phosphorylation involved as a key regulator of Ca2+ homeostasis in several cell types (HEK, MEF and isolated mice cardiomyocytes).
To assess translational potential, we developed a human-induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) model focused on modulation of SERCA2 activity.
hiPSC-derived cardiomyocytes were infected (6days, MOI 200 000) with the AAV9-Serca WT, the AAV9-Serca2S663A phosphoresistant or the AAV9-Serca2S663E phosphomimetic mutants. For Ca2+ERexperiments, basal and refilling slope were measured in hiPSC-CM using D4ER Ca2+ probe. Cytosolic Ca2+ imaging was investigated using Fura2 probe (2μM). Cell viability was evaluated after 5h hypoxia (1%O2) and 5h reoxygenation (H/R).
In opposite to SERCA2S663E cells, the evaluation of SERCA2 activity revealed that SERCA2S663A hiPSC-CM displayed significantly increased ER Ca2+ refilling rate (+56%) and ER Ca2+ content (+66%) versus SERCA2WT. Interestingly, SERCA2S663A displayed a significant decreased cell death after H/R stress compared to SERCA2WT. Although, measuring of cytosolic Ca2+ transients in beating control hiPSC-CMs, there were no changes (peak amplitude 0.08μm, area under curve 0.04μm2) in all mutants due to ineffective infection.
Our results provide an essential regulatory mechanism of Ca2+ homeostasis and cell death, based on the phosphorylation state of SERCA2 in human cell types, notably hiPSC-CM. Although still requiring some adjustments, hiPSC-CM appear to be an essential model for translational research in the field of heart disease.
Abstract only
Introduction:
Despite advances in cardioprotection, new therapeutic strategies capable of preventing acute myocardial ischemia-reperfusion injury and reducing secondary event of ...patients are still needed.
Hypothesis:
We hypothesized that limitation of SERCA2 phosphorylation on a serine/threonine residue at reperfusion could provide protection against reperfusion injury, via the activation of the Ca
2+
reuptake into SR/ER which confers detoxification of the cytosolic and mitochondrial Ca
2+
overload during reperfusion
.
Methods:
Combining
in silico
analysis with
in vitro
and
in vivo
genetic approaches, we discovered that the phosphorylation of SERCA2 at serine 663 is a clinical and pathophysiological event of cardiac function.
Results:
We demonstrated that the phosphorylation level of SERCA2 at serine 663 is increased with heart damage in both patient and mouse ischemic hearts. Mechanistically, we demonstrated that preventing serine 663 phosphorylation significantly increased SERCA2 Ca
2+
pumping activity into the reticulum and protected against hypoxia/reoxygenation-induced cell death, by counteracting the cytosolic and mitochondrial Ca
2+
overload. To link this specific residue event to a physiological role of SERCA2 in heart, we demonstrated that gene therapy for the phosphoresistant form of SERCA2 at serine 663 improved the excitation/contraction coupling of cardiomyocytes and significantly reduced infarct size in an
in vivo
myocardial infarction model, whereas mice expressing a phosphomimetic form of SERCA2 developed a larger infarct size.
Conclusions:
Together, these findings establish the pathophysiological role and the therapeutic potential of SERCA2 modulation in acute myocardial infarction, based on the hotspot phosphorylation level of SERCA2 on its serine 663 residue.
Coronary allograft vasculopathy (CAV) is the major limiting factor for long term survival after heart transplantation. The aim of this study was to identify gene candidates implicated in human CAV ...using a rat aortic allograft model in tandem with microarrays and quantitative real time PCR (Q-PCR).
Rat abdominal aortas were isografted (5) or allografted (5) from Brown-Norway to Lewis rats and grafts were harvested after day 8, 25 and 60. Agilent microarrays were then used to highlight differentially expressed genes between isografted and allografted rat aortas. Further investigation of a selected candidate gene was performed on human coronary arteries.
1829, 2582 and 1925 genes (fold changes >2 or <2 and p values <0.05) were differentially expressed at day 8, 25 and 60 respectively between isografs and allografts. Seventeen candidate genes were selected according to significant differential expression at day 60. These rat candidate genes were then validated by quantitative real time polymerase chain reaction (Q-PCR). One of these candidate genes, T-Cadherin (T-Cad) was further investigated, using immunohistochemistry (IHC), in human coronary arteries showing CAV compared to classical atherosclerosis present in ischemic cardiomyopathy (ICM) and normal coronary arteries present in dilated cardiomyopathy (DCM). Results showed an over expression of T-Cad in CAV and classical atherosclerosis compared to normal coronary arteries.
T-Cad was found to be over expressed in CAV. T-Cad could potentially act as a trigger for smooth muscle cells (SMCs) proliferation and vascular remodelling observed in CAV leading to a diffuse narrowing of the arterial lumen.
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