Clinical evaluation of rosuvastatin in heart transplant patients with hypercholesterolemia and therapeutic failure of other statin regimens: short-term and long-term efficacy and safety results.

We conducted an observational study of 30 heart transplant recipients with serum low-density lipoprotein cholesterol (LDL-c) >100 mg/dl despite previous statin therapy, who were treated with rosuvastatin 10 mg daily (5 mg in case of renal dysfunction). Serum lipids, creatine phosphokinase (CPK), bilirubin, and hepatic enzymes were prospectively measured 2, 4, and 12 weeks after the initiation of the drug. Clinical outcomes of patients who continued on long-term rosuvastatin therapy beyond this 12-week period were reviewed in February 2015. Over the 12-week period following rosuvastatin initiation, serum levels of total cholesterol (TC) and LDL-c and the ratio TC/high-density lipoprotein cholesterol (HDL-c) decreased steadily (P < 0.001). Average absolute reductions of these three parameters were -48.7 mg/dl, -46.6 mg/dl, and -0.9, respectively. Seventeen (57%) achieved a serum LDL-c < 100 mg/dl. No significant changes from baseline were observed in serum levels of triglycerides, HDL-c, hepatic enzymes, bilirubin, or CPK. Twenty-seven (90%) patients continued on long-term therapy with rosuvastatin over a median period of 3.6 years, with no further significant variation in lipid profile. The drug was suspended due to liver toxicity in 1 (3.3%) patient and due to muscle toxicity in 2 (6.7%) patients. All adverse reactions resolved rapidly after rosuvastatin withdrawal. Our study supports rosuvastatin as a reasonable alternative for heart transplant recipients with hypercholesterolemia and therapeutic failure of other statin regimens.

Reduced mitochondrial pyruvate carrier expression in hearts with heart failure and reduced ejection fraction patients: ischemic vs. non-ischemic origin.

Introduction and objectives: Mitochondrial pyruvate carrier (MPC) mediates the entry of pyruvate into mitochondria, determining whether pyruvate is incorporated into the Krebs cycle or metabolized in the cytosol. In heart failure (HF), a large amount of pyruvate is metabolized to lactate in the cytosol rather than being oxidized inside the mitochondria. Thus, MPC activity or expression might play a key role in the fate of pyruvate during HF. The purpose of this work was to study the levels of the two subunits of this carrier, named MPC1 and MPC2, in human hearts with HF of different etiologies. Methods: Protein and mRNA expression analyses were conducted in cardiac tissues from three donor groups: patients with HF with reduced ejection fraction (HFrEF) with ischemic cardiomyopathy (ICM) or idiopathic dilated cardiomyopathy (IDC), and donors without cardiac pathology (Control). MPC2 plasma levels were determined by ELISA. Results: Significant reductions in the levels of MPC1, MPC2, and Sirtuin 3 (SIRT3) were observed in ICM patients compared with the levels in the Control group. However, no statistically significant differences were revealed in the analysis of MPC1 and MPC2 gene expression among the groups. Interestingly, Pyruvate dehydrogenase complex (PDH) subunits expression were increased in the ICM patients. In the case of IDC patients, a significant decrease in MPC1 was observed only when compared with the Control group. Notably, plasma MPC2 levels were found to be elevated in both disease groups compared with that in the Control group. Conclusion: Decreases in MPC1 and/or MPC2 levels were detected in the cardiac tissues of HFrEF patients, with ischemic or idiopatic origen, indicating a potential reduction in mitochondrial pyruvate uptake in the heart, which could be linked to unfavorable clinical features.

Soluble HLA-G levels in heart transplant recipients: Dynamics and correlation with clinical outcomes.

PURPOSE: To describe the evolution of the serum levels of soluble HLA-G (s-HLA-G) during the first 12 months after heart transplantation (HT) and to correlate it with clinical outcomes. METHODS: Observational study based in a single-center cohort of 59 patients who underwent HT between December-2003 and March-2010. Soluble HLA-G levels were measured from serum samples extracted before HT, and 1, 3, 6 and 12 months after HT. The cumulative burden of s-HLA-G expression during the first post-transplant year was assessed by means of the area under the curve (AUC) of s-HLA-G levels over time and correlated with the acute rejection burden -as assessed by a rejection score-, the presence of coronary allograft vasculopathy (CAV) grade ≥ 1 and infections during the first post-transplant year; as well as with long-term patient and graft survival. Mean follow-up was 12.4 years. RESULTS: Soluble HLA-G levels decreased over the first post-transplant year (p = 0.020). The AUC of s-HLA-G levels during the first post-transplant year was higher among patients with infections vs. those without infections (p = 0.006). No association was found between the AUC of s-HLA-G levels and the burden of acute rejection or the development of CAV. Overall long-term survival, long-term survival free of late graft failure and cancer-free survival were not significantly different in patients with an AUC of s-HLA-G levels higher or lower than the median of the study population. CONCLUSIONS: Soluble HLA-G levels decreased over the first year after HT. Higher HLA-G expression was associated with a higher frequency of infections, but not with the burden of acute rejection or the development of CAV, neither with long-term patient or graft survival.

Cancer in patients with heart failure: Incidence, risk factors and prognostic impact.

AIMS: To assess the incidence of cancer diagnosis and cancer-related mortality in patients with heart failure (HF). METHODS: Observational study based in a prospective cohort of patients with HF referred to a specialized Spanish clinic between 2010 and 2019. The observed incidence of malignancies (excluding non-melanoma skin cancer) was compared to that expected for the general Spanish population according to the Global Cancer Observatory. RESULTS: We studied 1909 consecutive patients with HF. Over a median follow-up of 4.07 years, 165 new cases of malignancy were diagnosed. Observed age-standardized incidence rates of cancer were 861 (95% CI 618.4-2159.4) cases per 100,000 patients-years in men and 728.5 (95% CI 451.1-4308.7) cases per 100,000 patients-years in women; while age-standardized incidence rates of cancer expected for the general Spanish population were 479.4 cases per 100,000 patients-years in men (risk ratio = 1.80) and 295.5 cases per 100,000 patients-years in women (risk ratio = 2.46). Both a history of pre-existing malignancy at baseline and the development of new malignancies during follow-up were associated with reduced survival. Observed age-standardized cancer-related mortality was 344.1 (95% CI 202.1-1675) deaths per 100,000 patient-years in men and 217.0 (95% CI 32.8-3949.3) deaths per 100,000 patient-years in women; while age-standardized cancer-related mortality expected for the general Spanish population was 201.4 deaths per 100,000 patients-years in men (risk ratio = 1.71) and 96.2 deaths per 100,000 patients-years in women (risk ratio = 2.26). CONCLUSION: Patients with HF showed higher incidence rates of cancer diagnosis and cancer-related mortality than those expected for the general population.

Determinants of maximal oxygen uptake in patients with heart failure.

AIMS: Maximum oxygen uptake (VO2max ) is an essential parameter to assess functional capacity of patients with heart failure (HF). We aimed to identify clinical factors that determine its value, as they have not been well characterized yet. METHODS: We conducted a retrospective, observational, single-centre study of 362 consecutive patients with HF who underwent cardiopulmonary exercise testing (CPET) as part of standard clinical assessment since 2009-2019. CPET was performed on treadmill, according to Bruce's protocol (n = 360) or Naughton's protocol (n = 2). We performed multivariable linear regression analyses in order to identify independent clinical predictors associated with peak VO2max . RESULTS: Mean age of study patients was 57.3 ± 10.9 years, mean left ventricular ejection fraction was 32.8 ± 14.2%, and mean VO2max was 19.8 ± 5.2 mL/kg/min. Eighty-nine (24.6%) patients were women, and 114 (31.5%) had ischaemic heart disease. Multivariable linear regression analysis identified six independent clinical predictors of VO2max , including NYHA class (B coefficient = -2.585; P < 0.001), age (B coefficient per 1 year = -0.104; P < 0.001), tricuspid annulus plane systolic excursion (B coefficient per 1 mm = +0.209; P < 0.001), body mass index (B coefficient per 1 kg/m2  = -0.172; P = 0.002), haemoglobin (B coefficient per 1 g/dL = +0.418; P = 0.007) and NT-proBNP (B coefficient per 1000 pg/mL = -0.142; P = 0.019). CONCLUSIONS: The severity of HF (NYHA class, NT-proBNP) as well as age, body composition and haemoglobin levels influence significantly exercise capacity. In patients with HF, the right ventricular systolic function is of greater importance for the physical capacity than the left ventricular systolic function.

Incidence, risk factors and prognostic impact of cytomegalovirus infection after heart transplantation. / Incidencia, factores de riesgo e impacto pronóstico de la infección por citomegalovirus tras el trasplante cardiaco.

INTRODUCTION AND OBJECTIVES: To assess the risk factors of cytomegalovirus (CMV) infection after heart transplant (HT) and its influence on long-term prognosis. METHODS: We conducted a retrospective single-centre study of 222 HT recipients. Risk factors for CMV infection were identified by means of multivariable Cox́s regression. Kaplan-Meier analysis and Cox́s regression were used to assess the long-term prognostic impact of CMV infection during the first post-transplant year. RESULTS: Donor-recipient CMV serologic matching (hazard ratio [HR] 1.92, 95% confidence interval [95% CI] 1.2-3.09, p=.007), recipient age (HR 1.02, 95% CI: 1.00-1.1, p=.02), diabetes mellitus (HR 1.86, 95% CI: 1.4-3.05, p=.01), pre-transplant circulatory support (HR 1.59, 95% CI: 1.06-2.38, p=.03) and the use of tacrolimus (HR 1.64, 95% CI: 1.13-2.36, p=.009) were independently associated with increased risk of CMV infection. CMV infection during the first year post-HT was not associated with worse transplant outcomes in terms of mortality, incidence of heart failure, cardiac allograft vasculopathy or acute rejection. CONCLUSIONS: CMV infection was not associated with impaired long-term prognosis after HT.

Comparison of predicted and observed mortality in patients with heart failure treated at a specialized unit.

INTRODUCTION AND OBJECTIVES: To analyze survival in heart failure (HF) patients treated at a specialized unit. METHODS: Prospective cohort-based study of HF patients treated at a specialized unit from 2011 to 2017. Observed 1- and 3-year mortality rates were compared with those predicted by the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score. RESULTS: We studied 1280 patients, whose median MAGGIC risk score was 19 [interquartile range, 13-24]. Prescription rates of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor antagonists, and sacubitril-valsartan were 93%, 67%, 22%, 73%, and 16%, respectively. The MAGGIC risk score showed good discrimination for mortality at 1 year (c-statistic=0.71) and 3 years (c-statistic=0.76). Observed mortality was significantly lower than predicted mortality, both at 1 year (6.2% vs 10.9%; observed/predicted ratio=0.57; P<.001) and at 3 years (16.7% vs 27.7%; observed/predicted ratio=0.60; P<.001). This discrepancy was found in several subgroups, except in patients aged> 70 years (29.9% vs 34.7%; observed/predicted ratio=0.86; P=.126) and in patients with ejection fraction> 40% (19.6% vs 20.7%; observed/predicted ratio=0.95; P=.640). CONCLUSIONS: Mortality in HF patients treated at a specialized clinic was significantly lower than that predicted by the MAGGIC risk score.

Circulating Galectin-3 Following Heart Transplant: Long-term Dynamics and Prognostic Value.

INTRODUCTION AND OBJECTIVES: Circulating galectin-3 (Gal-3) is elevated and significantly correlates with all-cause and cardiovascular mortality in patients with heart failure. However, the relationship between serum Gal-3 and heart transplant (HT) outcomes is unclear. The aim of this study was to describe the longitudinal trend and prognostic value of Gal-3 levels after HT. METHODS: Banked serum samples were available from 122 HT recipients, collected before transplant and at 1, 3, 6, and 12 months posttransplant. Gal-3 levels in these serum samples were measured by enzyme immune assay. Multivariable Cox regression was performed to determine the prognostic value of 12-month posttransplant Gal-3 serum levels. The primary endpoint was the composite variable all-cause death or graft failure over long-term posttransplant follow-up. RESULTS: Circulating Gal-3 concentration steadily decreased during the first year after HT (median values: pretransplant, 19.1 ng/mL; 1-year posttransplant, 14.6 ng/mL; P<.001). Circulating Gal-3 levels 1-year posttransplant were associated with an increased risk of all-cause death or graft failure (adjusted HR per 1 ng/mL, 1.04; 95%CI, 1.01-1.08; P=.008). The predictive accuracy of this biomarker was moderate: area under the ROC curve, 0.72 (95%CI, 0.60-0.82; P<.001). CONCLUSIONS: Circulating Gal-3 steadily decreased during the first year after HT. However, 1-year posttransplant Gal-3 serum levels that remained elevated were associated with increased long-term risk of death and graft failure.

Venous thromboembolism in heart transplant recipients: incidence, recurrence and predisposing factors.

BACKGROUND: A high frequency of venous thromboembolism (VTE) has been observed after lung, kidney, and liver transplantation. However, data about the incidence of this complication among heart transplant (HT) recipients are lacking. METHODS: We analyzed the incidence, recurrence, and predisposing factors of VTE in a single-center cohort of 635 patients who underwent HT from April 1991 to April 2013. Deep venous thrombosis (DVT) and pulmonary embolism (PE) were considered as VTE episodes. RESULTS: During a median post-transplant follow-up of 8.4 years, 62 VTE episodes occurred in 54 patients (8.5%). Incidence rates of VTE, DVT, and PE were, respectively, 12.7 (95% confidence interval [CI], 9.7-16.3), 8.4 (95% CI, 6.0-11.4), and 7.0 (95% CI 4.8-9.7) episodes per 1,000 patient-years. Incidence rates of VTE during the first post-transplant year and beyond were, respectively, 45.1 (95% CI, 28.9-67.1) and 8.7 (95% CI 6.2-11.2) episodes per 1,000 patient-years. The incidence rate of VTE recurrence after a first VTE episode was 30.5 (95% CI, 13.2-60.2) episodes per 1,000 patient-years. By means of multivariable Cox regression, chronic renal dysfunction, older age, obesity, and the use of mammalian target of rapamycin inhibitors were identified as independent risk factors for VTE among HT recipients. CONCLUSIONS: VTE is a frequent complication after HT, mainly during the first post-operative year. In view of a high recurrence rate, long-term anti-coagulation should be considered in HT recipients who experience a first VTE episode.

Usefulness of the INTERMACS Scale for predicting outcomes after urgent heart transplantation.

INTRODUCTION AND OBJECTIVES: Our aim was to assess the prognostic value of the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) scale in patients undergoing urgent heart transplantation (HT). METHODS: Retrospective analysis of 111 patients treated with urgent HT at our institution from April, 1991 to October, 2009. Patients were retrospectively assigned to three levels of the INTERMACS scale according to their clinical status before HT. RESULTS: Patients at the INTERMACS 1 level (n=31) more frequently had ischemic heart disease (P=.03) and post-cardiothomy shock (P=.02) than patients at the INTERMACS 2 (n=55) and INTERMACS 3-4 (n=25) levels. Patients at the INTERMACS 1 level showed higher preoperative catecolamin doses (P=.001), a higher frequency of use of mechanical ventilation (P<.001), intraaortic balloon (P=.002) and ventricular assist devices (P=.002), and a higher frequency of preoperative infection (P=.015). The INTERMACS 1 group also presented higher central venous pressure (P=.02), AST (P=.002), ALT (P=.006) and serum creatinine (P<.001), and lower hemoglobin (P=.008) and creatinine clearance (P=.001). After HT, patients at the INTERMACS 1 level had a higher incidence of primary graft failure (P=.03) and postoperative need for renal replacement therapy (P=.004), and their long-term survival was lower than patients at the INTERMACS 2 (log rank 5.1, P=.023; HR 3.1, IC 95% 1.1-8.8) and INTERMACS 3-4 level (log rank 6.1, p=0.013; HR 6.8, IC 95% 1.2-39.1). CONCLUSIONS: Our results suggest that the INTERMACS scale may be a useful tool to stratify postoperative prognosis after urgent HT.