A Novel Circulating MicroRNA for the Detection of Acute Myocarditis.

BACKGROUND: The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis. METHODS: To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls. RESULTS: We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level. CONCLUSIONS: After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.).

Critical warm ischemia time point for cardiac donation after circulatory death.

Donation after circulatory death (DCD) represents a promising opportunity to overcome the relative shortage of donors for heart transplantation. However, the necessary period of warm ischemia is a concern. This study aims to determine the critical warm ischemia time based on in vivo biochemical changes. Sixteen DCD non-cardiac donors, without cardiovascular disease, underwent serial endomyocardial biopsies immediately before withdrawal of life-sustaining therapy (WLST), at circulatory arrest (CA) and every 2 min thereafter. Samples were processed into representative pools to assess calcium homeostasis, mitochondrial function and cellular viability. Compared to baseline, no significant deterioration was observed in any studied parameter at the time of CA (median: 9 min; IQR: 7-13 min; range: 4-19 min). Ten min after CA, phosphorylation of cAMP-dependent protein kinase-A on Thr197 and SERCA2 decreased markedly; and parallelly, mitochondrial complex II and IV activities decreased, and caspase 3/7 activity raised significantly. These results did not differ when donors with higher WLST to CA times (≥9 min) were analyzed separately. In human cardiomyocytes, the period from WLST to CA and the first 10 min after CA were not associated with a significant compromise in cellular function or viability. These findings may help to incorporate DCD into heart transplant programs.

The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study.

AIMS: Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population. METHODS AND RESULTS: The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5-5.3, P = 0.018) for OSS and 2.8 (0.3-5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3-5.6, P = 0.028) for OSS and 2.9 (0.2-5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM. CONCLUSION: In iron-deficient patients with HF and left ventricular ejection fraction <50% who had stabilized after an episode of acute HF, treatment with IV FCM, compared with placebo, results in clinically meaningful beneficial effects on HRQoL as early as 4 weeks after treatment initiation, lasting up to Week 24.

Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.

BACKGROUND: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. METHODS: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 µg/L, or 100-299 µg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed. FINDINGS: Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group. INTERPRETATION: In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death. FUNDING: Vifor Pharma.

Effect of low-dose colchicine in acute and chronic coronary syndromes: A systematic review and meta-analysis.

BACKGROUND: Sparse evidence of the prognostic benefit of the anti-inflammatory drug colchicine in chronic and acute coronary syndromes (CCS/ACS) exists. METHODS: We performed a systematic search of studies on CCS or ACS comparing colchicine vs. placebo and reporting data on cardiovascular outcomes (primary end points of each study) and/or changes in hs-CRP. RESULTS: Ten studies were selected: three on CCS (LoDoCo, LoDoCo2 and the CCS subgroup of COLCHICINE-PCI; total patient number = 6256), three on ACS (COLCOT, COPS, ACS subgroup of COLCHICINE-PCI; n = 5,654) and five (n = 532) on hs-CRP changes from 1 week to 12 months, in CCS and/or ACS. In patients with CCS, colchicine reduced by 49% risk of a composite end point (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.32 to 0.81, P = .005). The favourable effect of colchicine on the risk of cardiovascular events did not change when excluding COLCHICINE-PCI from analysis (HR 0.51, 95% CI 0.25 to 1.03, P = .061). In patients with ACS, the use of colchicine tended to decrease the occurrence of the combined end point compared with placebo (HR = 0.77, 95% CI 0.56 to 1.05, P = .100), and colchicine became significantly protective when removing COLCHICINE-PCI from analysis (HR = 0.72, 95% CI 0.56 to 0.92, P = .009). Furthermore, colchicine tended to reduce the hs-CRP increase (standardized mean difference=-0.31, 95% CI -0.72 to 0.1, P = .133) compared with placebo. CONCLUSIONS: Colchicine therapy near halves the risk of cardiovascular events in CCS compared with placebo and is associated with a nonsignificant 23% risk reduction in ACS, together with a trend towards a greater reduction of hs-CRP.

Prognostic impact of hyponatraemia and hypernatraemia at admission and discharge in heart failure patients with preserved, mid-range and reduced ejection fraction.

BACKGROUND: Hyponatraemia is common in patients with acute heart failure (HF). AIMS: To determine the impact of sodium disturbances on mortality and readmissions in HF with reduced left ventricular ejection fraction (HFrEF), preserved ejection fraction (HFpEF) and mid-range ejection fraction (HFmrEF). METHODS: This study was a prospective multicentre consecutive registry in 20 hospitals, including patients admitted due to acute HF in cardiology departments. Sodium <135 mmol/L was considered hyponatraemia, >145 mmol/L hypernatraemia and 135-145 mmol/L normal. RESULTS: A total of 1309 patients was included. Mean age was 72.0 ± 11.9 years, and 810 (61.9%) were male. Mean serum sodium level was 138.6 ± 4.7 mmol/L at hospital admission and 138.1 ± 4.1 mmol/L at discharge. The evolution of sodium levels was: normal-at-admission/normal-at-discharge 941 (71.9%), abnormal-at-admission/normal-at-discharge 127 (9.7%), normal-at-admission/abnormal-at-discharge 155 (11.8%) and abnormal-at-admission/abnormal-at-discharge 86 (6.6%). Hyponatraemia at discharge was more common in HFrEF (109 (20.7%)) than in HFpEF (79 (13.9%)) and HFmrEF (27 (12%)), P = 0.003. The prevalence of hypernatraemia at discharge was similar in the three groups: HFrEF (10 (1.9%)), HFpEF (12 (2.1%)) and HFmrEF (4 (1.9%)), P = 0.96. In multivariate analysis, abnormal sodium concentrations at hospital admission (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.15-1.76, P = 0.001) and discharge (HR 1.33, 95% CI 1.08-1.64, P = 0.007) were both independently associated with increased mortality and readmissions at 12 months. CONCLUSIONS: Hyponatraemia and hypernatraemia at admission and discharge predict a poor outcome in patients with acute HF regardless of left ventricular ejection fraction. Hyponatraemia at discharge is more frequent in HFrEF than in the other groups.

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.

Effect of concomitant antiplatelet therapy in patients with nonvalvular atrial fibrillation initiating non-vitamin K antagonists.

BACKGROUND: Antiplatelet therapy (APT) use in combination with oral anticoagulation is common among patients with atrial fibrillation, but there is scarce information regarding its effect on outcomes in patients on non-vitamin K antagonist oral anticoagulants (NOAC). We aimed to evaluate the safety and efficacy of APT use in a 'real-world' cohort of nonvalvular atrial fibrillation (NVAF) patients initiating NOAC. DESIGN: We conducted a retrospective multicentre study including 2361 consecutive NVAF patients initiating NOAC between January 2013 and December 2016. Patients with an acute ischaemic event within the last 12 months (acute coronary syndrome, stroke or revascularization) were excluded. Patients were followed up, and all clinical events were recorded at 3 months. The primary outcome of the study was major bleeding, and the secondary outcomes were stroke, nonfatal myocardial infarction, intracranial bleeding and death. RESULTS: One hundred forty-five (6.1%) patients received concomitant APT, and aspirin was the more common (79%). At 3 months, 25 (1.1%) patients had major bleeding, 8 (0.3%) had nonfatal myocardial infarction, 7 (0.3%) had ischaemic stroke, and 40 (1.7%) died. After multivariate adjustment, concomitant APT was associated with higher risk for major bleeding (HR = 3.62, 95% CI 1.32-9.89; P = .012), but was not associated with a higher risk of other clinical outcomes. CONCLUSIONS: Concomitant APT use is uncommon among these patients and does not seem to be associated with lower rates of ischaemic events or death. However, there are signals for an increased risk of bleeding, which reinforces current guideline recommendations.

Discharge treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker after a heart failure hospitalisation is associated with a better prognosis irrespective of left ventricular ejection fraction.

BACKGROUND: Medical therapy could improve the prognosis of real-life patients discharged after a heart failure (HF) hospitalisation. AIM: To determine the impact of discharge HF treatment on mortality and readmissions in different left ventricular ejection fraction (LVEF) groups. METHODS: Multicentre prospective registry in 20 Spanish hospitals. Patients were enrolled after a HF hospitalisation. RESULTS: A total of 1831 patients was included (583 (31.8%) HF with reduced ejection fraction (HFrEF); 227 (12.4%) HF with midrange ejection fraction (HFmrEF); 610 (33.3%) HF with preserved ejection fraction (HFpEF), and 411 (22.4%) with unknown LVEF). Angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARB) at discharge were independently associated with a reduction in: (i) all-cause mortality: hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.41-0.74, P < 0.001, with a similar effect in the four groups; (ii) mortality due to refractory HF HR 0.45, 95% CI 0.29-0.64, P < 0.001, with a similar effect in the three groups with known LVEF; (iii) mortality/HF admissions (HR 0.61; 95% CI: 0.50-0.74), more evident in HFrEF (HR 0.54; 95% CI: 0.38-0.78) compared with HRmEF (HR 0.64; 95% CI 0.40-1.02), or HFpEF (HR 0.70; 95% CI 0.53-0.92). In patients with HFrEF triple therapy (ACE inhibitor/ARB + beta blocker + mineralocorticoid receptor antagonist) was associated with the lowest mortality risk (HR 0.21; 95% CI: 0.08-0.57, P = 0.002) compared with patients that received none of these drugs. CONCLUSIONS: Discharge treatment with ACE inhibitor/ARB after a HF hospitalisation is associated with a reduction in all-cause and refractory HF mortality, irrespective of LVEF.

Lack of improvement in autonomic cardiac tone after sacubitril/valsartan at lower than target doses.

Autonomic regulation plays a role in the progression of heart failure with reduced ejection fraction (HrEF).Twenty-one HFrEF patients, 60.8 ±â€¯13.1 years, receiving angiotensin inhibition, were replaced by angiotensin receptor-neprilysin inhibitor (ARNI). A 24-hour Holter recording was performed before and after 3 months of the maximum tolerated dose of ARNi. We evaluated changes in autonomic tone using heart rate variability (SDNN, rMSSD, pNN50, LF, HF, LF/HF, α1, α2), and heart rate turbulence (TO and TS). ARNI was up-titrated to a maximum daily dose of 190 ±â€¯102 mg, 47.5% of the target dose. ARNI therapy was not associated with any improvement in any of the parameters related with heart rate variability or heart rate turbulence (p > 0.05 for all). ARNI use at lower than target doses did not improve autonomic cardiac tone as evaluated by 24-hour Holter monitoring.

Patient-Associated Predictors of 15- and 30-Day Readmission After Hospitalization for Acute Heart Failure.

BACKGROUND: Identifying readmission predictors in heart failure (HF) patients may help guide preventative efforts and save costs. We aimed to identify 15- and 30-day readmission predictors due to cardiovascular reasons. METHODS AND RESULTS: A total of 1831 patients with acute HF admission were prospectively followed during a year. Patient-associated variables were gathered at admission/discharge and events during follow-up. A multivariate Fine and Gray competing risk regression model and a cumulative incidence function were used to identify predictors and build a risk score model for 15- and 30-day readmission. The 15- and 30-day readmission rates due to cardiovascular reasons were 7.1% and 13.9%. Previous acute myocardial infarction, congestive signs at discharge, and length of stay > 9 days were predictors of 15- and 30-day readmission, while much weight loss and large NT-ProBNP reduction were protective factors. The NT-ProBNP reduction was larger at 30 days (> 55%) vs 15 days (> 40%) to protect from readmission. Glomerular filtration rate at discharge < 60 mL/min/1.73m2 and > 1 previous admissions due to HF were predictors of 30-day readmission, while first post-discharge control at an HF unit was a protective factor. CONCLUSIONS: Previous identified factors for early readmission were confirmed. The NT-ProBNP reduction should be increased (> 55%) to protect from 30-day readmission.

Early oxidative damage induced by doxorubicin: Source of production, protection by GKT137831 and effect on Ca(2+) transporters in HL-1 cardiomyocytes.

In atrial-derived HL-1 cells, ryanodine receptor and Na(+)/Ca(2+)-exchanger were altered early by 5 µM doxorubicin. The observed effects were an increase of cytosolic Ca(2+) at rest, ensuing ryanodine receptor phosphorylation, and the slowing of Ca(2+) transient decay after caffeine addition. Doxorubicin triggered a linear rise of reactive oxygen species (ROS) with no early effect on mitochondrial inner membrane potential. Doxorubicin and ROS were both detected in mitochondria by colocalization with fluorescence probes and doxorubicin-induced ROS was totally blocked by mitoTEMPO. The NADPH oxidase activity in the mitochondrial fraction was sensitive to inhibition by GKT137831, and doxorubicin-induced ROS decreased gradually as the GKT137831 concentration added in preincubation was increased. When doxorubicin-induced ROS was prevented by GKT137831, the kinetic response revealed a permanent degree of protection that was consistent with mitochondrial NADPH oxidase inhibition. In contrast, the ROS induction by doxorubicin after melatonin preincubation was totally eliminated at first but the effect was completely reversed with time. Limiting the source of ROS production is a better alternative for dealing with oxidative damage than using ROS scavengers. The short-term effect of doxorubicin on Ca(2+) transporters involved in myocardiac contractility was dependent on oxidative damage, and so the impairment was subsequent to ROS production.

Clinical relevance of sST2 in cardiac diseases.

ST2 has two main isoforms, ST2L and soluble isoform of ST2 (sST2), by alternative splicing. The interaction between interleukin (IL)-33 and the transmembrane isoform ST2L is up-regulated in response to myocardial stress and exerts cardio-protective actions in the myocardium by reducing fibrosis, hypertrophy and enhancing survival. The circulating isoform sST2, by sequestering IL-33, abrogates these favorable actions and will be elevated as a maladaptive response to cardiac diseases. Indeed, circulating sST2 concentrations correlate with a worse phenotype of disease including adverse remodeling and fibrosis, cardiac dysfunction, impaired hemodynamics and higher risk of progression. In patients with acute and chronic heart failure, sST2 concentrations are strongly predictive of death, regardless of the cause and left ventricle (LV) ejection fraction, and contribute relevant information in addition to other prognosticators and biomarkers, as natriuretic peptides or troponins. sST2 also retains prognostic information in the setting of acute myocardial infarction (AMI) and predicts cardiovascular death and risk of heart failure (HF) development in these patients. sST2 could also be a promising tool to stratify the risk of sudden cardiac death (SCD) in patients with depressed LV ejection fraction. Therefore, sST2 represents a clinically relevant biomarker reflecting pathophysiological processes and contributing predictive information in the setting of several cardiovascular diseases, and especially in patients with HF.

Donor/recipient sex mismatch and survival after heart transplantation: only an issue in male recipients? An analysis of the Spanish Heart Transplantation Registry.

The results of studies on the association between sex mismatch and survival after heart transplantation are conflicting. Data from the Spanish Heart Transplantation Registry. From 4625 recipients, 3707 (80%) were men. The donor was female in 943 male recipients (25%) and male in 481 female recipients (52%). Recipients of male hearts had a higher body mass index (25.9 ± 4.1 vs. 24.3 ± 3.7; P < 0.01), and male donors were younger than female donors (33.4 ± 12.7 vs. 38.2 ± 12.3; P < 0.01). No further relevant differences related to donor sex were detected. In the univariate analysis, mismatch was associated with mortality in men (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.06-1.32; P = 0.003) but not in women (HR, 0.91; 95% CI 0.74-1.12; P = 0.4). A significant interaction was detected between sex mismatch and recipient gender (P = 0.02). In the multivariate analysis, sex mismatch was associated with long-term mortality (HR, 1.14; 95% CI 1.01-1.29; P = 0.04), and there was a tendency toward significance for the interaction between sex mismatch and recipient gender (P = 0.08). In male recipients, mismatch increased mortality mainly during the first month and in patients with pulmonary gradient >13 mmHg. Sex mismatch seems to be associated with mortality after heart transplantation in men but not in women.

Adiponectin and p53 mRNA in epicardial and subcutaneous fat from heart failure patients.

OBJECTIVE: Heart failure (HF) is associated with a pro-inflammatory state in epicardial fat, but the involved mechanisms are not entirely clear. The aim of our study was to assess the relationship between p53 and adiponectin mRNA in epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) in patients with heart failure and its sympathetic regulation. METHODS: Epicardial adipose tissue and SAT samples were obtained from 63 patients undergoing elective cardiac surgery. EAT and SAT explants culture from seven patients were stimulated with isoprenaline 0.1 or 1 uM for 6 h. p53 and adiponectin mRNA expression was measured in frozen biopsies or explants culture from both fat pads by real-time polymerase chain reaction (PCR). RESULTS: We observed that EAT expressed more p53 mRNA than SAT (1.73 ± 0.07 vs. 1.69 ± 0.04, P < 0.001) and its levels were higher in HF patients (1.75 ± 0.07 vs. 1.70 ± 0.04, P < 0.01 in EAT and 1.70 ± 0.04 vs. 1.67 ± 0.04, P < 0.05 in SAT). Moreover, p53 mRNA expression was negatively correlated with adiponectin in EAT. After analysing the p53 mRNA regulation by isoprenaline, we observed that only EAT p53 expression increased after adrenergic stimulation (1.63 ± 0.01 vs. 1.66 ± 0.02; P = 0.024). CONCLUSIONS: p53 mRNA expression levels, inversely correlated with adiponectin, increase in EAT of HF patients and can be regulated by sympathetic activation pathway. Our findings can help to explain the deleterious effect of sympathetic activation in HF.

Modulation of IL-33/ST2 system in postinfarction heart failure: correlation with cardiac remodelling markers.

BACKGROUND: Interleukin (IL)-33 and sST2 are molecules with an opposite pathophysiologic implications in the myocardial response after acute myocardial infarction (AMI). Both may be a target for therapeutic interventions. The kinetics of IL-33 and sST2 expression in infarcted myocardium and their correlation with the ongoing processes of fibrosis, inflammation and apoptosis remains poorly defined. MATERIALS AND METHODS: Fifty Wistar rats underwent left anterior descending coronary artery surgical ligation and were sacrificed at 1, 2, 4, 12 or 24 weeks post-AMI. A sham-operated group was also included. The mRNA cardiac expression levels of IL-33, sST2, fibrosis markers, inflammatory markers and apoptosis markers were assessed by RT-PCR. The protein expression of IL-33 was also measured by Western blotting. RESULTS: The mRNA levels of IL-33 and sST2 were upregulated in the infarcted myocardium during the first week after AMI. However, while IL-33 levels remained elevated during the first 12 weeks post-AMI, sST2 levels showed a marked drop at 4 weeks. IL-33 protein expression showed a similar kinetic than mRNA expression. The expression of sST2 positively correlated with cardiac gene expression of inflammatory and fibrosis markers. However, the IL-33 level did not correlate with these cardiac remodelling markers. No correlation of sST2 with apoptosis markers was observed. CONCLUSION: After AMI, expression of sST2 is rapidly upregulated during the first 4 weeks and, in contrast to IL-33, its levels correlated with the ongoing processes of fibrosis and inflammation. These findings suggest differential regulation of IL33 and sST2. Therapeutic modulation of early sST2 expression may be of greater importance to prevent adverse remodelling after AMI.