Occurrence of Fatal and Nonfatal Adverse Outcomes after Heart Transplantation in Patients with Pretransplant Noncytotoxic HLA Antibodies

HLA antibodies (HLA ab) in transplant candidates have been associated with poor outcome. However, clinical relevance of noncytotoxic antibodies after heart transplant (HT) is controversial. By using a Luminex-based HLA screening, we retested pretransplant sera from HT recipients testing negative for cytotoxic HLA ab and for prospective crossmatch. Out of the 173 consecutive patients assayed (52±13y; 16% females; 47% ischemic etiology), 32 (18%) showed pretransplant HLA ab, and 12 (7%) tested positive against both class I and class II HLA. Recipients with any HLA ab had poorer survival than those without (65±9 versus 82±3%; P=0.02), accounting for a doubled independent mortality risk (P=0.04). In addition, HLA-ab detection was associated with increased prevalence of early graft failure (35 versus 15%; P=0.05) and late cellular rejection (29 versus 11%; P=0.03). Of the subgroup of 37 patients suspected for antibody mediated rejection (AMR), the 9 with pretransplant HLA ab were more likely to display pathological AMR grade 2 (P=0.04). By an inexpensive, luminex-based, HLA-screening assay, we were able to detect non-cytotoxic HLA ab predicting fatal and nonfatal adverse outcomes after heart transplant. Allocation strategies and desensitization protocols need to be developed and prospectively tested in these patients

Outcomes in Mitral Regurgitation Due to Flail Leaflets. A Multicenter European Study

Objectives: The purpose of this study was to assess incidence and predictors of events associated with nonsurgical and surgical management of severe mitral regurgitation (MR) in European institutions. Background: The management of patients with MR remains disputed, warranting multicenter studies to define clinical outcome in routine clinical practice. Methods: The MIDA (Mitral Regurgitation International DAtabase) is a registry created for multicenter study of MR with echocardiographically diagnosed flail leaflet as a model of pure, organic MR. Our cases were collected from 4 European centers. We enrolled 394 patients (age 64 ± 11 years; 67% men; 64% in New York Heart Association functional class I to II; left ventricular ejection fraction 67 ± 10%). Results: During a median follow-up of 3.9 years, linearized event rates/year under nonsurgical management were 5.4% for atrial fibrillation (AF), 8.0% for heart failure (HF), and 2.6% for death. Mitral valve (MV) surgery was performed in 315 (80%) patients (repair in 250 of 315, 80%). Perioperative mortality, defined as death within 30 days from the operation, was 0.7% (n = 2). Surgery during follow-up was independently associated with reduced risk of death (adjusted hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.21 to 0.84; p = 0.014). Benefit was largely driven by MV repair (adjusted HR vs. replacement 0.37, 95% CI 0.18 to 0.76; p = 0.007). In 102 patients strictly asymptomatic and with normal ventricular function, 5-year combined incidence of AF, HF, or cardiovascular death (CVD) was 42 ± 8%. In these patients, surgery also reduced rates of CVD/HF (HR 0.26, 95% CI 0.08 to 0.89; p = 0.032). Conclusions: In this multicenter study, nonsurgical management of severe MR was associated with notable rates of adverse events. Surgery especially MV repair performed during follow-up was beneficial in reducing rates of cardiac events. These findings support surgical consideration in patients with MR due to flail leaflets for whom MV repair is feasible. © 2008 American College of Cardiology Foundation

Effects of Beta-Blockade on Exercise Performance at High Altitude

Summary Aims Exposure to high altitude (HA) hypoxia decreases exercise performance in healthy subjects. Although β-blockers are known to affect exercise capacity in normoxia, no data are available comparing selective and nonselective β-adrenergic blockade on exercise performance in healthy subjects acutely exposed to HA hypoxia. We compared the impact of nebivolol and carvedilol on exercise capacity in healthy subjects acutely exposed to HA hypobaric hypoxia. Methods In this double-blind, placebo-controlled trial, 27 healthy untrained sea-level (SL) residents (15 males, age 38.3 ± 12.8 years) were randomized to placebo (n = 9), carvedilol 25 mg b.i.d. (n = 9), or nebivolol 5 mg o.d. (n = 9). Primary endpoints were measures of exercise performance evaluated by cardiopulmonary exercise testing at sea level without treatment, and after at least 3 weeks of treatment, both at SL and shortly after arrival at HA (4559 m). Results HA hypoxia significantly decreased resting and peak oxygen saturation, peak workload, VO2, and heart rate (HR) (P < 0.01). Changes from SL (no treatment) differed among treatments: (1) peak VO2 was better preserved with nebivolol (–22.5%) than with carvedilol (–37.6%) (P < 0.01); (2) peak HR decreased with carvedilol (–43.9 ± 11.9 beats/min) more than with nebivolol (–24.8 ± 13.6 beats/min) (P < 0.05); (3) peak minute ventilation (VE) decreased with carvedilol (–9.3%) and increased with nebivolol (+15.2%) (P= 0.053). Only peak VE changes independently predicted changes in peak VO2 at multivariate analysis (R= 0.62, P < 0.01). Conclusions Exercise performance is better preserved with nebivolol than with carvedilol under acute exposure to HA hypoxia in healthy subjects

Left atrial size is a potent predictor of mortality in mitral regurgitation due to flail leaflets results from a large international multicenter study

Background-Left atrium (LA) enlargement is common in organic mitral regurgitation (MR) and is an emerging prognostic indicator. However, outcome implications of LA enlargement have not been analyzed in the context of routine clinical practice and in a multicenter study. Methods and Results-The Mitral Regurgitation International DAtabase (MIDA) registry enrolls patients with organic MR due to flail leaflets, diagnosed in routine clinical practice, in 5 US and European centers. We investigated the relation between LA diameter and mortality under medical treatment and after mitral surgery in 788 patients in sinus rhythm (64±12 years; median LA, 48 [43 to 52] mm). LA diameter was independently associated with survival after diagnosis (hazard ratio, 1.08 [1.04 to 1.12] per 1 mm increment). Compared with patients with LA<55 mm, those with LA â¥55 mm had lower 8-year overall survival (P<0.001). LA â¥55 mm independently predicted overall mortality (hazard ratio, 3.67 [1.95 to 6.88]) and cardiac mortality (hazard ratio, 3.74 [1.72 to 8.13]) under medical treatment. The association of LA â¥55 mm and mortality was consistent in subgroups. Similar excess mortality associated with LA â¥55 mm was observed in asymptomatic and symptomatic patients (P for interaction, 0.77). In patients who underwent mitral surgery, LA â¥55 mm had no impact on postoperative outcome (P<0.20). Mitral surgery was associated with greater survival benefit in patients with LA â¥55 mm compared with LA <55 mm (P for interaction, 0.008). Conclusions-In MR caused by flail leaflets, LA diameter â¥55 mm is associated with increased mortality under medical treatment, independent of the presence of symptoms or left ventricular dysfunction. © 2011 American Heart Association, Inc

Prognostic implications of functional mitral regurgitation according to the severity of the underlying chronic heart failure: A long-term outcome study

AimsTo examine the independent prognostic role of functional mitral regurgitation (FMR) and its impact across the severity of chronic heart failure (CHF) in a large population of outpatients with systolic CHF followed at two multidisciplinary clinics.Methods and resultsEchocardiography was performed upon enrolment in 469 CHF patients. Follow-up for death and heart transplant was updated on January 2007. Five-year transplant-free survival was 82.7 in patients with no or Grade I FMR, 64.4 in Grade II, 58.5 in Grade III, and 46.5 in Grade IV (P < 0.0001). There was a strong graded association between FMR and the long-term risk of death and heart transplant, which remained significant after multivariable adjustment (P = 0.0003). The association between FMR and events was strong and independent in patients with less severe symptoms and in those at lower overall risk based on a propensity score analysis, while it was not significant in patients with more advanced CHF or in the high-risk subgroup (P < 0.0001 for interactions).ConclusionThis study clarifies previous apparently discrepant results by demonstrating that FMR is an independent determinant of death and heart transplantation only in less severe CHF and in patients with a lower risk profile. This finding indicates that FMR plays a major role in the early phase of CHF, suggesting that this should be the focus of strategies attempting to reduce it. \uc2\ua9 The Author 2010

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D