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BACKGROUND: Aging populations show higher incidences of myocardial infarction (MI) and heart failure (HF). Cardiac remodeling post-MI leads to progressive impaired cardiac function caused by a disarray of several processes including derailed autophagy. Microribonucleic acids (miRNAs) are known to be key players in cardiovascular disease but their involvement in cardiac autophagy and aging is not well understood.OBJECTIVES: This study sought to identify new miRNA candidates that regulate cardiac autophagy and aging.METHODS: We exploited a high-throughput, fluorescence-activated cell sorting-based green fluorescent protein-LC3 detection method to measure the autophagic flux in cardiomyocytes after transfection of a precursor miRNA library consisting of 380 miRNAs. This was followed by a series of molecular and in vivo studies.RESULTS: Together with additional expression screenings, we identified miR-22 as an abundant and strong inhibitor of the cardiac autophagy process. Cardiac miR-22 expression levels increased during aging of mice as well as in aging neonatal cardiomyocytes in vitro by a P53-dependent mechanism. Inhibition of miR-22 in aging cardiomyocytes in vitro activated autophagy and inhibited cellular hypertrophy. Pharmacological inhibition of miR-22 post-MI in older mice activated cardiac autophagy, prevented post-infarction remodeling, and improved cardiac function compared with control subjects. Interestingly, similar effects were less pronounced in younger mice with significantly lower cardiac miR-22 expression levels. In addition, circulating levels of miR-22 in 154 patients with systolic HF were highly associated with early mortality.CONCLUSIONS: We concluded that miR-22 is an important regulator of cardiac autophagy and a potential therapeutic target, especially in the older myocardium. Finally, circulating miR-22 provides prognostic information for HF patients, highlighting miR-22 as a promising therapeutic and biomarker candidate for cardiovascular disorders.

ObjectivesThe aim of this study was to compare the prognostic value of peak oxygen consumption (Vo2) and B-type natriuretic peptide (BNP) in patients with stable congestive heart failure (CHF).BackgroundPrevious studies have demonstrated that both peak Vo2and BNP are useful for risk stratification in patients with CHF. No study has compared the respective prognostic value of these two parameters in a large series of patients receiving a combination of angiotensin-converting enzyme inhibitors and of beta-blockers.MethodsPatients with stable CHF underwent radionuclide angiography, echocardiography, 24-h Holter monitoring, and a cardiopulmonary exercise test. Blood samples were drawn for standard measurements and for hormonal determinations.ResultsAfter a median follow-up period of 787 days, there were 75 cardiac-related deaths and three urgent transplantations. Independent predictors of cardiac survival were percent of maximal predicted Vo2(%Vo2, relative risk [RR] = 2.84 [95% confidence interval, CI = 1.73 to 4.65], p < 0.00001), BNP (RR = 3.17 [95% CI 1.68 to 5.96], p = 0.0004), left atrial diameter (LAD) (RR = 2.04 [95% CI 1.25 to 3.34], p = 0.004), age (RR = 1.93 [95% CI 1.22 to 3.05], p = 0.005), and aldosterone (RR = 1.84 [95% CI 1.12 to 3.00], p = 0.015). In patients with infra-median levels of BNP (

Objectives. This study analyzed the kinetics of oxygen consumption during and after a maximal cardiopulmonary exercise test in patients with dilated cardiomyopathy. The prognostic information derived from indexes of recovery was also studied. Background. Previous studies have examined the kinetics of oxygen consumption during a short recovery period in a limited number of patients. To our knowledge, no study has examined the prognostic information derived from indexes of recovery. Methods. We studied 153 patients and 55 control subjects. We calculated the ratio between total oxygen consumption during exercise and recovery, the half-recovery time of peak oxygen consumption, the time constant of recovery, the recovery time and the ratio between duration of exercise and recovery time. Results. Recovery of oxygen consumption was significantly delayed in patients, and this delay was related to the degree of exercise intolerance. After a median follow-up period of 439 days, for the total study group, percent of predicted peak oxygen consumption (p = 0.003) and ejection fraction (p = 0.03) were independent predictors of survival. In a subgroup of patients with moderate exercise intolerance (percent peak oxygen consumption >40%), the ratio between total oxygen consumption during exercise and recovery (p = 0.013) and the ejection fraction (p = 0.013) were independent predictors of survival. Conclusions. The kinetics of oxygen consumption during recovery was delayed in patients with dilated cardiomyopathy. Although indexes of recovery were not prognostic markers in the total study group, the ratio between total oxygen consumption during exercise and recovery was an independent prognostic marker in patients with moderate exercise intolerance.

OBJECTIVES The purpose of this study was to prospectively investigate the effects of surgical correction of mitral regurgitation (MR) on exercise performance, cardiac function and neurohormonal activation. BACKGROUND Little is known about the effect of surgical correction of MR on functional status or on neurohormonal activation. METHODS Cardiopulmonary exercise test, radionuclide angiography and blood samples for assessment of neurohormonal status were obtained in 40 patients with nonischemic MR before and within one year (216 ± 80 days) after surgery. Twenty-four patients underwent mitral valve repair (MVr), and 16 underwent valve replacement (VR) with anterior chordal transection. RESULTS Despite an improvement in New York Heart Association functional class, exercise performance did not change (peak oxygen consumption: 19.3 ± 6.1 to 18.5 ± 5.6 ml/kg/min, percentage of maximal predicted oxygen consumption: 79.5 ± 18.2% to 76.8 ± 16.9%). After surgery, left ventricular (LV) ejection fraction (EF) decreased (64.2 ± 10.3% to 59.9 ± 11.4%, p = 0.003) while right ventricular (RV) EF increased (41.4 ± 9.6% to 44.7 ± 9.5%, p = 0.03). Left ventricular EF did not change after MVr (64.3 ± 11.5% to 61.5 ± 12.2%), but RVEF improved (40.4 ± 9.2% to 46.0 ± 10.0%, p = 0.02). In contrast, VR was associated with an impairment of LV function in the apicolateral area and a decrease in LVEF (64.1 ± 8.5% to 57.4 ± 10.0%, p = 0.01), whereas RVEF did not change (42.9 ± 10.3% to 42.8 ± 8.6%). Moreover, there was only a slight decrease in neurohormonal activation after surgery. CONCLUSIONS Despite an improvement in symptomatic status, exercise performance was not improved seven months after either MVr or VR for MR, and neurohormonal activation persisted. Compared with MVr, VR resulted in a significant impairment of cardiac function in this study.

In normal subjects, after a maximal exercise, oxygen consumption (VO2) declines exponentially towards baseline value. Few studies have examined the kinetics of VO2 after exercise in patients with dilated csrdiomyopathy (DCM). We studied the kinetics of post exercise VO2 in 167 cardiopulmonary exercise tests performed in 153 ambulatory patients with DCM and in 45 controls. Patients and controls performed the same exercise (bicycle:l0 watts/min, Medical Graphic analyzer). Mean left ventricular ejection fraction was 29.8 ± 12% (mean ± SD). The VO2-time relationship was fitted to a monoexponential curve for the determination of the time constant of recovery (tRec). We calculated the ratio between total VO2 during exercise and during recovery (RVO2, area under VO2 curves), the half recovery time of peak VO2 (½pVO2), the post exercise anaerobic time (PEAT: time during recovery necessary for the respiratory exchange ratio (VCO2/VO2) to become l1) and the ratio between exercise duration and PEAT (RPEAT). Patients were divided in 3 subgroups according to their peak VO2 (g15, g10 and ≤10 ml/min/kg). Result: Contro g15 g10 ≤10 p n 45 88 53 26 Duration exercise s 1299 ± 375 844 ± 171 619 ± 114 445 ± 111 l0.0001 Peak VO2 ml/min 2641 ± 893 1515 ± 362 995 ± 166 637 ± 176 l0.0001 Peak VCO2/VO2 1.24 ± 0.11 1.26 ± 0.12 1.26 ± 0.12 1.28 ± 0.13 NS RVO2 5.61 ± 2.48 2.9 ± 0.9 1.97 ± 0.63 1.41 ± 0.65 l0.0001 ½pVO2 s 70.4 ± 29.4 105 ± 43.4 136 ± 57.7 173 ± 71.8 l0.0001 PEATs 428 ± 147 516 ± 166 535 ± 165 544 ± 208 l0.01 RPEAT 35 ± 189 178 ± 0.61 1.26 ± 0.45 0.97 ± 0.54 l0.0001 tRec s 80.3 ± 26.3 128 ± 120 142 ± 733 204 ± 158 l0.0001 In multiple regression analysis, the parameter most closely correlated with peak VO2 was the RPEAT (F = 127, P l 0.0001). No relation was found between age or ejection fraction and post exercise parameters. In conclusion, recovery of VO2 is delayed in patients with DCM and is related to the degree of exercise impairment. Post exercise parameters are a novel marker for exercise intolerance.