Pharmacologic inhibition of the mitochondrial Na+/Ca2+ exchanger protects against ventricular arrhythmias in a porcine model of ischemia-reperfusion.

BACKGROUND: The mitochondrial Na+/Ca2+ exchanger (mNCX) has been implicated in the pathogenesis of arrhythmogenicity and myocardial reperfusion injury, rendering its inhibition a potential therapeutic strategy. We examined the effects of CGP-37157, a selective mNCX inhibitor, on arrhythmogenesis, infarct size (IS), and no reflow area (NRA) in a porcine model of ischemia-reperfusion. METHODS: Forty pigs underwent myocardial ischemia for 60 minutes, followed by 2 hours of reperfusion. Animals were randomized to receive intracoronary infusion of 0.02 mg/kg CGP-37157 or vehicle, either before ischemia (n=17) or before reperfusion (n=17). Animals were monitored for arrhythmias. Myocardial area at risk (AR), IS, and NRA were measured by histopathology. RESULTS: AR, NRA, and IS were comparable between groups. Administration of CGP-37157 before ischemia resulted in the following: (a) suppression of ventricular tachyarrhythmias (events/pig: 1.5±1.1 vs 3.5±1.9, p=0.014), (b) easier cardioversion of ventricular tachyarrhythmias (defibrillations required for cardioversion of each episode: 2.6±2.3 vs 6.2±2.1, p=0.006), and (c) decreased maximal depression of the J point (0.75±0.27 mm vs 1.75±0.82 mm, p=0.007), compared to controls. Administration of CGP-37157 before reperfusion expedited ST-segment resolution; complete ST-segment resolution within 30 minutes of reperfusion was observed in 7/8 CGP-37157-treated animals versus 1/9 controls (p=0.003). CONCLUSIONS: In a porcine model of myocardial infarction, intracoronary administration of CGP-37157 did not decrease IS or NRA. However, it suppressed ventricular arrhythmias, decreased depression of the J point during ischemia and expedited ST-segment resolution after reperfusion. These findings motivate further investigation of pharmacologic mNCX inhibition as a potential therapeutic strategy to suppress arrhythmias in the injured heart.

High furosemide dose has detrimental effects on survival of patients with stable heart failure.

INTRODUCTION: High doses of furosemide for heart failure (HF) have been correlated with an increased mortality, though whether they are a marker of disease severity or an independent predictor is unknown. We hypothesized that, in patients presenting with stable HF, the likelihood of long-term major adverse clinical events is increased by higher furosemide doses. METHODS: We retrospectively recorded the doses of furosemide prescribed to 173 consecutive, clinically stable patients during a first ambulatory HF department visit. The low-dose group included 103 patients treated with 80 mg and the high-dose group included 70 patients treated with >80 mg of furosemide daily. Proportional hazard regression analyses were performed with single and multiple variables in search of correlates of long-term adverse clinical events. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. RESULTS: The baseline characteristics of the 2 groups were similar, except for estimated glomerular filtration rate, which was higher in the low- than the high-dose group (72.9 ± 19.4 vs. 60.8 ± 22.0 mL/min/ m2, p<0.001). The 3-year survival free from the composite endpoint was significantly higher in the lowdose group than in the high-dose group (93.1% vs. 60.0%, p<0.001). By multiple variable analysis, highdose furosemide was an independent predictor of an adverse outcome at 3 years (adjusted HR: 15.25; 95% CI:1.06-219.39, p=0.045). The incidence of deterioration of renal function and episodes of hypokalemia during follow up was also higher in the high furosemide dose (73.2% vs. 48.3, p=0.003, and 43.1% vs. 6.5%, p<0.001, respectively). CONCLUSIONS: High doses of furosemide administered in order to stabilize HF patients and continued thereafter are associated with an adverse clinical outcome.

Cardiosphere-derived progenitor cells for myocardial repair following myocardial infarction.

In the recent years, the existence of cardiac regeneration in mammalian models and even humans has been confirmed in several, carefully designed and executed studies. However, the intrinsic rate of cardiomyocyte renewal is not sufficient to replenish the large number of cells lost after a major injury in the heart, such as myocardial infarction. Therefore, exogenously administered cells with progenitor properties have been used in order to augment this process. From the several candidate cell populations, cardiac derived progenitor cells appear particularly attractive for this purpose, based on data from many experimental studies but also preliminary clinical applications. Cardiosphere-derived cells are a mixed cell population that has shown great potential in stimulating endogenous mechanisms of cardiac repair and attenuating adverse remodeling of the heart. In the present review, we discuss in detail the existing evidence regarding the therapeutic role of cardiosphere-derived progenitor cell administration in the post-myocardial infarction setting. Proof-of-concept studies in rodents, as well as more clinically relevant experiments in large animal models, have provided consistent results regarding the potential of these cells to improve cardiac structure and function after myocardial infarction. Existing data about the underlying mechanisms that are implicated in myocardial regeneration triggered by these cells are presented, as well as preliminary data from clinical applications and future perspectives of this novel therapeutic option.

Elevated left ventricular filling pressures can be estimated with accuracy by a new mathematical model.

BACKGROUND: Although the clinical assessment of jugular venous pressure (JVP) provides accurate estimate of right atrial pressure (RAP), there is no reliable non-invasive method for assessing pulmonary capillary wedge pressure (PCWP). Our objective was to evaluate the sensitivity and specificity for detecting elevated left ventricular filling pressures using a model for PCWP estimation, based on the clinical assessment of RAP and association between RAP and PCWP, which is unique for each patient, identified in a recent right heart catheterization (RHC). METHODS: The study included 377 patients (age, 54.3 ± 13 years) with heart failure with reduced ejection fraction (left ventricular ejection fraction of 30.5 ± 10.8%) who underwent 2 RHCs within 1 year. In Group A (189 randomly selected patients), hemodynamic variables with significant correlation with the current wedge pressure (PCWP(2)) were identified and an equation estimating PCWP(2) based on these variables was formed. The validity of the equation was evaluated in the remaining 188 patients (Group B). The equation was also evaluated, prospectively in 39 new patients where RAP was estimated clinically, by physicians blinded to the results of the RHC. RESULTS: PCWP(2) in Group A correlated with RAP(1), systolic pulmonary artery pressure (SPAP(1)), and PCWP(1) of the first RHC and with RAP(2) and SPAP(2) of the second. The equation is PCWP(2) = [3RAP(2) + (PCWP(1) - RAP(1)) + 4]/2. In Group B, the sensitivity and specificity of estimated PCWP(2) for diagnosis of elevated LV filling pressures (invasive values >18 mm Hg) was significant, reflected by an area under the curve (AUC) of 0.954 (p < 0.001). In the prospective sub-group, where JVP was entered in the formula as an estimate of RAP(2), correlation between estimated and measured PCWP(2) was r = 0.803 (p < 0.001). CONCLUSIONS: The current PCWP of a patient with heart failure can be estimated accurately by a simple equation based on measurements of a previous RHC and the current value of clinically assessed JVP.