Caspase inhibition modulates left ventricular remodeling following myocardial infarction through cellular and extracellular mechanisms.

Background: Myocyte death occurs by necrosis and caspase-mediated apoptosis in myocardial infarction (MI). In vitro studies suggest caspase activation causes myocardial contractile protein degradation without inducing apoptosis. Thus, caspase activation may evoke left ventricular (LV) remodeling through independent processes post-MI.

Differential effects of protein kinase C isoform activation in endothelin-mediated myocyte contractile dysfunction with cardioplegic arrest and reperfusion.

Background: Increased myocardial interstitial levels of endothelin (ET) occur during cardioplegic arrest (CA) and may contribute to contractile dysfunction. Endothelin receptor transduction involves the protein kinase-C (PKC) family comprised of multiple isoforms with diverse functions. Which PKC isoforms may be involved in ET-induced contractile dysfunction after CA remains unknown.

Chronic matrix metalloproteinase inhibition following myocardial infarction in mice: differential effects on short and long-term survival.

Left ventricular (LV) remodeling occurs after myocardial infarction (MI), and the matrix metalloproteinases (MMPs) contribute to adverse LV remodeling after MI. Short-term pharmacological MMP inhibition (MMPi; days to weeks) in animal models of MI have demonstrated a reduction in adverse LV remodeling. However, the long-term effects (months) of MMPi on survival and LV remodeling after MI have not been examined.

Selective targeting of matrix metalloproteinase inhibition in post-infarction myocardial remodeling.

Background: A cause-effect relationship has been established between MMP activation and left ventricular (LV) remodeling following myocardial infarction. The goal of the present study was to examine a selective MMP inhibitor (sMMPi) strategy that effectively spared MMP-1, -3, and -7 with effect to regional and global left ventricular remodeling in a pig model of myocardial infarction.

Methods And Results: Pigs instrumented with coronary snares and radiopaque markers within the area at risk were randomized to myocardial infarction-only (n = 10) or sMMPi (PGE-530742, 1 mg/kg TID) begun 3 days prior to myocardial infarction.

A multidimensional proteomic approach to identify hypertrophy-associated proteins.

Left ventricular hypertrophy (LVH) is a leading cause of congestive heart failure. The exact mechanisms that control cardiac growth and regulate the transition to failure are not fully understood, in part due to the lack of a complete inventory of proteins associated with LVH. We investigated the proteomic basis of LVH using the transverse aortic constriction model of pressure overload in mice coupled with a multidimensional approach to identify known and novel proteins that may be relevant to the development and maintenance of LVH.

Cardiac support device modifies left ventricular geometry and myocardial structure after myocardial infarction.

Background: Whether mechanical restraint of the left ventricle (LV) can influence remodeling after myocardial infarction (MI) remains poorly understood. This study surgically placed a cardiac support device (CSD) over the entire LV and examined LV and myocyte geometry and function after MI.

Methods And Results: Post-MI sheep (35 to 45 kg; MI size, 23+/-2%) were randomized to placement of the CorCap CSD (Acorn Cardiovascular, Inc) (MI+CSD; n=6) or remained untreated (MI only; n=5).

Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition.

Alterations in matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been implicated in adverse left ventricular (LV) remodeling after myocardial infarction (MI). However, the direct mechanistic role of TIMPs in the post-MI remodeling process has not been completely established. The goal of this project was to define the effects of altering endogenous MMP inhibitory control through combined genetic and pharmacological approaches on post-MI remodeling in mice.

Caspase inhibition attenuates contractile dysfunction following cardioplegic arrest and rewarming in the setting of left ventricular failure.

Hyperkalemic cardioplegic arrest (HCA) and rewarming evokes postoperative myocyte contractile dysfunction, a phenomenon of particular importance in settings of preexisting left ventricular (LV) failure. Caspases are intracellular proteolytic enzymes recently demonstrated to degrade myocardial contractile proteins. This study tested the hypothesis that myocyte contractile dysfunction induced by HCA could be ameliorated with caspase inhibition in the setting of compromised myocardial function.

Myocyte contractility with caspase inhibition and simulated hyperkalemic cardioplegic arrest.

Background: Exposure of left ventricular (LV) myocytes to simulated hyperkalemic cardioplegic arrest (HCA) has been demonstrated to perturb ionic homeostasis and adversely affect myocyte contractility on rewarming. Altered ionic homeostasis can cause cytosolic activation of the caspases. While caspases participate in apoptosis, these proteases can degrade myocyte contractile proteins, and thereby alter myocyte contractility.

Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling: a potentially novel pathway.

Objective: Myocyte death occurs by necrosis and caspase-mediated apoptosis in the setting of myocardial infarction. In vitro studies suggest that caspase activation within myocytes causes contractile protein degradation without inducing cell death. Thus, caspase activation may evoke left ventricular remodeling through 2 independent processes post-myocardial infarction.

Modulation of calcium transport improves myocardial contractility and enzyme profiles after prolonged ischemia-reperfusion.

Background: Ischemia-reperfusion (IR) injury causes myocardial dysfunction in part through intracellular calcium overload. A recently described pharmacologic compound, MCC-135 (5-methyl-2-[1-piperazinyl] benzenesulfonic acid monohydrate, Mitsubishi Pharma Corporation), alters intracellular calcium levels. This project tested the hypothesis that MCC-135 would influence regional myocardial contractility when administered at reperfusion and after a prolonged period of ischemia.

Direct inhibition of the sodium/hydrogen exchanger after prolonged regional ischemia improves contractility on reperfusion independent of myocardial viability.

Background: A mechanism for myocardial dysfunction after ischemia and reperfusion is Na(+)/H(+) exchanger activation. Although past in vivo models of limited ischemia and reperfusion intervals demonstrate that Na(+)/H(+) exchanger inhibition confers myocardial protection when administered at the onset of ischemia, the effect of Na(+)/H(+) exchanger inhibition on myocardial function after prolonged ischemia and reperfusion remains unknown. This investigation tested the hypothesis that Na(+)/H(+) exchanger inhibition instituted at reperfusion and after prolonged coronary occlusion in pigs would influence myocardial contractility independent of myocardial viability.

Selective targeting and timing of matrix metalloproteinase inhibition in post-myocardial infarction remodeling.

Background: A cause-and-effect relationship exists between matrix metalloproteinase (MMP) induction and left ventricular (LV) remodeling after myocardial infarction (MI). Whether broad-spectrum MMP inhibition is necessary and the timing at which MMP inhibition should be instituted after MI remain unclear. This study examined the effects of MMP-1 and MMP-7-sparing inhibition (sMMPi) on regional and global LV remodeling when instituted before or after MI.

Cardiorenal effects of adenosine subtype 1 (A1) receptor inhibition in an experimental model of heart failure.

Background: Elaboration of a number of bioactive substances, including adenosine, occurs in heart failure (HF). Adenosine, through the adenosine subtype 1 (A1) receptor, can reduce renal perfusion pressure and glomerular filtration rate and increase tubular sodium reabsorption, which can affect natriuresis and aquaresis. Accordingly, the present study examined the acute effects of selective A1 receptor blockade on hemodynamics and renal function in a model of HF.