Potentiating mitochondrial aldehyde dehydrogenase 2 to treat post-infarction heart failure.

Heart failure (HF) is common after acute myocardial infarction (MI) with an estimated one in five individuals aged 65 years or older who experience a first MI subsequently developing HF over the next 5 years. While a temporal trend towards reduction in HF hospitalizations post-MI has been noted, survival remains pooreven in the era of primary reperfusion therapy, multiagent neurohormonal modulation and device implantation, with a 1-year mortality for patients hospitalized for HF after MI of over 45%. Complex changes in ventricular geometry ensue within hours of MI— particularly for transmural infarcts—and progress well beyond the acute episode in a process termed ventricular remodelling. The degree of ventricular remodelling—described by parameters such as left ventricular (LV) end-systolic volume—has emerged as a key predictor of long-term survival post-MI. All therapies proved to beneficially alter HF clinical outcomes, including renin–angiotensin– aldosterone system (RAAS) inhibition, beta-adrenergic receptor blockade, cardiac resynchronization therapy, and LV assist devices, have been associated with LV reverse remodelling, highlighting it as a therapeutic target. Modern definitions of cardiac remodelling build on earlier, largely morphological descriptions of infarct expansion, progressive ventricular dilatation, and eccentric hypertrophy culminating in systolic failure. These reflect complex changes in: gene expression, molecular response (altered expression of proteins resulting in impaired sarcoplasmic calcium cycling and abnormal excitation–contraction coupling, increased AT1 receptor expression, and altered b-adrenoceptor function), cellular adaptations (altered myocyte shape, size, and increased levels of apoptosis), and interstitial [matrix metalloproteinase (MMP)-mediated extracellular matrix remodelling, RAASand TGF-b-mediated fibrosis, activation and recruitment of inflammatory and progenitor cells, and reduced capillary density] in the pathogenesis and progression of post-MI HF. The ability of current evidencebased therapies to induce reverse remodelling depends on their ability to favourably alter some of these pathological changes, including via effects on intraventricular haemodynamics and loading conditions. Generation of excessive reactive oxygen species (ROS) and reactive nitrogen species (RNS)—which include superoxide (O2 ) produced as a by-product of mitochondrial oxidative phosphorylation, the hydroxyl radical (†OH), hydrogen peroxide (H2O2), and peroxynitrite (†ONOO2) formed by the reaction of O2 2 with nitric oxide—has emerged as a key molecular mechanism mediating the development and progression of both ischaemic and non-ischaemic HF. Direct measurements of ROS have identified enhanced superoxide (O2 ) generation in a preclinical model of failing myocardium, while pericardial levels of 8-iso-prostaglandin F2a (a marker of free radical-mediated oxidant stress) are elevated in symptomatic human HF and correlate with functional status and degree of ventricular remodelling. Excessive ROS-mediated oxidant stress exerts a multitude of deleterious effects on processes integral to LV remodelling post-MI, including direct activation of hypertrophic and pro-apoptotic signalling pathways, activation of MMPs, modification of proteins involved in excitation–contraction coupling, and mitochondrial damage. As both the largest potential intracellular source of ROS in cardiomyocytes and central components of the cardiac bioenergetic machinery, mitochondria are positioned to engage in a vicious cycle of excessive ROS production, secondary impairment of mitochondrial function, further ROS generation, and ultimately cellular injury or death. Support for this paradigm comes from observed reductions in mitochondrial template availability and electron transport chain oxidative capacity in a murine coronary ligation model of HF. In addition to causing direct mtDNA damage with consequent reduced mitochondrial protein expression, the action of mitochondrialderived ROS and RNS on membrane phospholipids and other polyunsaturated fatty acids results in lipid peroxidation products (LPPs). Failure to neutralize these LPP by endogenous antioxidant mechanisms leads to LPP decomposition to form aldehydes, some of which are highly reactive and toxic to the cell, including 4-hydroxynonenal (4-HNE), 4-hydroxyhexanal (4-HHE), and malondialdehyde. Both 4-HNE and 4-HHE are stable, lipophilic and highly reactive electrophiles, which can modify proteins (interaction with cysteine and methionine groups in addition to covalent modification of amide groups of lysine and histidine via Michael addition) generally acting to reduce protein function.