It is commonly held that cardiac remodelling, represented by changes in muscle mass, size, and shape of the heart, explains the progression of congestive heart failure (CHF). However, this concept does not provide any clear information regarding the development of cardiac dysfunction in CHF. Extensive research has revealed that various subcellular organelles such as the extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus undergo varying degrees of changes in their biochemical composition and molecular structure in CHF. This subcellular remodelling occurs due to alterations in cardiac gene expression as well as activation of different proteases and phospholipases in the failing hearts. Several mechanisms including increased ventricular wall stress, prolonged activation of the renin-angiotensin and sympathetic systems, and oxidative stress have been suggested to account for subcellular remodelling in CHF. Furthermore, subcellular remodelling is associated with changes in cardiomyocyte structure, cation homeostasis as well as functional activities of cation channels and transporters, receptor-mediated signal transduction, Ca(2+)-cycling proteins, contractile and regulatory proteins, and energy production during the development of heart failure. The existing evidence supports the view that subcellular remodelling may result in cardiac dysfunction and thus play a critical role in the transition of cardiac hypertrophy to heart failure.

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Persistent pulmonary hypertension of the newborn (PPHN) results in right ventricular (RV) hypertrophy followed by right heart failure and an associated mitochondrial dysfunction. The phospholipid cardiolipin plays a key role in maintaining mitochondrial respiratory and cardiac function via modulation of the activities of enzymes involved in oxidative phosphorylation. In this study, changes in cardiolipin and cardiolipin metabolism were investigated during the development of right heart failure. Newborn piglets (<24 h old) were exposed to a hypoxic (10% O(2)) environment for 3 days, resulting in the induction of PPHN. Two sets of control piglets were used: 1) newborn or 2) exposed to a normoxic (21% O(2)) environment for 3 days. Cardiolipin biosynthetic and remodeling enzymes, mitochondrial complex II + III activity, incorporation of [1-(14)C]linoleoyl-CoA into cardiolipin precursors, and the tetralinoleoyl-cardiolipin pool size were determined in both the RV and left ventricle (LV). PPHN resulted in an increased heart-to-body weight ratio, RV-to-LV plus septum weight ratio, and expression of brain naturetic peptide in RV. In addition, PPHN reduced cardiolipin biosynthesis and remodeling in the RV and LV, which resulted in decreased tetralinoleoyl-cardiolipin levels and reduced complex II + III activity and protein levels of mitochondrial complexes II, III, and IV in the RV. This is the first study to examine the pattern of cardiolipin metabolism during the early development of both the RV and LV of the newborn piglet and to demonstrate that PPHN-induced alterations in cardiolipin biosynthetic and remodeling enzymes contribute to reduced tetralinoleoyl-cardiolipin and mitochondrial respiratory chain function during the development of RV hypertrophy. These defects in cardiolipin may play an important role in the rapid development of RV dysfunction and right heart failure in PPHN.