Search

Idiopathic dilated cardiomyopathy (IDC) is characterized by left ventricular (LV) enlargement with systolic dysfunction, other causes excluded. When inherited, it represents familial dilated cardiomyopathy (FDC). We hypothesized that IDC or FDC would show with cardiac magnetic resonance (CMR) increased myocardial accumulation of gadolinium contrast at steady state and decreased baseline myocardial blood flow (MBF) due to structural alterations of the extracellular matrix compared with normal myocardium. CMR was performed in nine persons affected with IDC/FDC. Healthy controls came from the general population (n = 6) or were unaffected family members of FDC patients (n = 3) without signs or symptoms of IDC/FDC or any structural cardiac abnormalities. The myocardial partition coefficient for gadolinium contrast ([[lambda].sub.Gd]) was determined by T1 measurements. LV shape and function and MBF were assessed by standard CMR methods. [[lambda].sub.Gd] was elevated in IDC/FDC patients vs. healthy controls ([[lambda].sub.Gd] = 0.56 [+ or -] 0.15 vs. 0.41 [+ or -] 0.06; P = 0.002), and correlated with LV enlargement (r = 0.61 for [[lambda].sub.Gd] vs. end-diastolic volume indexed by height; P < 0.0l) and with ejection fraction (r = -0.80; P < 0.001). The extracellular volume fraction was higher in IDC patients than in healthy controls (0.31 [+ or -] 0.05 vs. 0.24 [+ or -] 0.03; P = 0.002). Resting MBF was lower in IDC patients (0.64 [+ or -] 0.13 vs. 0.91 [+ or -] 0.22; P = 0.01) than unaffected controls and correlated with both the partition coefficient (r = -0.57; P = 0.012) and the extracellular volume fraction (r = -0.56; P = 0.019). The expansion of the extracellular space correlated with reduced MBF and ventricular dilation. Expansion of the extracellular matrix may be a key contributor to contractile dysfunction in IDC patients. idiopathic dilated cardiomyopathy; partition coefficient; myocardial blood flow

The nitrite anion is reduced to nitric oxide (NO*) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO* signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type (+/+) and knockout (-/-) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO* generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO* generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO* by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin+/+ but not in myoglobin-/ hearts, nitrite treatment resulted in an improved recovery of postischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin+/+ mice, whereas in rnyoglobin-/- mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation, myoglobin knockout mice

Within hibernating myocardium, it is uncertain whether a normal energetic state is present at baseline and whether maintaining that energy state during a catecholamine challenge is dependent on ATP-dependent potassium channel opening. In this study, 16 swine underwent a thoracotomy with placement of an external constrictor on the left anterior descending coronary artery (LAD) (hibernation model). Seven additional swine underwent a sham operation. At 10 wk, the myocardial energetic state in the LAD region was assessed by [sup.31]P-NMR spectroscopy, and the ratio of phosphocreatine to ATP (PCr/ATP) was determined at baseline, during glibenclamide treatment (0.5 mg/kg bolus with 50 [micro]g/min iv), and during addition of dobutamine (40 [micro]g x [kg.sup.-1] x [min.sup.-1] iv). At baseline, transmural blood flow in the LAD and remote region was 0.75 [+ or -] 0.11 and 0.88 [+ or -] 0.09 ml x [min.sup.-1] x [g.sup.-1], respectively (P < 0.01), in hibernating hearts and 0.83 [+ or -] 0.12 and 0.88 [+ or -] 0.15 ml x [min.sup.-1] x [g.sup.-1], respectively (not significant), in sham-operated hearts. Under basal conditions, PCr/ATP in the LAD region of hibernating and sham pigs was 2.15 [+ or -] 0.04 and 2.11 [+ or -] 0.05, respectively (not significant). In sham pigs, addition of dobutamine to glibenclamide increased the double product from 10.4 [+ or -] 0.8 to 23.9 [+ or -] 4.0 mmHg x beats x [min.sup.-1] x 1,000 (P < 0.05) and decreased transmural PCr/ATP from 2.06 [+ or -] 0.06 to 1.69 [+ or -] 0.06 (P < 0.05). Dobutamine increased the double product in hibernating pigs in a similar fashion and, despite a 40% lower blood flow response, induced an equivalent decrease in PCr/ATP from 2.04 [+ or -] 0.04 to 1.73 [+ or -] 0.08 (P < 0.05). In conclusion, we found that, in chronic hibernating swine myocardium with reduced basal blood flow and perfusion reserve, the transmural energetic state, defined by PCr/ATP, is normal during addition of dobutamine, despite inhibition of ATP-dependent potassium channel opening with glibenclamide. These data suggest that important adaptations other than the ATP-dependent potassium channel opening allow hibernating myocardium to operate over a lower range of the oxygen supply-demand relationship to protect against myocardial ischemia. myocardial ischemia; high-energy phosphates; preconditioning; hibernation; mitochondrial adaptations

The orientation of MRI-measured diffusion tensor in the myocardium has been directly correlated to the tissue fiber direction and widely characterized. However, the scalar anisotropy indexes have mostly been assumed to be uniform throughout the myocardial wall. The present study examines the fractional anisotropy (FA) as a function of transmural depth and circumferential and longitudinal locations in the normal sheep cardiac left ventricle. Results indicate that FA remains relatively constant from the epicardium to the midwall and then decreases (25.7%) steadily toward the endocardium. The decrease of FA corresponds to 7.9% and 12.9% increases in the secondary and tertiary diffusion tensor diffusivities, respectively. The transmural location of the FA transition coincides with the location where myocardial fibers run exactly circumferentially. There is also a significant difference in the midwall-endocardium FA slope between the septum and the posterior or lateral left ventricular free wall. These findings are consistent with the cellular microstructure from histological studies of the myocardium and suggest a role for MR diffusion tensor imaging in characterization of not only fiber orientation but, also, other tissue parameters, such as the extracellular volume fraction. fractional anisotropy; left ventricle; extracellular volume fraction; cardiac electrophysiology and biomechanics

Multiple extracardiac stimuli, such as workload and circulating nutrients (e.g., fatty acids), known to influence myocardial metabolism and contractile function exhibit marked circadian rhythms. The aim of the present study was to investigate whether the rat heart exhibits circadian rhythms in its responsiveness to changes in workload and/or fatty acid (oleate) availability. Thus, hearts were isolated from male Wistar rats (housed during a 12:12-h light-dark cycle: lights on at 9 AM) at 9 AM, 3 PM, 9 PM, and 3 AM and perfused in the working mode ex vivo with 5 mM glucose plus either 0.4 or 0.8 mM oleate. Following 20-min perfusion at normal workload (i.e., 100 cm [H.sub.2]O afterload), hearts were challenged with increased workload (140 cm [H.sub.2]O afterload plus 1 [micro]M epinephrine). In the presence of 0.4 mM oleate, myocardial metabolism exhibited a marked circadian rhythm, with decreased rates of glucose oxidation, increased rates of lactate release, decreased glycogenolysis capacity, and increased channeling of oleate into nonoxidative pathways during the light phase. Rat hearts also exhibited a modest circadian rhythm in responsiveness to the workload challenge when perfused in the presence of 0.4 mM oleate, with increased myocardial oxygen consumption at the dark-to-light phase transition. However, rat hearts perfused in the presence of 0.8 mM oleate exhibited a markedly blunted contractile function response to the workload challenge during the light phase. In conclusion, these studies expose marked circadian rhythmicities in myocardial oxidative and nonoxidative metabolism as well as responsiveness of the rat heart to changes in workload and fatty acid availability. fatty acids; glucose; glycogen; triglyceride

Myocardial ischemia-reperfusion (I/R) injury is associated with contractile dysfunction, arrhythmias, and myocyte death. Intracellular [Ca.sup.2+] overload with reduced activity of sarco(endo)plasmic reticulum [Ca.sup.2+]-ATPase (SERCA) is a critical mechanism of this injury. Although upregulation of SERCA function is well documented to improve postischemic cardiac function, there are conflicting reports where pharmacological inhibition of SERCA improved postischemic function. SERCA2a is the primary cardiac isoform regulating intracellular [Ca.sup.2+] homeostasis; however, SERCA1a has been shown to substitute SERCA2a with faster [Ca.sup.2+] transport kinetics. Therefore, to further address this issue and to evaluate whether SERCAla expression could improve postischemic cardiac function and myocardial salvage, in vitro and in vivo myocardial I/R studies were performed on SERCAla transgenic (SERCA[1a.sup.+/+]) and nontransgenic (NTG) mice. Langendorff-per-fused hearts were subjected to 30 min of global ischemia followed by reperfusion. Baseline preischemic coronary flow and left ventricular developed pressure were significantly greater in [SERCA1a.sup.+/+] mice compared with NTG mice. Independent of reperfusion-induced oxidative stress, [SERCA1a.sup.+/+] hearts demonstrated greatly improved postischemic (45 min) contractile recovery with less persistent arrhythmias compared with NTG hearts. Morphometry showed betterpreserved myocardial structure with less infarction, and electron microscopy demonstrated better-preserved myofibrillar and mitochondrial ultrastructure in [SERCA1a.sup.+/+] hearts. Importantly, intraischemic [Ca.sup.2+] levels were significantly lower in [SERCA1a.sup.+/+] hearts. The cardioprotective effect of SERCA1a was also observed during in vivo regional I/R with reduced myocardial infarct size after 24 h of reperfusion. Thus [SERCA1a.sup.+/+] hearts were markedly protected against I/R injury, suggesting that expression of SERCA 1a isoform reduces postischemic [Ca.sup.2+] overload and thus provides potent myocardial protection. myocardial ischemia-reperfusion; sarco(endo)plasmic reticulum calcium-adenosine triphosphatase; free radicals: postischemic function

To characterize developmental changes in impulse propagation within atrial musculature, we performed high-speed optical mapping of activation sequence of the developing chick atria using voltage-sensitive dye. The activation maps were correlated with detailed morphological studies using scanning electron microscopy, histology, and whole mount confocal imaging with three-dimensional reconstruction. A preferential pathway appeared during development within the roof of the atria, transmitting the impulse rapidly from the right-sided sinoatrial node to the left atrium. The morphological substrate of this pathway, the bundle of Bachman, apparent from stage 29 onward, was a prominent ridge of pectinate muscles continuous with the terminal crest. Further acceleration of impulse propagation was noted along the ridges formed by the developing pectinate muscles, ramifying from the terminal crest toward the atrioventricular groove. In contrast, when the impulse reached the interatrial septum, slowing was often observed, suggesting that the septum acts as a barrier or sink for electrical current. We conclude that these inhomogeneities in atrial impulse propagation are consistent with existence of a specialized network of fast-conducting tissues. The purpose of these preferential pathways appears to be to assure synchronous atrial activation and contraction rather than rapid impulse conduction between the sinoatrial and atrioventricular nodes. chick embryo; optical mapping; conduction system; internodal pathways; pectinate muscles

A study was conducted to evaluate the potential of high-frequency static two-dimensional (2-D) elastography for in vivo exploration of the mechanical behavior of skin, using a combination of a 20MHz sonographer and a patented extensiometer device able to apply calibrated uniaxial stretching of the skin. The mechanical behavior of the hypodermis seemed mainly to be determined by its structures and its expansion of the dermis.

Heart failure may be a result of myocyte apoptosis, the biologically regulated programmed cell death of muscle cells. Researchers found evidence of apoptosis in five of seven hearts taken from patients with severe heart failure who were receiving a heart transplant. In contrast, locally apoptotic tissue was identified from four patients with recent heart attacks only near the damaged region. The hearts of four car accident victims contained few apoptotic cells. The prevention of cell death may become a future therapeutic angle for the treatment of heart disease and heart failure.