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Background-The role of adaptive immunity, especially CD4ϩ T-helper cells, has not yet been systematically investigated in wound healing and remodeling after myocardial infarction (MI). Therefore, we studied whether CD4 ϩ T cells become activated and influence wound healing after experimental MI in mice. Methods and Results-When we compared sham versus MI in wild-type (WT) mice, T-cell receptor-dependent activation of both conventional Foxp3 Ϫ and regulatory Foxp3 ϩ CD4 ϩ T cells could be demonstrated in heart-draining lymph nodes within the first week after MI. Concomitantly, we found infiltration of CD4 ϩ T cells in infarcted myocardium. To study the role of CD4 ϩ T cells in wound healing and remodeling, CD4 ϩ T-cell-deficient mice (CD4 knockout [KO], MHCII ⌬/⌬ ) and T-cell receptor-transgenic OT-II mice recognizing an irrelevant ovalbumin-derived peptide were studied. Serial echocardiography up to day 56 after MI revealed increased left ventricular dilation in CD4 KO compared with WT mice. Within the infarcted myocardium, CD4 KO mice displayed higher total numbers of leukocytes and proinflammatory monocytes (18.3Ϯ3.0 10

ObjectiveThe long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards ‘hard’ clinical end-points in comparison with the natural course of the disease.MethodsA total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain.ResultsDuring a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min−1 per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry.ConclusionDespite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.

SUMMARY The effects of angiotensin-converting enzyme inhibitor (CEI) SQ14225 on infarct size and regional myocardial blood flow were studied in 21 anesthetized dogs subjected to 6 hours of coronary occlusion. An area of myocardium at risk of necrosis was determined in vivo after 15 minutes of coronary occlusion but before CEI treatment (AR1) using an autoradiographic technique and after treatment after 6 hours of coronary occlusion (AR2) using a fluorescent dye technique. An MYOCARDIAL ISCHEMIA and, ultimately, infarction result from an imbalance between oxygen supply and oxygen demand. Coronary occlusion may induce hypotension, which results in baroreceptor activation and then systemic reflex vasoconstriction. -3 Systemic vasoconstriction may worsen the imbalance between myocardial oxygen supply and demand. Renal nerve activity,' a determinant of renin release,5 may be increased as well. Moreover, hypotension may activate intrarenal vascular pressoreceptors and may thus increase renin release directly.5 Because angiotensin II is a potent systemic and coronary vasoconstrictor, activation of the renin-angiotensin system may increase myocardial oxygen demand and decrease myocardial oxygen supply. Because interference with angiotensin II-production might exert a beneficial effect in myocardial ischemia and myocardial infarction, we studied the effects of the angiotensin-converting enzyme inhibitor (CEI) captopril (SQ14225) on infarct size after experimental coronary occlusion. To elucidate the mechanism of the salutary action of the drug, we also determined the effect of CEI on regional myocardial blood flow (RMBF) and measured plasma renin activity (PRA). Methods Twenty-one mongrel dogs of either sex weighing 16-28 kg that had been maintained on normal laboratory chow and had free access to water were anesthetized with i.v. thiamylal sodium (10 mg/kg), intubated and ventilated with room air using a Harvard respirator pump. Anesthesia was maintained by additional thiamylal sodium when needed. Lead aVF of the ECG was monitored. Saline was infused at a rate of 2 ml/min throughout the experiment to minimize hypovolemia and renin release. The chest was opened in the fifth left intercostal space and the heart was suspended in a pericardial cradle. The left anterior descending coronary artery was freed up approximately 2 cm from its origin just distal to the first major diagonal branch. Polyethylene catheters were placed in the femoral artery and vein and in the left atrial appendage. Arterial and left atrial pressures were measured by Statham P23Db pressure transducers.Infarct size after coronary occlusion depends on both the quantity of myocardium perfused by the occluded coronary vessel and the quantity of collateral flow to the jeopardized tissue.7'9 The variations in infarct size after coronary occlusion can be limited when these factors are taken into account by determining the area of myocardium at risk of developing necrosis and expressing infarct size as a percentage of the area at risk. In the present study, ...

In the present work, we studied clinical and haemodynamic correlates of impaired cardiac high-energy phosphate metabolism in patients with heart failure due to dilated cardiomyopathy (DCM). Myocardial 31P-magnetic resonance (MR) spectra were obtained at 1.5 T in 14 volunteers and 23 patients with DCM (mean ejection fraction 34%) in order to quantify the creatine phosphate (CP)/ATP ratio. In addition, patients underwent cardiac catheterization and echocardiography. Compared to volunteers (2.02 +/- 0.11), CP/ATP ratios were significantly reduced in DCM patients (1.54 +/- 0.10; P < 0.05), indicating impaired high-energy phosphate metabolism. CP/ATP ratios correlated with the clinical severity of heart failure estimated from the NYHA class (r = 0.47, P < 0.01); also, CP/ATP correlated with left ventricular ejection fraction (r = 0.54, P < 0.01) and left ventricular end-diastolic wall thickness (r = 0.51, P < 0.01). Thus, 31P-MR spectroscopy can detect abnormal cardiac high-energy phosphate metabolism in patients with heart failure due to DCM. These abnormalities correlate with clinical and haemodynamic parameters. Future studies will have to determine whether 31P-MR spectroscopy can contribute to the routine clinical evaluation of patients with heart failure.