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Background— Life-threatening ventricular tachyarrhythmias can occur in young patients without structural heart disease (idiopathic forms). In many patients, these are typically triggered by an increased sympathetic tone, eg, by physical or mental stress. In contrast, in Brugada syndrome, ventricular tachyarrhythmias more often occur during rest or sleep when the vagal tone is predominant. Furthermore, adrenergic agonists can reduce the level of ST-segment elevation, whereas it is increased by parasympathetic agonists or adrenergic antagonists. The aim of this study was to investigate presynaptic and postsynaptic myocardial sympathetic function in patients with Brugada syndrome. Methods and Results— Nine patients with Brugada syndrome (6 male, 3 female; age, 41±13 years) were enrolled in this study. The cardiac autonomic nervous system was assessed noninvasively, quantifying myocardial presynaptic and postsynaptic sympathetic function by means of positron emission tomography with the norepinephrine analogue 11 C-Hydroxyephedrine ( 11 C-HED) and the nonselective β-blocker 11 C-CGP 12177 ( 11 C-CGP). Presynaptic sympathetic norepinephrine recycling, assessed by 11 C-HED, was globally increased in patients with Brugada syndrome compared with a group of age-matched healthy control subjects (92.9±16.2 mL/g versus 69.1±14.2 mL/g; P 11 C-CGP, was similar in patients and control subjects (10.4±6.7 pmol/g versus 10.2±2.9 pmol/g; P =NS). Conclusions— The present study on autonomic innervation in Brugada syndrome describes an enhanced presynaptic norepinephrine recycling with preserved β-adrenoceptor density, further supporting the hypothesis of an autonomic dysfunction in Brugada syndrome. This is a further step toward the understanding of the pathophysiology of the disease with potential future impact on therapeutic strategies.

Background— Nitric oxide (NO) is an endothelial mediator that regulates vascular smooth muscle tone, but it may exert its cardiovascular action also by modulating the autonomic control of vasomotor tone. We assessed the effect of simultaneous inhibition of both endothelial (eNOS) and neuronal (nNOS) NO synthase isoforms on myocardial blood flow (MBF) and coronary flow reserve (CFR) in volunteers and in (denervated) transplant recipients. Methods and Results— MBF (mL · min −1 · g −1 ) was measured at rest and during adenosine-induced hyperemia with positron emission tomography and 15 O-labeled water. CFR was calculated as adenosine/resting MBF. Measurements were repeated during one of the following intravenous infusions: group 1 (n=12), saline; group 2 (n=9), 3 mg/kg N G -monomethyl- l -arginine (L-NMMA), which crosses the blood-brain barrier and inhibits both eNOS and nNOS; group 3 (n=13), 10 mg/kg L-NMMA; group 4 (n=8), phenylephrine titrated to simulate the hemodynamic changes in group 3; and group 5 (n=6), 10 mg/kg L-NMMA infused into the heart transplant recipients. After intervention, hyperemic MBF and CFR were unchanged in groups 1, 2, and 4. By contrast, both hyperemic MBF (+53%, P P Conclusions— The results of the present study suggest that maximal adenosine-induced hyperemia and CFR in humans are constrained by neurally mediated vasoconstriction, which can be relieved by systemic NOS inhibition with L-NMMA.

Background— Increased extravascular compression and reduced diastolic perfusion time (DPT), rather than vascular remodeling, influence coronary microcirculatory dysfunction in aortic stenosis (AS). However, alterations after aortic valve replacement (AVR) remain unclear. The aim of the present study was to quantify changes in transmural perfusion and coronary vasodilator reserve (CVR), a measure of microcirculatory function, after AVR and determine the relative contribution of left ventricular mass (LVM) regression, change in aortic valve area (AVA), and DPT. Methods and Results— Twenty-two patients with AS were studied before and 1 year after AVR using echocardiography to measure AVA, cardiovascular magnetic resonance to assess LVM, and positron emission tomography to quantify resting and hyperemic myocardial blood flow (MBF) and CVR. Regression of LVM occurred in all patients (from 129±30 to 94±24 g/m 2 ; P r =0.44; P =0.04). Conclusions— Changes in coronary microcirculatory function in patients with AS after AVR are not directly dependent on regression of LVM. Reduced extravascular compression and increased DPT are proposed as the main mechanisms for improvement in MBF and CVR after AVR.

Abstract —The use of quantitative coronary angiography, combined with Doppler and PET, has recently been directed at the study of α-adrenergic coronary vasomotion in humans. Confirming prior animal experiments, there is no evidence of α-adrenergic coronary constrictor tone at rest. Again confirming prior experiments, responses to α-adrenoceptor activation are augmented in the presence of coronary endothelial dysfunction and atherosclerosis, involving both α 1 - and α 2 -adrenoceptors in epicardial conduit arteries and microvessels. Such augmented α-adrenergic coronary constriction is observed during exercise and coronary interventions, and it is powerful enough to induce myocardial ischemia and limit myocardial function. Recent studies indicate a genetic determination of α 2 -adrenergic coronary constriction.

The last 3 decades have witnessed an unprecedented improvement in the outcome of patients with acute coronary syndromes. The widespread use of thrombolytic therapy and percutaneous coronary interventions, in association with increasingly potent antithrombotic agents, has contributed to significant reductions in mortality and morbidity in these patients. Although overall survival has improved, a downside of this success has been the greater number of patients with residual left ventricular (LV) dysfunction undergoing progressive LV remodeling and congestive heart failure. This problem is compounded by the rising age of our population and the higher prevalence of comorbidities such as diabetes mellitus that confer an increased risk of coronary artery disease (CAD) and congestive heart failure. Patients with CAD represent by far the most numerous cohort among those with congestive heart failure, and their treatment remains a partial success.1 Typically, these patients have multivessel disease, increased LV volumes, and variable degrees of regional and/or global systolic dysfunction, although more cases of isolated diastolic dysfunction have been reported recently.2–4 In these patients, coronary revascularization may lead to symptomatic and prognostic improvement, and these clinical benefits are accompanied by evidence of reverse LV remodeling. In this context, the concept of myocardial viability was developed and a number of different techniques have been used to demonstrate the presence of viable tissue before coronary revascularization. The aim of this review article is to summarize our current understanding of the concept of myocardial viability and its clinical implications in patients with CAD and chronic LV dysfunction. Throughout this review, we use the term viability to describe dysfunctional myocardium subtended by diseased coronary arteries with limited or absent scarring that therefore has the potential for functional recovery. Viability is a prospective definition, but it does not imply evidence of functional recovery after interventions. The term hibernation, which …

Cardiac progenitor cells (CPCs) have been identified in the adult heart. However, the molecular mechanisms involved in the commitment of CPCs to the myocyte lineage remain to be determined. Notch-1 is a transmembrane receptor activated by the DSL family of ligands which include Jagged1 and Delta-4. Upon ligand binding, the activated receptor undergoes cleavage by γ-secretase, and its intracellular portion (Notch intracellular domain, NICD) is released, translocates to the nucleus and exerts its function as a transcriptional regulator. The objective of this study was to determine whether the components of the Notch pathway are present in the CPCs of the adult mammalian heart and whether activation of the Notch-1 receptor promotes the differentiation of CPCs into myocytes. For this purpose, c-kit-positive CPCs were isolated from the mouse heart and analyzed by FACS and immunocytochemistry. Notch-1 receptor was detected in ~50% of c-kit-positive CPCs. CPCs were then plated on culture dishes coated with immobilized Jagged1 or Delta-4 and maintained in low-serum medium. Additional groups of cells were similarly exposed to the ligands but were also treated with γ-secretase inhibitor. After 5 days in culture, the number of CPCs was markedly lower in the presence of the Notch ligands and significantly higher in the presence of the γ-secretase inhibitor. After 8 days in culture, cells became confluent and did not express any longer c-kit. With respect to cells treated with the γ-secretase inhibitor, exposure to Jagged1 and Delta-4 resulted respectively in a 10-fold and 20-fold increase in the fraction of CPCs positive for Nkx2.5. These findings were consistent with a positive effect of Notch on CPC differentiation and Nkx2.5 upregulation. To establish whether Notch influenced cardiomyogenesis in vivo, infarcted mice were treated for 11 days with the γ-secretase inhibitor. The regenerative response of the infarcted heart, defined by the percentage of BrdU-positive myocytes distributed in the border zone, was 50% lower in animals that received the γ-secretase inhibitor. Thus, Notch1 modulates CPC differentiation in vitro and myocardial regeneration in vivo after infarction.

To establish whether progenitor cells are present in the human heart (hCPCs) and have phenotypic properties distinct from human hematopoietic stem cells (hHSCs), samples of human myocardium were enzymatically dissociated and c-kit-positive-cells were sorted and plated immediately to obtain clones derived from single founder cells. By FACS analysis, freshly isolated hCPCs comprised 1.1±1.0% of the population and were negative for HSC markers, CD34 and CD133, and KDR. They were also negative for epitopes of monocytes, CD14 and CD16, mast cells, CD45, and lymphocytes, CD3 and CD20. The phenotype of hCPCs was completely different from that of human bone marrow cells which were positive for these surface antigens. Only small fractions of hCPCs expressed GATA4 and Nkx2.5. Of 1,530 seeded hCPCs, 11 clones were generated accounting for 0.7% cloning efficiency. Subsequently, these cells were injected in immunodeficient mice and rats at the time of coronary occlusion and 5 days after infarction. This was done to assess whether hCPCs differentiated into myocytes and coronary vessels immediately after ischemic injury and in the presence of a well-developed infarct. In both cases, hCPCs regenerated the infarcted myocardium. Connexin 43 and N-cadherin were detected between recipient rodent myocytes and newly formed human myocytes. The problem was then whether the structural integration of these two myocyte populations had a physiological counterpart. Studies were performed using an ex vivo preparation together with two-photon microscopy and laser line-scan imaging. EGFP-positive-hCPCs were injected in infarcted mice and the heart was studied 2-weeks later. The heart was perfused with an oxygenated Tyrode solution containing the calcium indicator Rhod-2 and stimulated at 1 Hz. Calcium transients was recorded in EGFP positive human myocytes and EGFP negative mouse myocytes. The synchronicity in calcium tracings between these two distinct cell pools was apparent, pointing to the functional integration of newly formed EGFP-positive human myocytes with the surrounding EGFP-negative mouse myocytes. Thus, the human heart contains hCPCs which are not of bone marrow origin and possess the ability to acquire the cardiomyocyte and coronary vascular cell lineages.