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Objectives. This study investigated the neuronal reuptake of norepinephrine (uptake-1) and the beta-adrenoceptor density in patients,vith idiopathic right ventricular outflow tract tachycardia (RVO-VT). Background. Clinical findings, such as the inducibility of ventricular tachycardia by stress or catecholamine infusion, and the therapeutic efficacy of antiarrhythmic drugs with antiadrenergic properties suggest abnormalities of cardiac sympathetic innervation in patients,vith idiopathic RVO-VT. Methods. Eight patients with idiopathic RVO-VT and a total of 29 age-matched control subjects were investigated by positron emission tomography using [C-11] hydroxyephedrine (HED) (volume of distribution of [C-11]HED) to assess presynaptic norepinephrine reuptake; [C-11] CGP 12177 (maximal binding capacity of [C-11]CGP 12177) to measure postsynaptic beta-adrenoceptor density; and oxygen-15-labeled water for quantification of myocardial blood flow (MBF). Results. Both myocardial catecholamine reuptake and beta adrenoceptor density were significantly reduced in patients with idiopathic RVO-VT. The volume of distribution of [C-11]HED in patients with RVO-VT was (mean +/- SD) 41.0 +/- 13.5 versus 71.0 +/- 18.8 ml/g in control subjects (p < 0.002). The maximal binding capacity of the beta-adrenoceptor antagonist [C-11] CGP 12177 was 6.8 +/- 1.2 pmol/g in patients with RVO-VT versus 10.2 +/- 2.9 pmol/g in control subjects (p < 0.004). There were no significant differences in MBF at rest (0.98 +/- 0.14 vs. 0.97 +/- 0.24 ml/min per g, p = NS) between patients with RVO-VT and control subjects. Conclusions. The findings of the present study suggest that myocardial beta-adrenoceptor downregulation in patients with RVO-VT occurs subsequently to increased local synaptic catecholamine levels caused by impaired catecholamine reuptake.

The effects of intravenous ergotamine (0.25 mg) on basal and hyperemic (dipyridamole) myocardial blood flow (MBF), measured with positron emission tomography and H2(15)O, were assessed in 15 migraineurs in a double-blind, randomized, placebo controlled, crossover study. Ergotamine produced a 27% reduction in hyperemic MBF (2.62 +/- 0.11 vs 3.72 +/- 1.05 ml x min(-1) x g(-1); p

Objectives: To determine the predictive value of quantitative evaluation of myocardial viability on changes in left ventricular function, exercise capacity, and quality of life after coronary artery bypass grafting in patients with ischemic heart failure (congestive heart failure, New York Heart Association class ≥ III) with and without angina. Methods: Thirty-five patients, 14 with congestive heart failure and angina (CHF-angina) and 21 with congestive heart failure without angina (CHF–no angina) were studied at baseline and 6 months after coronary bypass grafting. Left ventricular function was evaluated with transthoracic echocardiography and radionuclide ventriculography. Myocardial viability was assessed with [18F]-2-fluoro-2-deoxy-d-glucose using positron emission tomography. Peak aerobic capacity (peak oxygen consumption) and anaerobic threshold were assessed with treadmill exercise test and quality of life with a questionnaire. Results: A total of 286 of 336 dysfunctional left ventricular segments were viable. There were two perioperative deaths (5.7%) and three late deaths. Left ventricular ejection fraction increased from 23% ± 7% to 32% ± 9% (p < 0.0001), and a linear correlation was found between the number of viable segments and the changes in ejection fraction (r = 0.65; p = 0.0001). Receiver operating characteristics curve identified eight viable segments as the best predictor for increase of ejection fraction more than 5 percentage points. Peak oxygen consumption increased from 15 ± 4 to 22 ± 5 ml/kg per minute (p < 0.0001). Preoperatively, anaerobic threshold was identified in one patient from the CHF-angina group and in all from the CHF–no angina group and increased from 13 ± 4 to 19 ± 4 ml/kg per minute (p < 0.0001). Quality of life scores improved significantly in both groups. No correlation was found between the amount of viable dysfunctional myocardium and changes in exercise capacity or quality of life. Conclusions: In patients with postischemic congestive heart failure the amount of viable myocardium dictates the degree of improvement in left ventricular function after revascularization. (J Thorac Cardiovasc Surg 1998;115:791-9

Background —Postprandial angina pectoris has been recognized for more than two centuries and can be identified in up to 10% of patients with chronic ischemic heart disease. Redistribution of myocardial blood flow, from a region supplied by a severely stenotic coronary artery to those supplied by less diseased or normal vessels, is a potential mechanism of postprandial angina. Methods and Results —To test this hypothesis, we have determined the effects of a standard liquid meal on whole heart and regional myocardial blood flow, measured by means of dynamic positron emission tomography (PET) with 15 O-labeled water in 14 patients with a reproducible history of postprandial angina and 7 matched control subjects. The standard liquid meal precipitated angina pectoris in all patients. Baseline whole heart blood flow was similar and increased normally after the meal in patients (0.97±0.14 to 1.14±0.25 mL · min −1 · g −1 , P −1 · g −1 , P P P =NS versus baseline). In patients, analysis of regional myocardial blood flow demonstrated decreased myocardial blood flow in territories supplied by stenotic arteries (1.01±0.35 to 0.76±0.27 mL · min −1 · g −1 , P −1 · g −1 , P Conclusions —The standard liquid meal induced angina pectoris in patients with coronary artery disease. Although whole heart blood flow increased appropriately for the greater cardiac work, there was a redistribution of regional blood flow from territories supplied by severely stenosed coronary arteries to those supplied by less diseased or normal arteries. This redistribution may be the cause of myocardial ischemia in postprandial angina.

The members of the ESC PCI guidelines task force appreciate the comments made by Dr Nienaber regarding our analysis and recommendations for drug-eluting stents (DES). (1) Dr Nienaber states that our recommendations for DES should not have been based on the TAXUS-VI trial, because this trial investigated the moderate-release form of the Taxus stent which has not been marketed. First, in the TAXUS-II trial, there were no clinically or angiographically relevant differences between the marketed slow-release and the not marketed moderate-release forms in equivalent lesions. Furthermore, comparing the TAXUS-VI results with TAXUS-V also did not reveal clinically relevant differences between the slow-release and the moderate-release forms. From Dr Nienaber's point of view, we should also not have recommended the Cypher stent—at least for Germany: the currently marketed Cypher Select stent was not the one that was investigated in the SIRIUS trial (Cypher Bx Velocity). As another example, in most European countries, clopidogrel is not labelled for use after coronary stent implantation. Should the ESC PCI guidelines therefore not recommend clopidogrel after stent implantation? (2) Regarding the use of DES for in-stent restenosis, …

Background— Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease. The relative extent to which CMD affects both sexes is largely unknown. Methods and Results— We investigated 405 men and 813 women who were referred for evaluation of suspected coronary artery disease with no previous history of coronary artery disease and no visual evidence of coronary artery disease on rest/stress positron emission tomography myocardial perfusion imaging. Coronary flow reserve was quantified, and coronary flow reserve P =0.0002). Regardless of sex, coronary flow reserve was a powerful incremental predictor of major adverse cardiac events (hazard ratio, 0.80 [95% confidence interval, 0.75–086] per 10% increase in coronary flow reserve; P P =0.56; equivalence P =0.041). Conclusions— CMD is highly prevalent among at-risk individuals and is associated with adverse outcomes regardless of sex. The high prevalence of CMD in both sexes suggests that it may be a useful target for future therapeutic interventions.

Objectives This study sought to evaluate the impact of baseline activated clotting time (ACT)-guided heparin administration on major bleeding after transfemoral transcatheter aortic valve implantation (TAVI). Background Bleeding after TAVI is frequent and associated with unfavorable prognosis. Proper intraprocedural heparin dose administration may reduce the risk of potential overdosing in this frail study group. Methods Of the patients who underwent transfemoral TAVI in our center from November 1, 2007 to June 31, 2012, 362 were retrospectively analyzed. Because abnormally high baseline ACT values were noted, heparin was administered at the operator's discretion, according to baseline ACT (ACT-guided, n = 174) or patient's body weight (non-ACT-guided, n = 188). The primary study objective was 30-day major bleeding as defined by the Valve Academic Research Consortium criteria. Secondary objectives were any life-threatening, and minor bleeding, and other Valve Academic Research Consortium outcomes at 30 days. Results Bleeding occurred in 167 (46.1%) patients; of these, 76 (21.0%) had major bleeding. The ACT-guided group had a significantly lower occurrence of major (7.5% vs. 33.5%, p < 0.001), life-threatening (12.1% vs. 20.2%, p = 0.04), and any bleeding (25.9% vs. 64.9%, p < 0.001). Conversely, no differences were noted in the other study objectives. After adjustment for potential confounders, the protective odds ratio for ACT-guided therapy on major bleeding was 6.4 (95% confidence interval: 2.3 to 17.9; p < 0.001) at 30 days. Conclusions In our experience, heparin administration according to baseline ACT was correlated with a significantly lower occurrence of major bleeding in transfemoral TAVI. This strategy might be a useful tool in reducing bleeding in this high-risk study group. (C) 2014 by the American College of Cardiology Foundation OI Giustino, Gennaro/0000-0002-5400-9516

This editorial refers to ‘Impact of anatomical and functional severity of coronary atherosclerotic plaques on the transmural perfusion gradient: a [15O]H2O PET study’, by I. Danad et al. on page doi:10.1093/eurheartj/ehu170 In 1974 Gould et al .1 described the relationship between coronary stenosis severity, induced by a snare controlled by a micrometer constrictor, and coronary blood flow measured with a electromagnetic flowmeter proximal to the snare, in anaesthetized dogs. Twenty years later, two independent studies from London2 and Los Angeles3 reported the relationship between coronary stenosis severity, measured by quantitative angiography, and myocardial blood flow (MBF) and coronary flow reserve (CFR), measured non-invasively with positron emission tomography (PET) in patients with coronary artery disease (CAD). Measurements with radioactive microspheres in animals have demonstrated that in the normal heart, MBF has a homogeneous transmural distribution across the left ventricular (LV) wall both at baseline and during pharmacologically induced vasodilatation. The resting flow remains evenly distributed in the presence of a severe epicardial stenosis, but maximal MBF becomes grossly abnormal during hyperaemia,1 and during exercise is reduced to a larger extent in the subendocardium compared with the subepicardium.4 Among the factors that contribute to this selective impairment of MBF in the subendocardium and to its greater vulnerability to myocardial ischaemia, the most significant include heart rate and diastolic perfusion time, cardiac contractility, and LV chamber pressure.5 The spatial resolution of …

Non-sustained ventricular tachycardia on Holter and syncope have been considered risk factors for sudden death in hypertrophic cardiomyopathy. Aims In these patients the coronary vasodilator reserve is impaired despite normal coronaries, so we evaluated the correlation between the severity of coronary vasodilator reserve impairment and the occurrence of syncope and non-sustained ventricular tachycardia. Methods and Results Eighty-four patients with hypertrophic cardiomyopathy (62 males, age 43 +/- 12 years) had a two-dimensional echocardiographic study and a 48-h Holter. Myocardial blood flow was measured by positron emission tomography, at baseline and after dipyridamole, and the coronary vasodilator reserve was computed as dipyridamole myocardial blood flow/baseline myocardial blood flow. In 27 patients, subendocardial and subepicardial myocardial blood flow was measured in the septum and the subendocardial/subepicardial ratio was computed. Twenty of 84 patients had at least one syncopal episode, and 26 had at least one run of non-sustained ventricular tachycardia on Holter. Baseline and dipyridamole myocardial blood flow, coronary vasodilator reserve, and baseline and dipyridamole subendocardial/subepicardial myocardial blood flow ratio were similar in patients with and without syncope and with and without non-sustained ventricular tachycardia on Holter. However, patients with nonsustained- ventricular tachycardia had larger left ventricular end-diastolic (47+/-6 vs 44+/-5 mm, P

The long-term consequences of CAD remain a prominent clinical problem. Particularly with new therapeutic strategies that reduce the mortality associated with acute coronary syndromes, more patients suffer from the long-term sequelae of this condition. In this setting, the identification of those segments of myocardium that appear dysfunctional distal to coronary stenoses and that can improve after coronary revascularization is of considerable clinical importance. Although the diagnostic and therapeutic aspects of this problem are clearly defined, the pathophysiological mechanisms underlying the dysfunctional myocardium are controversial. It was demonstrated more than 20 years ago1 2 that resting wall-motion abnormalities in patients with CAD can improve after administration of an inotropic agent or after coronary bypass. An article published in 1978 by Diamond et al3 presaged the concept of hibernating myocardium: “Reports of sometimes dramatic improvement in segmental left ventricular function following coronary bypass surgery, although not universal, leaves the clear implication that ischemic non-infarcted myocardium can exist in a state of function hibernation.” Rahimtoola, in an article published in 1985,4 popularized this concept and later suggested that “hibernating myocardium is a state of persistently impaired myocardial and left ventricular function at rest due to reduced coronary blood flow that can be partially or completely restored to normal either by improving blood flow or by reducing oxygen demand.”5 Since the introduction of the term “hibernation,”3 4 5 6 the clinical importance of reversible left ventricular dysfunction has been widely accepted. The concept of an adaptive process that decreases myocardial oxygen consumption in the presence of either chronically or intermittently reduced oxygen delivery has generated considerable clinical and experimental interest. Accordingly, our aims were to (1) review the current criteria of the definition of hibernating myocardium, (2) summarize recent clinical as well as experimental data pertaining to this subject, …

Biodistribution and metabolism of [ N - methyl - 11 C ]- m - hydroxyephedrine ([ 11 C]mHED), an analogue of noradrenaline, were assessed in rats. Pretreatment with desipramine, an uptake 1 , blocker, reduced uptake of radioactivity in myocardium but not in lung, liver, kidney, and muscle. Brain uptake was negligible. HPLC showed six radioactive metabolites in plasma and liver but none in myocardium. Co-injection of unlabelled mHED or metaraminol with [ 11 C]mHED demonstrated no difference between the in vivo binding potentials for mHED and metaraminol in myocardium.

Positron Emission Tomography (PET) is the only available technique that permits quantification of regional myocardial perfusion in humans. To this end, tracer kinetic models and appropriate tracers such as 13N-Ammonia and 15O labeled water are required. Quantification is possible because accurate radioactivity quantities can be measured externally, both for the vascular and myocardial compartments. Normal value for baseline and maximal perfusion after pharmacologically induced vasodilatation of the resistance microcirculatory vessels are age-dependent. The functional hemodynamic significance of epicardial stenoses can be estimated from the progressive reduction in coronary perfusion reserve, which decreases progressively when stenosis severity reaches 40% in diameter. The effect of revascularization procedures such as CABG and PTCA can be objectively measured. In addition, there is increasing evidence from PET studies that resistive vessel dysfunction (probably through endothelial factors) contributes to the reduced perfusion reserve in patients with epicardial coronary artery disease. Therefore quantification of myocardial perfusion with PET appears an ideally suited endpoint for primary and secondary prevention trials.

Many patients undergoing coronary angiography because of chest pain syndromes, believed to be indicative of obstructive atherosclerosis of the epicardial coronary arteries, are found to have normal angiograms. In the past two decades, a number of studies have reported that abnormalities in the function and structure of the coronary microcirculation may occur in patients without obstructive atherosclerosis, but with risk factors or with myocardial diseases as well as in patients with obstructive atherosclerosis; furthermore, coronary microvascular dysfunction (CMD) can be iatrogenic. In some instances, CMD represents an epiphenomenon, whereas in others it is an important marker of risk or may even contribute to the pathogenesis of cardiovascular and myocardial diseases, thus becoming a therapeutic target. This review article provides an update on the clinical relevance of CMD in different clinical settings and also the implications for therapy.

Cardiovascular risk factors (e.g., hypercholesterolemia, smoking, hypertension, diabetes, etc.) have all been shown to cause CMD, as indicated by reduced CFR, before any obstructive stenosis can be detected in epicardial coronary arteries. The occurrence of chest pain in the absence of any other cardiac or systemic disease results in the clinical picture of primary microvascular angina (MVA), which usually presents with a stable, exercise-related angina syndrome, but can also occur as an acute syndrome suggesting a non-ST elevation ACS. Takotsubo cardiomyopathy is likely also caused by a sudden acute vasoconstriction of resistive coronary arteries resulting in severe impairment of med-distal LV segments.

Among patients with obstructive CAD, improvement of coronary microvascular function has mainly been attempted in two conditions, i.e., refractory angina and MVO. In refractory angina patients, therapies have been directed to stimulate collateral circulation, and have included angiogenic treatment, enhanced external counterpulsation, and exercise. Several forms of therapy have also been attempted to prevent or treat MVO in the setting of STEMI, including pharmacological (e.g., adenosine, nitroprusside) and nonpharmacological (e.g., antiembolic devices, ischemic conditioning) tools. This chapter discusses the main results observed with these interventions in these clinical settings.

CMD has been documented in most patients with myocardial diseases, including HCM, dilated cardiomyopathy, aortic stenosis, myocarditis, Anderson-Fabry disease, and cardiac amyloidosis. In this setting CMD is mainly caused by structural alterations. The consequent reduction of CFR is responsible for effort-induced myocardial ischemia and angina. CMD can be severe enough to determine focal areas of myocardial necrosis. Recent data indicate that in patients with HCM or dilated cardiomyopathy the presence of focal areas of myocardial necrosis, detected by CMR, is associated with a worse prognosis, mainly driven by sudden death, probably caused by myocardial necrosis-related ventricular arrhythmias. This prognostic information is additive to that provided by traditional risk factors and can therefore improve the identification of patients who need ICD implantation.

This chapter reviews the main noninvasive (TTDE, myocardial contrast echocardiography, PET, and CMR) and invasive (thermodilution, gas wash-out method, intracoronary Doppler recording) methods and techniques proposed to assess coronary microvascular function in the clinical setting and to identify the various mechanisms of CMD. Pros and cons of each method are discussed and compared.

CMD can occur in several patients undergoing PCI or CABG. In the setting of PCI, CMD is mainly caused by distal embolization, which most frequently occurs during treatment of saphenous vein grafts. In about one-third of patients distal embolization causes infarctlets, which are suggested by a transient increase of markers of myocardial necrosis and can be detected by CMR. Evidence of cardiac necrosis is associated with a worse prognosis. Myocardial necrosis may also occur in the setting of CABG, due to various mechanisms, including air embolism, graft or native artery closure, global ischemia with suboptimal cardioplegia and low postoperative flow, and is associated, again, with increased mortality rates.

In this first chapter of the book, we discuss the functional anatomy and provide an in-depth description of the physiology of coronary microcirculation. The various intrinsic (i.e., vascular) and extrinsic (extravascular) physiologic mechanisms involved in the fine regulation of myocardial blood flow (MBF) are described. We then discuss the general principles responsible for the adaptation of MBF to various physiological and pathological conditions.

CMD can be sustained by several pathogenetic mechanisms. The importance of these mechanisms appears to vary in different clinical settings, but several of them may coexist in the same condition. Structural abnormalities of small coronary arteries can be responsible for CMD and have been described, in particular, in patients with hypertrophic cardiomyopathy or arterial hypertension. Functional microvascular abnormalities responsible for CMD have been described in most cases, and may consist of impaired coronary microvascular dilatation (endothelium-dependent and/or endothelium-independent) and/or increased coronary microvascular constriction. Finally, extravascular mechanisms, resulting in increased compression of resistive vessels by increased intramural pressure, may also sustain CMD.

Hypertension and cardiomyopathies share maladaptive changes of cardiac morphology, eventually leading to heart failure. These include left ventricular hypertrophy (LVH), myocardial fibrosis, and structural remodeling of coronary microcirculation, which is the morphologic hallmark of coronary microvascular dysfunction. To pinpoint the complex molecular mechanisms and pathways underlying LVH-associated cardiac remodeling independent of blood pressure effects, we employed gene network approaches to the rat heart. We used the Spontaneously Hypertensive Rat model showing many features of human hypertensive cardiomyopathy, for which we collected histological and histomorphometric data of the heart and coronary vasculature, and genome-wide cardiac gene expression. Here, we provide a large catalogue of gene co-expression networks in the heart that are significantly associated with quantitative variation in LVH, microvascular remodeling, and fibrosis-related traits. Many of these networks were significantly conserved to human idiopathic and/or ischemic cardiomyopathy patients, suggesting a potential role for these co-expressed genes in human heart disease.

A 76-year-old woman presented with a one-week history of dyspnea on minimal exertion and at rest. In the emergency room she underwent echocardiography and thoracic computed tomography scan with diagnosis of bilateral pulmonary embolism. Due to right ventricular dilatation and increasing values of NT-probrain natriuretic peptide, both markers of high risk that classify pulmonary embolism as "submassive" according to current international guidelines, we opted for thrombolysis. The patient underwent intra-arterial bilateral pulmonary thrombolysis facilitated by ultrasound, the first case in Italy. The patient recovered from pulmonary embolism after 10h of therapy, with improved gas exchange and symptoms. Subsequently, she developed arterial bleeding at the puncture site, due to accidental puncture of a branch of the femoral artery. The patient was treated with percutaneous embolization and transfusions. In patients with pulmonary embolism, even if not massive, thrombolysis should be considered, especially in the presence of high-risk markers. Direct intra-arterial pulmonary thrombolysis, facilitated by ultrasound, is an effective procedure that provides an alternative to conventional thrombolysis with the advantage of a lower thrombolytic dose.

Percutaneous renal denervation has emerged as an effective adjunct in the management of resistant hypertension. However, the limits of the renal anatomical criteria that can be successfully treated are still unknown. In this report, we describe the case of a middle-aged man with essential resistant hypertension and two small left accessory renal arteries that underwent renal denervation of both principal renal arteries. He responded well with a progressive reduction in blood pressure measuring of 16/10, 32/17 and 45/24 mmHg at 1, 6 and 12 months, respectively. At 12 months, 94% of ambulatory measurements were below 140/90 mmHg and the number of anti-hypertensive medications had decreased from six to three. Thus, it would appear that the presence of two non-ablated left accessory renal arteries does not influence the response to renal denervation.

We present the case of a 52-year-old man with normal coronary arteries admitted to our department after being resuscitated from ventricular fibrillation. Transthoracic echocardiography raised suspicion of left-ventricular non-compaction. Cardiac magnetic resonance excluded this, but showed several systolic bulgings of the right ventricle and a characteristic focal 'crinkling' of the right-ventricular outflow tract known as the 'accordion' sign, a specific marker of desmosomal gene mutations, thus suggesting the presence of an arrhythmogenic cardiomyopathy. Extensive mid-myocardial late gadolinium enhancement and fatty infiltration, predominantly of the left ventricle, finally confirmed the diagnosis of left dominant arrhythmogenic cardiomyopathy, a rare variant of arrhythmogenic right-ventricular cardiomyopathy.

Objectives Myocardial beta-adrenoceptor density has been found to be reduced in hypertrophic cardiomyopathy, even when systolic function is preserved. Our purpose in the current study was to investigate whether beta-adrenoceptor down-regulation was unique to hypertrophic cardiomyoparhy, or is also present in secondary myocardial hypertrophy. Methods Myocardial beta-adrenoceptor density was measured in 11 patients with hypertrophic cardiomyopathy, eight patients with left ventricular hypertrophy secondary to arterial hypertension or aortic valve disease and 18 normal control subjects, using positron emission tomography with C-11-CGP-12177 as the myocardial beta-adrenoceptor ligand. Results Reflecting the natural incidence of the conditions, the age of the hypertrophic cardiomyopathy patients was 37 (10) [mean (SD), range 20-51] years and that of the secondary hypertrophy patients 64 (18), [range 26-80] years; P

Background: It has been hypothesized that an interaction between sympathetic nervous activity and an abnormal myocardium plays a role in the development and progression of hypertrophic cardiomyopathy (HCM). Methods: In the present study we investigated cardiac autonomic function by 24-hour spectral analysis of heart rate variability (HRV) in 18 patients with HCM, without evidence of heart failure, and 18 controls of similar age. Results: We found a significant reduction of 24 hour variance in HCM patients relative to controls (15,000 ± 9480 ms2 vs 24,720 ± 12,450 ms2 respectively; p < 0.05). Moreover, a loss of the expected day-night changes in the low frequency (LF) spectral component (expressed in normalized units), and LF/HF ratio (HF; high frequency component) were observed in HCM patients. Decreased day-night changes in LF/HF ratio were previously reported in patients with mild hypertension, uncomplicated coronary disease, and after myocardial infarction, conditions in which it seems to exist a higher than normal sympathetic activity. No significant correlations were found between HRV indices and echocardiographic standard measures of systolic and diastolic function parameters. Conclusions: These data are consistent with the presence of an alteration in neural modulation of heart period in HCM patients, noninvasively detectable by continuous 24 hour HRV analysis.

Background Chronically dysfunctional myocardium may improve after coronary revascularization. This condition was thought to be due to a chronically reduced myocardial blood flow (MBF). Recently, however, it has been shown that in patients without previous infarction but with chronic left ventricular dysfunction, baseline MBF was normal. Methods and Results To study the pathophysiology of chronic left ventricular dysfunction in patients with previous infarction, regional MBF (milliliter per minute per gram of water-perfusable tissue) and glucose utilization (MRG; micromoles per minute per gram) during hyperinsulinemic euglycemic clamp were measured with positron emission tomography in 30 patients before bypass. At baseline, 133 myocardial segments were normal, and 107 were dysfunctional. After revascularization, 59 of 107 segments improved, while 48 of 107 were unchanged. MBF was 0.92±0.25 mL · min −1 · g −1 in normal segments, 0.87±0.31 mL · min −1 · g −1 in improved segments ( P =NS versus normal), and 0.82±0.40 mL · min −1 · g −1 in unchanged segments ( P 0.42 mL · min −1 · g −1 , a cutoff value corresponding to the mean MBF minus 2 SD in normal segments. The MRG was 0.71±0.14 μmol · min −1 · g −1 in 9 age-matched normal subjects, 0.45±0.19 μmol · min −1 · g −1 ( P −1 · g −1 in improved segments ( P =NS versus normal), and 0.34±0.17 μmol · min −1 · g −1 in unchanged segments ( P Conclusions The results suggest that resting MBF measured with 15 O-labeled water in chronically dysfunctional segments is not reduced and that the myocardium of these patients is less sensitive to insulin than that of normal subjects.

OBJECTIVE--To assess the relation between left ventricular function and myocardial beta adrenoceptor density. METHODS--17 patients with hypertrophic cardiomyopathy, six with and 11 without heart failure, were studied. Left ventricular function was assessed by echocardiography, and myocardial beta adrenoceptors by positron emission tomography. Patient data were compared with those obtained in normal controls. RESULTS--Myocardial beta adrenoceptor density in the 17 patients was 7.00 (SD 1.90) pmol/g v 11.50 (2.18) pmol/g in normal controls (P < 0.01). beta Adrenoceptor density in the six patients with left ventricular failure was 5.61 (0.88) pmol/g v 7.71 (1.86) pmol/g in the 11 patients with normal ventricular function (P < 0.05), and there was a significant correlation (r = 0.52; P < 0.05) between left ventricular fractional shortening and myocardial beta adrenoceptor density. A positive correlation (r = 0.51; P < 0.05) was also found between myocardial beta adrenoceptor density and the E/A transmitral flow ratio, an index of left ventricular diastolic function. CONCLUSIONS--There is myocardial beta adrenoceptor downregulation in patients with hypertrophic cardiomyopathy with or without signs of heart failure.

Editorial

The link between myocardial ischemia and obstructive atherosclerosis of the epicardial coronary arteries is well established, and coronary angiography has demonstrated a relationship between the severity and extent of coronary artery disease (CAD) and survival. In the past 20 years technological advances in positron emission tomography (PET) have enabled the noninvasive measurement of absolute (ml/min/g) myocardial blood flow (MBF) and flow reserve. In the absence of detectable CAD, a reduced maximum MBF and CFR can be ascribed to coronary microvascular dysfunction.

Non-invasive imaging techniques (positron emission tomography and cardiovascular/cardiac magnetic resonance) provide accurate and reproducible measurements of global and regional myocardial blood flow (MBF) in absolute units of ml/min/g of tissue, thus providing unique pathophysiological and diagnostic insights into the functioning of the coronary microcirculation. There is compelling evidence suggesting that, in many instances, in the absence of angiographically demonstrable stenosis of the epicardial coronary arteries, significant abnormalities of global myocardial perfusion can be demonstrated in individuals with either risk factors for coronary artery disease or different cardiomyopathies accompanied by alteration of the structure of the microvasculature. In this context, measurement of MBF gives unique diagnostic information regarding the functioning of the coronary microcirculation and provides a quantitative surrogate endpoint against which the efficacy of treatments can be established. In this review article, we discuss the more recent advances regarding the non-invasive measurement of MBF and flow reserve and their clinical applications for the detection of coronary microvascular dysfunction.

Using unitary transformations together with a previously described statistical theory for optimal linear dimension reduction it is shown how pixels in a sequence of images can be decomposed into a sum of variates, covariates, and residual vectors, with all covariances equal to zero. It is demonstrated that this decomposition is optimal with respect to noise. In addition, it results in simplified and well conditioned equations for dimension reduction and elimination of covariates. The factor images are not degraded by subdivision of the time intervals. In contrast to traditional factor analysis, the factors can be measured directly or calculated based on physiological models. This procedure not only solves the rotation problem associated with factor analysis, but also eliminates the need for calculation of the principal components altogether. Examples are given of factor images of the heart, generated from a dynamic study using oxygen-15-labelled water and positron emission tomography. As a special application of the method, it is shown that the factor images may reveal any contamination of the blood curve derived from the original dynamic images with myocardial activity.

The relevance of tricuspid regurgitation (TR) has reached full clinical and pathophysiological recognition only recently. We aimed to evaluate the prevalence and significance of TR from a cohort of patients at a tertiary center and the proportion of patients who met criteria for intervention. A

The mechanisms underlying coronary microvascular remodeling and dysfunction, which are critical determinants of abnormal myocardial blood flow regulation in human hypertension, are poorly understood. The spontaneously hypertensive rat (SHR) exhibits many features of human hypertensive cardiomyopathy. We demonstrate that remodeling of intramural coronary arterioles is apparent in the SHR already at 4 weeks of age, i.e. before the onset of systemic hypertension. To uncover possible genetic determinants of coronary microvascular remodeling, we carried out detailed histological and histomorphometric analysis of the heart and coronary vasculature in 30 weeks old SHR, age-matched Brown Norway (BN-Lx) parentals and BXH/HXB recombinant inbred (RI) strains. Using previously mapped expression quantitative trait loci (eQTLs), we carried out a genome-wide association analysis between genetic determinants of cardiac gene expression and histomorphometric traits. This identified 36 robustly mapped eQTLs in the heart which were associated with medial area of intramural coronary arterioles [false discovery rate (FDR) ~5 %]. Transcripts, which were both under cis-acting genetic regulation and significantly correlated with medial area (FDR

We report the case of a 73-year-old patient with severe left ventricular hypertrophy presenting with acute ST-segment elevation mimicking acute myocardial infarction on ECG during a hypertensive crisis. Unexpectedly, emergency coronary angiography showed no evidence of coronary thrombosis or spasm. Electrocardiographic alterations gradually resolved after lowering blood pressure.

The mid- and long-term outcome of revascularization procedures is still uncertain in patients with chronic left ventricular systolic dysfunction due to coronary artery disease. The identification of dysfunctional myocardial segments with residual viability that can improve after revascularization is pivotal for further patient management. Hibernating myocardium (chronically dysfunctional but still viable tissue) can be identified by positron emission tomography and cardiac magnetic resonance and its presence and extent can predict functional recovery after revascularization. Before beta-blockers were introduced as routine care for heart failure, surgical revascularization appeared to improve survival in these patients. Nowadays, novel medical treatments and devices such as cardiac resynchronization therapy and implantable cardioverter-defibrillators have improved prognosis of these patients and their use is supported by a number of clinical trials. A recently concluded randomized trial, the STICH (Surgical Treatment for Ischemic Heart Failure) trial, has assessed the prognostic benefit derived from revascularization added to optimal medical therapy in patients with ischemic left ventricular dysfunction. This is an overview of the pathophysiological mechanisms as well as the main clinical studies and meta-analyses that have addressed this issue in the past four decades. Furthermore, a brief proposal for a randomized trial to assess effect on prognosis of revascularization of hibernating myocardium will be presented.

Two distinct types of left ventricular hypertrophy (LVH) have been described: the so called "physiologic" hypertrophy, which is normally found in professional athletes, and "pathologic" LVH which is found in patients with inherited heart muscle disease such as hypertrophic cardiomyopathy (HCM) or patients with cardiac and systemic diseases characterized by pressure or volume overload. Patients with pathologic LVH have often symptoms and signs suggestive of myocardial ischemia despite normal coronary angiograms. Under these circumstances ischemia is due to coronary microvascular dysfunction (CMD). The abnormalities of the coronary microcirculation may be unrelated to the degree of LVH and cause a reduction in maximum myocardial blood flow which, in the absence of epicardial stenoses, is suggestive of CMD. There is no technique that enables direct visualization of coronary microcirculation in vivo in humans. Therefore, its assessment relies on the measurement of parameters which reflect its functional status, such as myocardial blood flow and coronary flow reserve which is an integrated measure of flow through both the large epicardial coronary arteries and the microcirculation. In this review article we discuss the pathophysiological mechanisms responsible for CMD in patients with primary and secondary LVH and how the recognition of this phenomenon is providing new important information on patient stratification and prognosis. Finally, we discuss how assessment of CMD may be used as a valuable surrogate marker to test the efficacy of old and new drugs. This article is part of a Special Issue entitled "Coronary Blood Flow". (C) 2011 Elsevier Ltd. All rights reserved.

The increasing use of thrombolytic therapy and primary percutaneous coronary interventions in association with optimized anti-thrombotic therapy has contributed to significantly reducing short-term mortality and morbidity in patients with acute coronary syndromes. The change of the epidemiology of myocardial infarction over the past 2 decades is due to the increase in NSTEMI infarctions counterbalanced by a substantial reduction in ST-segment elevation [1]. Nevertheless, no further improvement in long term survival could be observed, probably due to the greater number of patients with residual left ventricular (LV) dysfunction undergoing progressive LV remodeling and congestive heart failure (CHF). A problem compounded by the rising age of the population and the higher prevalence of co-morbidities such as diabetes mellitus and hypertension which confer an increased risk of coronary artery disease (CAD) and CHF. Patients with CAD represent by far the most numerous cohort amongst those with CHF and their treatment remains a partial success [2].

Over the last several decades, basic cardiovascular research has significantly enhanced our understanding of pathobiological processes leading to formation, progression, and complications of atherosclerotic plaques. By harnessing these advances in cardiovascular biology, imaging has advanced beyond its traditional anatomical domains to a tool that permits probing of particular molecular structures to image cellular behaviour and metabolic pathways involved in atherosclerosis. From the nascent atherosclerotic plaque to the death of inflammatory cells, several potential molecular and micro-anatomical targets for imaging with particular selective imaging probes and with a variety of imaging modalities have emerged from preclinical and animal investigations. Yet, substantive barriers stand between experimental use and wide clinical application of these novel imaging strategies. Each of the imaging modalities described herein faces hurdles-for example, sensitivity, resolution, radiation exposure, reproducibility, availability, standardization, or costs. This review summarizes the published literature reporting on functional imaging of vascular inflammation in atherosclerotic plaques emphasizing those techniques that have the greatest and/or most immediate potential for broad application in clinical practice. The prospective evaluation of these techniques and standardization of protocols by multinational networks could serve to determine their added value in clinical practice and guide their development and deployment.

"Endomyocardial fibrosis (EMF) is a rare condition, but in certain tropical. countries it is a major cause of illness and death. Moreover, the etiology of the disease is unknown, it has no specific treatment, and it carries a poor prognosis. As both the heart and the peritoneum may be affected by the. inflammation and deposition of fibrous tissue, even left ventricular EMF may. present with gross ascites mimicking right-heart failure. Notwithstanding. attempts to standardize the diagnostic criteria, the clinical presentation may. still be challenging. The case is described of calcified left ventricular EMF presenting with right-heart failure in the absence of right ventricular fibrosis. "

In patients with hypertrophic cardiomyopathy (HCM), positron emission tomography (PET) and cardiac magnetic resonance (CMR) are potentially useful tools for risk stratification. Parameters which could be linked to clinical ourcomes are accurate measures of myocardial ischemia and fibrosis.

"\"The epidemic of cardiovascular disease is a global phenomenon and the magnitude. of its increase in incidence and prevalence in low-income countries has. potentially major implications for those high-income countries that characterize . the developed world. The \"epidemiologic transition\" provides a useful framework. for understanding changes in the patterns of disease as a result of socioeconomic. and demographic developments. According to the migratory flow, the burden of. African immigrants in Italy is rising, and there is a need to re-assess the. clinical management of anything but obsolete western cardiovascular disorders. also delving into the rare tropical neglected diseases. Rheumatic fever and. tropical cardiac diseases, such as endomyocardial fibrosis in Africa and Chagas. disease in Latin America, require a human resource framework to direct into. research and intervention programs. This review will focus upon endomyocardial. fibrosis, by far the most common type of restrictive cardiomyopathy worldwide,. still an unsolved puzzle from a pathophysiological point of view and in need of. more attention from the international community of cardiologists. In this paper. the data from the literature are implemented by our personal experience at the. St. Raphael of St. Francis Hospital-Nsambya and the Ugandan Heart Institute of Kampala, the capital town of Uganda. \""

Objectives. The aim of this study was to investigate coronary vasodilator reserve and metabolism in myocardium subtended by angiographically normal arteries remote from ischemia.Background. After infarction, structural and functional changes occur in remote myocardium often subtended by normal arteries. Whether changes occur in regions remote from ischemic but noninfarcted myocardium is unknown.Methods. Coronary vasodilator reserve was measured with positron emission tomography in 12 patients with single-vessel disease using intravenous dipyridamole (0.56 mg/kg for 4 min). In another 10 patients, simultaneous arterial/great cardiac vein catheterization was performed during atrial pacing to measure myocardial metabolism in regions subtended by diseased or normal arteries.Results. Basal myocardial blood flow in stenosis-related regions was comparable to that in remote regions but was lower after dipyridamole administration (1.73 ± 0.91 vs. 2.89 ± 0.93 ml/min per g, p < 0.01), giving coronary vasodilator reserve values of 1.80 ± 0.82 and 2.73 ± 0.89 (p < 0.01). In normal control subjects, basal myocardial blood flow was 0.92 ± 0.13 and 3.67 ±0.94 ml/min per g in the basal state and after dipyridamole (both p < 0.05 vs. values in remote regions), and coronary vasodilator reserve was 4.07 ± 0.98 (p < 0.01 vs. values in remote regions). During pacing there was net lactate release in diseased regions (−18 ± 27%, p < 0.05 vs. values in remote regions and control subjects) and extraction in remote regions (38 ± 17%) and in normal control subjects (26 ± 11%). Glucose and alanine extraction were increased in diseased (8 ± 6% and 6 ± 6%) and remote regions (6 ± 3% and 4 ± 3%), compared with values in normal control subjects (2 ± 3% and −1 ± 3%, both p < 0.05 vs. diseased and remote regions).Conclusions. Coronary vasodilator reserve is reduced and glucose and alanine metabolism is abnormal in regions subtended by normal arteries remote from ischemic but noninfarcted myocardium.

Myocardial muscle is considered to be a target tissue for insulin action, but direct measurements of insulin's effects on cardiac hemodynamics and intermediary metabolism in humans are scarce. We combined great cardiac vein (GCV)/arterial catheterization with the euglycemic insulin clamp technique and thermodilution in six healthy middle-aged (53 +/- 2 yr) volunteers. In the fasting state, the myocardium extracted free fatty acid (FFA), lactate, pyruvate, glycerol, and beta-hydroxybutyrate (6.4 +/- 0.8, 6.2 +/- 1.0, 0.58 +/- 0.12, 0.44 +/- 0.15, and 11 +/- 2 mumol/min, respectively) and consumed 0.26 +/- 0.02 mmol/min oxygen. As fasting plasma insulin (73 +/- 6 pmol/l) was raised and clamped at 503 +/- 16 pmol/l for 100 min while maintaining euglycemia (approximately 5 mmol/l), arterial levels of lactate and pyruvate rose (by 121 and 159%, respectively), whereas FFA, glycerol, and beta-hydroxybutyrate fell (by 69, 48, and 85%, respectively, all P < 0.001). Correspondingly, net myocardial uptake of glucose, lactate, and pyruvate increased to 18.9 +/- 3.5, 32.0 +/- 2.3, and 2.7 +/- 0.5 mumol/min, respectively, whereas net extraction of circulating FFA, glycerol, and beta-hydroxybutyrate was abolished (all P < 0.001). The stimulation of lactate and pyruvate uptake was the result of both increased arterial supply and enhanced myocardial extraction ratio (from 19 +/- 3 to 51 +/- 6% for lactate, from 26 +/- 5 to 44 +/- 5% for pyruvate, P < 0.001 for both). This shift from fat to carbohydrate fuel usage occurred in the absence of changes in oxygen consumption, heart rate, GCV blood flow, aortic pressures, coronary vascular resistance, and left ventricular end-diastolic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated whether PET/CT angiography using 11C-(R)-PK11195, a selective ligand for the translocator protein (18 kDa) expressed in activated macrophages, could allow imaging and quantification of arterial wall inflammation in patients with large-vessel vasculitis. Methods: Seven patients with systemic inflammatory disorders (3 symptomatic patients with clinical suspicion of active vasculitis and 4 asymptomatic patients) underwent PET with 11C-(R)-PK11195 and CT angiography to colocalize arterial wall uptake of 11C-(R)-PK11195. Tissue regions of interest were defined in bone marrow, lung parenchyma, wall of the ascending aorta, aortic arch, and descending aorta. Blood-derived and image-derived input functions (IFs) were generated. A reversible 1-tissue compartment with 2 kinetic rate constants and a fractional blood volume term were used to fit the time–activity curves to calculate total volume of distribution (VT). The correlation between VT and standardized uptake values was assessed. Results: VT was significantly higher in symptomatic than in asymptomatic patients using both image-derived total plasma IF (0.55 ± 0.15 vs. 0.27 ± 0.12, P = 0.009) and image-derived parent plasma IF (1.40 ± 0.50 vs. 0.58 ± 0.25, P = 0.018). A good correlation was observed between VT and standardized uptake value (R = 0.79; P = 0.03). Conclusion:11C-(R)-PK11195 imaging allows visualization of macrophage infiltration in inflamed arterial walls. Tracer uptake can be quantified with image-derived IF without the need for metabolite corrections and evaluated semiquantitatively with standardized uptake values.