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Background and aims Obesity-related cardiometabolic risk factors associate with COVID-19 severity and outcomes. Epicardial adipose tissue (EAT) is associated with cardiometabolic disturbances, is a source of proinflammatory cytokines and a marker of visceral adiposity. We investigated the relation between EAT characteristics and outcomes in COVID-19 patients. Methods and results This post-hoc analysis of a large prospective investigation included all adult patients (≥18 years) admitted to San Raffaele University Hospital in Milan, Italy, from February 25th to April 19th, 2020 with confirmed SARS-CoV-2 infection who underwent a chest computed tomography (CT) scan for COVID-19 pneumonia and had anthropometric data available for analyses. EAT volume and attenuation (EAT-At, a marker of EAT inflammation) were measured on CT scan. Primary outcome was critical illness, defined as admission to intensive care unit (ICU), invasive ventilation or death. Cox regression and regression tree analyses were used to assess the relationship between clinical variables, EAT characteristics and critical illness. One-hundred and ninety-two patients were included (median [25th-75th percentile] age 60 years [53-70], 76% men). Co-morbidities included overweight/obesity (70%), arterial hypertension (40%), and diabetes (16%). At multivariable Cox regression analysis, EAT-At (HR 1.12 [1.04-1.21]) independently predicted critical illness, while increasing PaO2/FiO2 was protective (HR 0.996 [95% CI 0.993; 1.00]). CRP, plasma glucose on admission, EAT-At and PaO2/FiO2 identified five risk groups that significantly differed with respect to time to death or admission to ICU (log-rank p, Graphical abstract Image 1

Ischemic heart disease secondary to coronary vascular dysfunction causes angina and impairs quality of life and prognosis. About one-half of patients with symptoms and signs of ischemia turn out not to have obstructive coronary artery disease, and coronary vascular dysfunction may be relevant. Adjunctive tests of coronary vasomotion include guidewire-based techniques with adenosine and reactivity testing, typically by intracoronary infusion of acetylcholine. The CorMicA (Coronary Microvascular Angina) trial provided evidence that routine management guided by an interventional diagnostic procedure and stratified therapy improves angina and quality of life in patients with angina but no obstructive coronary artery disease. In this paper, the COVADIS study group provide a comprehensive review of why, how, and when coronary vascular dysfunction should be assessed invasively. They discuss the rationale through a shared understanding of vascular pathophysiology and clinical evidence. They propose a consensus approach to how an interventional diagnostic procedure is performed with focus on practical aspects. Finally, the authors discuss the clinical scenarios in patients with stable and acute coronary syndromes in which measurement of coronary vascular function may be helpful for patient care.

BackgroudThe aim of this study was to assess the prognostic association of plasma levels ofIn this international prospective cohort study of MVA by the Coronary Vasomotor Disorders International Study (COVADIS) group, we examined the association between plasma NT-proBNP levels and the incidence of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina.We examined a total of 226 MVA patients (M/F 66/160, 61.9 ± 10.2 [SD] yrs.) with both plasma NT-proBNP levels and echocardiography data available at the time of enrolment. The median level of NT-proBNP level was 94 pg/ml, while mean left ventricular ejection fraction was 69.2 ± 10.9 % and E/e' 10.7 ± 5.2. During follow-up period of a median of 365 days (IQR 365-482), 29 MACEs occurred. Receiver-operating characteristics curve analysis identified plasma NT-proBNP level of 78 pg/ml as the optimal cut-off value. Multivariable logistic regression analysis revealed that plasma NT-proBNP level ≥ 78 pg/ml significantly correlated with the incidence of MACE (odds ratio (OR) [95 % confidence interval (CI)] 3.11[1.14-8.49], P = 0.001). Accordingly, Kaplan-Meier survival analysis showed a significantly worse prognosis in the group with NT-proBNP ≥ 78 (log-rank test, P 0.03). Finally, a significant positive correlation was observed between plasma NT-proBNP levels and E/e' (R = 0.445, P 0.0001).These results indicate that plasma NT-proBNP levels may represent a novel prognostic biomarker for MVA patients.

Background Possible ethnic differences in clinical characteristics and long-term prognosis of contemporary patients with vasospastic angina (VSA) remain to be elucidated. Methods and results The Japanese Coronary Spasm Association (JCSA) conducted an international, prospective, and multicenter registry study for VSA patients. A total of 1457 VSA patients (Japanese/Caucasians, 1339/118) were enrolled based on the same diagnostic criteria. Compared with Caucasian patients, Japanese patients were characterized by higher proportions of males (68 vs. 51%) and smoking history (60 vs. 49%). Japanese patients more often had angina especially during the night and early morning hours, compared with Caucasians. Ninety-five percent of Japanese and 84% of Caucasian patients underwent pharmacological provocation test. Importantly, no significant differences in the patterns of coronary spasm were apparent, with diffuse spasm most frequently noted in both ethnicities. The prescription rate of calcium-channel blockers was higher in Japanese (96 vs. 86%), whereas the uses of nitrates (46 vs. 59%), statins (43 vs. 65%), renin-angiotensin-system inhibitors (27 vs. 51%), and β-blockers (10 vs. 24%) were more common in Caucasian patients. Survival rate free from major adverse cardiac events (MACE) was slightly but significantly higher in Japanese than in Caucasians (86.7 vs. 76.6% at 5 years, P Conclusion These results indicate that there are ethnic differences in clinical profiles and long-term prognosis of contemporary VSA patients.

BACKGROUND Fulminant myocarditis (FM) is a form of acute myocarditis characterized by severe left ventricular systolic dysfunction requiring inotropes and/or mechanical circulatory support. A single-center study found that a patient with FM had better outcomes than those with acute nonfulminant myocarditis (NFM) presenting with left ventricular systolic dysfunction, but otherwise hemodynamically stable. This was recently challenged, so disagreement still exists. OBJECTIVES This study sought to provide additional evidence on the outcome of FM and to ascertain whether patient stratification based on the main histologic subtypes can provide additional prognostic information. METHODS A total of 220 patients (median age 42 years, 46.3% female) with histologically proven acute myocarditis (onset of symptoms

Objectives This study assessed the incidence of long-term adverse outcomes in patients with Takotsubo syndrome (TTS). Background The long-term prognosis of TTS is controversial. It is also unclear whether presenting characteristics are associated with the subsequent long-term prognosis. Methods We searched the PubMed, Embase, and Cochrane databases and reviewed cited references up to March 31, 2018, to identify studies with >6 months of follow-up data. Results Overall, we selected 54 studies that included a total of 4,679 patients (4,077 women and 602 men). Death during admission occurred in 112 patients (2.4%), yielding a frequency of 1.8% (95% confidence interval [CI]: 1.2% to 2.5%), with significant heterogeneity (I2 = 78%; p Conclusions Our update analysis of patients discharged alive after TTS showed that long-term rates of overall mortality and recurrence were not trivial, and that some presenting features (older age, physical stressor, and atypical ballooning) were significantly associated with an unfavorable long-term prognosis.

Chest pain stands as one of the most frequent patient presentations in the emergency department (ED). Despite established diagnostic algorithms for identifying several important causes of chest pain, such as acute myocardial infarction (AMI), aortic dissection, and pulmonary embolism, guidance on managing patients with recurrent chest pain, one of the top 3 reasons for repeated hospitalization in the United States, is less defined. The assessment of symptoms, serial ECG, and necrosis biomarkers plays a major role in patient management. Notably, the recently introduced high-sensitivity troponin T (hs-TnT) assay is helping to identify ischemia in patients previously undiagnosed by conventional testing. In Europe, with the use of this assay for over a decade, the identification of patients with AMI has substantially increased, particularly of patients with type 2 AMI, which is seen in the absence of atherosclerotic obstruction of the epicardial coronaries on angiography. Use of hs-TnT is in particular relevant in women, in whom the use of a sex-specific threshold for elevated hs-TnT has almost doubled the diagnosis of AMI. With the advent of the hs-TnT assay in the United States in 2017, a similar phenomenon is expected. Thus, it is important to learn from the European experience and to develop sex-specific nuanced algorithms for the evaluation of additional causes of myocardial ischemia/necrosis, such as coronary artery vasomotor disorders and coronary microvascular dysfunction. The latter has a high prevalence among symptomatic women presenting to the ED, a group in whom recurrent chest pain is common. This commentary describes the tools available for diagnosing epicardial- and non–epicardial-related myocardial ischemia in patients with recurrent chest pain in the ED setting. A sex-specific, nuanced approach applied to select groups of patients being observed in the ED has the potential to reduce admissions and to allow for the initiation of timely, appropriate medical treatment and outpatient follow-up in an at-risk population. The costs and availability of advanced diagnostics may pose some limitation to the widespread adoption of such protocols.

Study objective The Coronary Vasomotor Disorders International Study Group (COVADIS) invited leading experts to address strategies to enhance our clinical understanding of INOCA with an emphasis on the management of coronary vasomotor disorders. Design Under-recognition of coronary vasomotor disorders, distinguishing different presentations of angina due to vasospasm and/or abnormal microvascular vasodilatation, developing invasive/non-invasive testing and treatment protocols, integrating diagnostic protocols into cardiologists' workflow and trials to inform guideline development were identified as key knowledge gaps and will be briefly addressed in this Viewpoint article. Setting Virtual international meeting. Participants Leading international experts in ischemic heart disease with no obstructive coronary artery disease. Interventions None. Main outcome measures None. Results Topics discussed include: 1. Obstructive epicardial disease, functional vasospasm and microvascular disorders; 2. Under-recognition of coronary vasomotor disorders in clinical practice; 3. Complexity of coronary vasomotor disorders; 4. Understanding different presentations - vasospastic disease and microvascular angina; 5. Invasive/noninvasive testing and treatment protocols for vasospasm and microvascular angina assessment; 6. Treatment challenges; 7. Integrating diagnostic protocols into cardiologists' workflow; 8. The path forward to advance our approach to managing myocardial ischemia. Conclusions Obstructive epicardial disease, functional vasospasm and microvascular disorders often co-exist and contribute to myocardial ischemia. Under-recognition, the complexity of coronary vasomotor disorders, understanding different presentations, testing and treatment protocols, treatment challenges, and integrating diagnostic protocols into cardiologists' workflow all contribute to the path forward to advance our management of myocardial ischemia for improved patient outcomes.

Background Eosinophilic myocarditis (EM) is an acute life-threatening inflammatory disease of the heart. Neither large case series nor clinical trials on this specific myocarditis have been reported. Objectives Based on a systematic revision of all published histologically proven cases, this study aimed to describe the clinical presentation, treatment, and outcome of EM. Methods The study screened 443 manuscripts in MEDLINE and EMBASE on cases of EM published until June 2017. The authors identified 264 patients and included in the main analysis 179 patients admitted to hospital with histologically proven EM. Results Median age was 41 years (interquartile range: 27 to 53 years) with similar prevalence in both sexes; pediatric cases (≤16 years of age) accounted for 10.1%. The main symptom at presentation was dyspnea (59.4%), with peripheral eosinophilia observed in 75.9%. Median left ventricular ejection fraction at presentation was 35% (interquartile range: 25% to 50%). The disorders most frequently associated with EM were hypersensitivity and eosinophilic granulomatosis with polyangiitis, which accounted for 34.1% and 12.8% of cases, respectively, whereas idiopathic or undefined forms accounted for 35.7% of cases. Steroids were administered in 77.7% of patients. A temporary mechanical circulatory support (n = 30) was instituted in 16.8% of patients. In-hospital death was 22.3% (n = 40), with the highest occurrence in the hypersensitivity form (36.1%; p = 0.026). Conclusions EM has a poor prognosis during the acute phase, despite a publication bias that could have led to an overestimation of mortality. Associated conditions are identified in approximately 65% of cases. Specific trials and multicenter registries are needed to provide evidence-based treatments to improve in-hospital outcome.

Ivabradine is a heart rate reducing agent that exhibits anti-ischemic effects through the inhibition of funny electrical current in the sinus node resulting in heart rate reduction, thus enabling longer diastolic perfusion time, and reduced myocardial oxygen consumption without detrimental changes in arterial blood pressure, coronary vasomotion, and ventricular contractility. The current guideline-based clinical use of Ivabradine is reserved for patients with stable angina pectoris who cannot tolerate or whose symptoms are inadequately controlled with beta blockers. In patients with chronic heart failure and reduced ejection fraction, Ivabradine has demonstrated beneficial effects in improving clinical outcomes when added to conventional therapy. However, the role of Ivabradine in acute coronary syndromes has not been established. Based on the results from some relevant preclinical studies and a limited amount of clinical data that were reported recently, the role of Ivabradine in acute ischemic events warrants further investigation. The aim of this review is to provide an overview of the available literature on the potential role of Ivabradine in the clinical context of acute coronary syndromes.

Background The presence of late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) has diagnostic and prognostic value in patients with acute myocarditis (AM). Aim of our study was to quantify the changes in LGE extension (LGE%) early after AM and evaluate its relations with biventricular function and morphology. Methods We investigated 76 consecutive patients with AM (acute onset of chest pain/heart failure/ventricular arrhythmias not explained by other causes, and raised troponin) that met CMR criteria based on myocardial oedema at T2-weighted images and LGE on post-contrast images at median time of 6 days from onset of symptoms. We quantified LGE% at baseline and after 148 days in 49 patients. Results Median left ventricular (LV)-ejection fraction (EF) was 64% (interquartile range [Q1–Q3]: 56–67%), and LGE% 9.4% (Q1–Q3: 7.5–13.2%). LGE% was correlated with LV end-systolic volume index (LV-ESVi; r = + 0.34; p = 0.003). LGE% was inversely correlated with LV-EF (r = − 0.31; p = 0.009) and time to CMR scan (r = − 0.25; p = 0.028). In the 49 patients with a second CMR scan, despite no significant variations in LV-EF, a significant decrease of LGE% was observed (p < 0.0001) with a relative reduction of 42% compared with baseline. Patients showing increased LV-ESVi at follow up had a lower decrease of LGE% (p = 0.038). Conclusions In the acute phase of AM the LGE extension is a dynamic process that reflects impairment of LV function and is time dependent. LGE% appears one of the CMR parameters with the largest relative variations in the first months after AM

Cardiovascular magnetic resonance (CMR) has evolved from a pioneering research tool to an established noninvasive imaging method for detecting inducible myocardial perfusion deficits. In this consensus document, experts of different imaging techniques summarize the existing body of evidence regarding CMR perfusion as a viable complement to other established noninvasive tools for the assessment of perfusion and discuss the advantages and pitfalls of the technique. A rapid, standardized CMR perfusion protocol is described, which is safe, clinically feasible, and cost-effective for centers with contemporary magnetic resonance equipment. CMR perfusion can be recommended as a routine diagnostic tool to identify inducible myocardial ischemia.

Heart rate plays a major role in myocardial ischemia. A high heart rate increases myocardial performance and oxygen demand and reduces diastolic time. Ivabradine reduces heart rate by inhibiting the If current of sinoatrial-node cells. In contrast to beta-blockers, ivabradine has no negative inotropic and lusitropic effect for a comparable heart rate reduction. Consequently, diastolic duration is increased with ivabradine compared to beta-blockers. This has potential consequences on coronary blood flow since compression of the vasculature by the surrounding myocardium during systole impedes flow and coronary blood flow is mainly diastolic. Moreover, ivabradine does not unmask alpha-adrenergic vasoconstriction and, unlike beta-blockers, maintains coronary dilation during exercise. In comparison with beta-blockers, ivabradine increases coronary flow reserve and collateral perfusion promoting the development of coronary collaterals. Ivabradine attenuates myocardial ischemia and its consequences even in the absence of heart rate reduction, possibly through reduced formation of reactive oxygen species. In conclusion, ivabradine differs from other anti-anginal agents by improving coronary blood flow and by additional pleiotropic effects. These properties make ivabradine an effective anti-anginal and anti-ischemic agent for the treatment of patients with coronary artery disease.

Coronary artery diseases and particularly acute myocardial infarction are the leading causes of mortality and morbidity in western countries. Despite the achievements of the last decades with the advent of double antiplatelet therapy, new antithrombotics and reperfusion strategies (either pharmacological or mechanical), many patients still have adverse cardiovascular events after ST-segment elevation acute myocardial infarction; at least some of these adverse events are related to the no reflow phenomenon that occurs after primary percutaneous coronary intervention. In our review we will discuss the various aspects of this phenomenon.

The growing discoveries coming from clinical and basic research during the past decades have revolutionized our knowledge regarding pathophysiologic mechanisms underlying the atherosclerotic process and its thrombotic complications.The traditional view focusing on the severity of stenosis of atherosclerotic plaque has given way to the evidence that the clinical complications of atherosclerotic vascular disease, particularly the propensity to develop thrombotic complications, are determined mainly by the biological composition of the plaque.This paradigm shift has reinforced the need to move from the sole anatomical assessment toward combined anatomic and functional imaging modalities enabling the molecular and cellular characterization of the disease on top of its structural properties.Together, the progress to identify molecular targets related to plaque vulnerability and the improvement of imaging techniques for the detection of such molecular targets have allowed us to obtain new important pathophysiological information.This might allow better patient stratification for the identification of subjects at high risk to develop premature atherosclerosis who might need an aggressive therapeutic approach.Nuclear techniques, magnetic resonance imaging, computed tomography angiography, and contrast-enhanced ultrasound represent the currently available non-invasive imaging modalities for molecular imaging which can provide different and complementary insights into the biological features of the atherosclerotic process. This clinical review will discuss the evidence and potential translational applications of the individual imaging techniques particularly concerning their ability to detect the main atherosclerotic features related to plaque vulnerability, such as plaque inflammation and intertwined neovascularization.

Alteration of circulating T-cell subpopulations may reflect the local immune process in plaques [(1)][1], providing insights on atherosclerosis pathogenesis. Only limited knowledge concerning the relationship between circulating lymphocytes and features of atherosclerotic lesions is available [(2

In hypertrophic cardiomyopathy, the plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) correlate with functional capacity. However, their prognostic relevance remains unresolved. We followed up 183 stable outpatients with hypertrophic cardiomyopathy (age 50 ± 17 years, 64% men) for 3.9 ± 2.8 years after NT-proBNP measurement. The primary end point included cardiovascular death, heart transplantation, resuscitated cardiac arrest, and appropriate implantable cardioverter-defibrillator intervention. The secondary end point (SE) included heart failure-related death or hospitalization, progression to end-stage disease, and stroke. The median NT-proBNP level was 615 pg/ml (intertertile range 310 to 1,025). The incidence of the primary end point in the lower, middle, and upper tertiles was 0%, 1.3%, and 2.1% annually, respectively (overall p = 0.01). On multivariate analysis, the only independent predictors of the primary end point were NT-proBNP (hazard ratio for log-transformed values 5.8, 95% confidence interval 1.07 to 31.6; p = 0.04) and a restrictive left ventricular filling pattern (hazard ratio 5.19, 95% confidence interval 1.3 to 21.9; p = 0.02). The NT-proBNP cutoff value of 810 pg/ml had the best sensitivity for the primary end point (88%), but the specificity was low (61%). The incidence of the SE in the lower, middle, and upper NT-proBNP tertiles was 4.6%, 12.0%, and 11.2% annually, respectively (overall p = 0.001). An NT-proBNP level of310 pg/ml was associated with a 75% reduction in the rate of SE compared with a level of ≥310 pg/ml (hazard ratio 0.25, 95% confidence interval 0.11 to 0.57; p = 0.001), independent of age, left ventricular outflow tract obstruction, or atrial fibrillation. In conclusion, in stable outpatients with hypertrophic cardiomyopathy, plasma NT-proBNP proved a powerful independent predictor of death and heart failure-related events. Although the positive predictive accuracy of an elevated NT-proBNP level was modest, low values reflected true clinical stability, suggesting the possibility of avoiding or postponing aggressive treatment options.

Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.

Atherosclerosis is a systemic and multifocal disease, which starts early in life, and that usually takes decades before overt disease eventually appears as a consequence of progressive obstruction or abrupt thrombotic occlusion. This silent course makes necessary to develop predictors of disease long before symptomatic lesions develop. Besides several classical risk factors and new emerging humoral risk predictors, imaging may constitute a formidable diagnostic and prognostic tool in order to identify presence, extension, progression (or regression) of disease as well as vulnerability of atherosclerotic lesions. This review summarizes the rapidly growing clinical and research field in imaging atherosclerosis from different perspectives opening important opportunities for timely detection and treatment of atherosclerosis.

Objectives The purpose of this study was to assess the diagnostic accuracy of blood oxygen-level dependent (BOLD) MRI in suspected coronary artery disease (CAD). Background By exploiting the paramagnetic properties of deoxyhemoglobin, BOLD magnetic resonance imaging can detect myocardial ischemia. We applied BOLD imaging and first-pass perfusion techniques to: 1) examine the pathophysiological relationship between coronary stenosis, perfusion, ventricular scar, and myocardial oxygenation; and 2) evaluate the diagnostic performance of BOLD imaging in the clinical setting. Methods BOLD and first-pass perfusion images were acquired at rest and stress (4 to 5 min intravenous adenosine, 140 μg/kg/min) and assessed quantitatively (using a BOLD signal intensity index [stress/resting signal intensity], and absolute quantification of perfusion by model-independent deconvolution). A BOLD signal intensity index threshold to identify ischemic myocardium was first determined in a derivation arm (25 CAD patients and 20 healthy volunteers). To determine diagnostic performance, this was then applied in a separate group comprising 60 patients with suspected CAD referred for diagnostic angiography. Results Prospective evaluation of BOLD imaging yielded an accuracy of 84%, a sensitivity of 92%, and a specificity of 72% for detecting myocardial ischemia and 86%, 92%, and 72%, respectively, for identifying significant coronary stenosis. Segment-based analysis revealed evidence of dissociation between oxygenation and perfusion (r = −0.26), with a weaker correlation of quantitative coronary angiography with myocardial oxygenation (r = −0.20) than with perfusion (r = −0.40; p = 0.005 for difference). Hypertension increased the odds of an abnormal BOLD response, but diabetes mellitus, hypercholesterolemia, and the presence of ventricular scar were not associated with significant deoxygenation. Conclusions BOLD imaging provides valuable insights into the pathophysiology of CAD; myocardial hypoperfusion is not necessarily commensurate with deoxygenation. In the clinical setting, BOLD imaging achieves favorable accuracy for identifying the anatomic and functional significance of CAD.

ObjectivesWe sought to investigate whether positron emission tomography/computed tomography (CT) angiography using [11C]-PK11195, a selective ligand for peripheral benzodiazepine receptors expressed in activated macrophages, can be used to image vascular inflammation.BackgroundActivated macrophages and T lymphocytes are fundamental elements in the pathogenesis of large-vessel vasculitides.MethodsFifteen patients (age 52 ± 16 years) with systemic inflammatory disorders (6 consecutive symptomatic patients with clinical suspicion of active vasculitis and 9 asymptomatic control patients) underwent positron emission tomography with [11C]-PK11195 and CT angiography. [11C]-PK11195 uptake was measured by calculating target-to-background ratios of activity normalized to venous blood.ResultsCoregistration of positron emission tomography with contrast-enhanced CT angiography facilitated localization of [11C]-PK11195 arterial wall uptake. Visual analysis revealed focal [11C]-PK11195 uptake in the arterial wall of all 6 symptomatic patients, but in none of the asymptomatic controls. Although serum inflammatory biomarkers (C-reactive protein, erythrocyte sedimentation rate, white cell count) did not differ significantly between the 2 groups, symptomatic patients had increased [11C]-PK11195 vascular uptake (target-to-background ratio 2.41 ± 1.59 vs. 0.98 ± 0.10; p = 0.001).ConclusionsBy binding to activated macrophages in the vessel wall, [11C]-PK11195 enables noninvasive imaging of vascular inflammation. Alternative longer-lived radioligands for probing peripheral benzodiazepine receptors are being tested for wider clinical applications.

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Several studies have evaluated the influence of different dietary habits on the risk of acute myocardial infarction and on the long-term prognosis after a coronary event, whilst no clear data are available on the in-hospital and short-term prognosis. We assessed the role of dietary habits and, in

Considerable focus has been directed towards coronary arterial disease in the management of coronary heart disease, however the coronary microcirculation plays a major role in the regulation of coronary blood flow. Thus while we have multiple medical and revascularisation therapies to treat large vessel coronary artery disease, therapies directed towards the microcirculation are very limited. This review paper summarises important aspects of coronary microvascular dysfunction including (a) methods of assessment, (b) clinical classification of associated disorders, (c) possible pathophysiological mechanisms, and (d) potential therapies. Hence this will provide important background to advancing our understanding and management of coronary heart disease by targeting the coronary microcirculation.

Objectives This study’s aim was to examine whether treatment with pioglitazone, added to conventional lipid-lowering therapy, would improve myocardial glucose utilization (MGU) and blood flow (MBF) in nondiabetic patients with familial combined hyperlipidemia (FCHL). Background Thiazolidinediones were found to improve insulin sensitivity and MGU in type 2 diabetes and MBF in Mexican Americans with insulin resistance. Familial combined hyperlipidemia is a complex genetic disorder conferring a high risk of premature coronary artery disease, characterized by high serum cholesterol and/or triglyceride, low high-density lipoprotein (HDL) cholesterol, and insulin resistance. Methods We undertook a randomized, double-blind, placebo-controlled study in 26 patients with FCHL, treated with pioglitazone or matching placebo 30 mg daily for 4 weeks, followed by 45 mg daily for 12 weeks. Positron emission tomography was used to measure MBF at rest and during adenosine-induced hyperemia and MGU during euglycemic hyperinsulinemic clamp at baseline and after treatment. Results Whereas no change was observed in the placebo group after treatment, patients receiving pioglitazone showed a significant increase in whole body glucose disposal (3.93 ± 1.59 mg/kg/min to 5.24 ± 1.65 mg/kg/min; p = 0.004) and MGU (0.62 ± 0.26 μmol/g/min to 0.81 ± 0.14 μmol/g/min; p = 0.0007), accompanied by a significant improvement in resting MBF (1.11 ± 0.20 ml/min/g to 1.25 ± 0.21 ml/min/g; p = 0.008). Furthermore, in the pioglitazone group HDL cholesterol (+28%; p = 0.003) and adiponectin (+156.2%; p = 0.0001) were increased and plasma insulin (−35%; p = 0.017) was reduced. Conclusions In patients with FCHL treated with conventional lipid-lowering therapy, the addition of pioglitazone led to significant improvements in MGU and MBF, with a favorable effect on blood lipid and metabolic parameters. (A study to investigate the effect of pioglitazone on whole body and myocardial glucose uptake and myocardial blood flow/coronary vasodilator reserve in patients with familial combined hyperlipidaemia; http://www.controlled-trials.com/mrct/trial/230761/ISRCTN78563659; ISRCTN78563659)

ObjectivesThis research was designed to assess the effect of type 2 diabetes mellitus (T2DM) on myocardial glucose utilization in patients with heart failure secondary to coronary artery disease.BackgroundPatients with T2DM and coronary artery disease have an increased morbidity and mortality compared with patients with coronary artery disease without diabetes that may relate to a reduction in the ability of the myocardium to utilize glucose.MethodsMyocardial blood flow and glucose utilization were assessed during a hyperinsulinemic clamp by 18F-flurodeoxyglucose and positron emission tomography in 54 patients (19 with T2DM) with multivessel coronary artery disease and heart failure. In a subgroup of 18 patients, myocardial biopsies were obtained during coronary bypass surgery to assess glucose transporter (GLUT4) distribution and protein concentration, and compared with myocardium from transplant donor hearts.ResultsMyocardial blood flow was similar in patients without diabetes and those with T2DM. Myocardial glucose utilization was lower in patients with T2DM (0.34 ± 0.16 vs. 0.47 ± 0.24 μmol·min−1·g−1, p = 0.0002) despite comparable plasma insulin concentrations and a higher blood glucose concentration. Extraction of glucose by the myocardium was reduced in patients with T2DM (7.1 ± 3.1% vs. 13.5 ± 5.2%, p < 0.01). Myocardial GLUT4 protein was similar in patients with and without T2DM (p = 0.75).ConclusionsPatients with coronary artery disease and heart failure exhibit myocardial insulin resistance, and this is greater in those with T2DM. This may limit the ability of the myocardium in patients with T2DM to withstand ischemia and may contribute to the increased cardiovascular morbidity and mortality in such patients.

OBJECTIVES In patients with coronary artery disease (CAD), we sought to demonstrate normal myocardial blood flow (MBF) and myocardial oxygen consumption (MMRO2) to post-ischemic myocardium that exhibited reversible dysfunction and the relation between the severity of the dysfunction and the preceding ischemia. BACKGROUND In animal models of stunning, MBF and MMRO2 are normal or near normal, and the severity of stunning is related to the degree of the preceding ischemia. METHODS Myocardial blood flow and MMRO2 were measured using positron emission tomography and oxygen 15-labelled water ((H2O)-O-15) and oxygen 15-labelled oxygen (O-15(2)), respectively, In 14 patients with CAD and normal left ventricular (LV) function. Global ejection fraction and regional LV systolic function (SF) were measured using quantitative echocardiography during and after dobutamine-induced ischemia. RESULTS Ejection fraction and SF were reduced 30 min after dobutamine (both: p < 0.01) but recovered by 120 min. Myocardial blood flow (ml/min per g) to regions with reversible LV dysfunction was normal at baseline and during dysfunction (0.88 [0.82 to 0.99] and 1.09 [0.75 to 1.37], respectively, p = NS) as was MMRO2 (ml/min per 100 g) (16.64 [10.16 to 16.18] and 11.68 [8.43 to 15.30] respectively, p = NS). Left ventricular dysfunction was related to stenosis severity and peak MBF. Regions were divided into those subtended by a stenosis of 80% luminal diameter. Systolic function 30 min after dobutamine was 93.9% (83.4% to 104.4%) (p = NS), 85.4% (80.0% to 90.9%) and 67.4% (56.2% to 78.7%) (both: p < 0.001), respectively. Peak MBF was 2.0 (1.71 to 2.31), 1.75 (1.65 to 1.85) (p = 0.01 compared with

Cardiac imaging with positron emission tomography offers unrivaled sensitivity and specificity to probe cardiovascular physiology in health and disease. The use of positron emission tomography to noninvasively measure regional myocardial blood flow and assess myocardial viability in patients with ventricular dysfunction and coronary artery disease has contributed greatly to our understanding of the pathophysiology of ischemic heart failure. The advances and the need for further studies to establish both the natural history of such ventricular dysfunction and the role of coronary revascularization are discussed.

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

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.

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

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.

Compared to normal volunteers, coronary vasodilation reserve is reduced in patients with hypertrophic cardiomyopathy but not in rowing athletes with left ventricular hypertrophy. Positron emission tomography can provide complementary information to distinguish between the athlete's heart and hypertrophic cardiomyopathy.

multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation 2009;120:28–34. [9] Olsson AG, Lindahl C, Holme I, et al. LDL cholesterol goals and cardiovascular risk during statin treatment: the IDEAL study. Eur J Cardiovasc Prev Rehabil 2011;18:262–9. [10] Melloni C, Shah BR, Ou FS, et al. Lipid-lowering intensification and low-density lipoprotein cholesterol achievement from hospital admission to 1-year follow-up after an acute coronary syndrome event: results from theMedications ApplIed aNd SusTAINed Over Time (MAINTAIN) registry. Am Heart J 2010;160:1121–9.

Myocardial infarction in persons aged below 45 years is a rareevent, usually not related to coronary atherosclerosis, but mostly oc-curs as a consequence of cocaine abuse, congenital coronary abnor-malities, or spasm. We present the case of a young man with anacute anterior myocardial infarction caused by a rare protein defi-ciency in the coagulation system.A29‐year-oldman,of Africandescent,withnopriorhistoryof car-diac event, presented at our emergency department complaining ofsevere acute chest pain radiating to the left arm. Electrocardiographyshowed 2 mm ST elevation in V1 to V4. Transthoracic echocardiogra-phy revealed akinesia of the anterior wall and apex with mild globaldysfunction (ejection fraction 50%). Loading doses of ASA andclopidogrel were administered before coronary angiography thatshowed a large proximal thrombus in the left anterior descending cor-onary artery (LAD) causing total occlusion. Intracoronary abciximabwas administered, and, given large clot burden, thrombus aspirationwas performed before deploying two bare metal stents. At the endof the procedure the patient developed cardiogenic shock requiringadrenaline administration and IABP. Despite arterial patency beingrestored, TIMI flow 1 persisted in the LAD (Fig. 1A).Afterwards,contrast-enhancedcardiacmagneticresonance(CMR)showed transmural infarct of left ventricular apex that appeared thinand akinetic and multiple necrosis foci on interventricular septum(Fig. 1B). A complete thrombophilic screening was carried out, finallyrevealing a combined deficiency of proteins S and C: plasma protein Cand S concentration were respectively 39% and 43% of normal. A ther-apy with low molecular weight heparin was started at a dosage of6000 IU once daily, and 12 months dual antiplatelet therapy was rec-ommended. Two months later therapy was converted to oral antico-agulant with dabigatran 220 mg once daily. At 6 months follow up,the patient remained asymptomatic. Family history revealed recur-rence of severe thromboembolism among his relatives.Protein C is a vitamin K-dependentprotein, synthesized in theliver,that inactivates coagulation factors Va and VIIIa, which are required tothrombin generation and factor X activation. This process is stronglysupported by protein S activity as cofactor. Moreover Protein C hasestablished antin flammatory activity and seems to harbor cyto-protectivepropertiesonendothelialcells.Itisestimatedthatcongenitalprotein C deficiency is present in 2 to 5% of patients with thromboem-bolism [1]. Prevalence of clinically symptomatic deficiencies of proteinC in the general population lies between 1:16,000 and 1:36,000 whilethat of symptomatic protein S deficiency is 1:20,000. Both protein Cand S deficiencies are associated with increased risk of developingdeep venous thrombosis (risk ratio 8.1 for protein S deficiency and 7.3for protein C deficiency) [2] and higher risk of recurrent thrombosis,with typically young age of onset and family cluster occurrence. Thefew available reports of families with combined protein C and S defi-ciency suggest that both genes segregate independently as an autoso-mal dominant trait. Although venous district is typically involved(deep veins, pulmonary artery, jugular vein), arterial thrombosis hasbeen reported. Aorta, mesenteric and cerebral arteries can be affected[3]. Patients with C protein deficiency are at potential risk of warfarininduced skin necrosis, and for that we preferred LMWE and dabigatranto vitamin K antagonist.After acute myocardial infarction inadequate tissue perfusion mayoccur despite early and successful reopening of the infarct-related ar-tery with primary percutaneous coronary intervention. This situation,known as “No Reflow” (NR), significantly affects outcome [4]. NR canbe related to ischemia-reperfusion injury or to downstream emboli-zation of atherosclerotic material into the microvasculature. CMR al-lows the detection of myocardial injury with high accuracy: theintensity of myocardial enhancement is related to expansion of theinterstitial volume secondary to cell necrosis; persistent hypo-perfusion on first pass contrast-enhanced images suggests microvas-cular obstruction (Fig. 2A), which impedes delivery of contrastmedium, or dysfunction of coronary microvasculature that can be re-liably assessed by positron emission tomography (Fig. 2B).Current approaches for prevention and treatment of NR includevasodilators, glycoprotein IIb/IIIa inhibitors and thrombus aspiration.Although we used all of the above, the patient did not achievesuccessful reperfusion. Thrombophilia may have contributed to ex-tensive myocardial damage through a greater and diffuse pro