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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

Aims To provide multi-national, multi-ethnic data on the clinical characteristics and prognosis of patients with microvascular angina (MVA). Methods and results The Coronary Vasomotor Disorders International Study Group proposed the diagnostic criteria for MVA. We prospectively evaluated the clinical characteristics of patients according to these criteria and their prognosis. The primary endpoint was the composite of major cardiovascular events (MACE), verified by institutional investigators, which included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. During the period from 1 July 2015 to 31 December 2018, 686 patients with MVA were registered from 14 institutes in 7 countries from 4 continents. Among them, 64% were female and the main ethnic groups were Caucasians (61%) and Asians (29%). During follow-up of a median of 398 days (IQR 365–744), 78 MACE occurred (6.4% in men vs. 8.6% in women, P = 0.19). Multivariable Cox proportional hazard analysis disclosed that hypertension and previous history of coronary artery disease (CAD), including acute coronary syndrome and stable angina pectoris, were independent predictors of MACE. There was no sex or ethnic difference in prognosis, although women had lower Seattle Angina Questionnaire scores than men (P < 0.05). Conclusions This first international study provides novel evidence that MVA is an important health problem regardless of sex or ethnicity that a diagnosis of MVA portends a substantial risk for MACE associated with hypertension and previous history of CAD, and that women have a lower quality of life than men despite the comparable prognosis., Graphical Abstract

Myocardial infarction with nonobstructed coronary arteries (MINOCA) can be triggered by intense emotions. We report 5 cases of emotional stress–related death where forensic examination attributed myocardial infarction to a coronary spasm, with the ultimate cause of death being arrhythmias in 4 cases and cardiac rupture in the fifth. (Level of Difficulty: Beginner.), Graphical abstract, Myocardial infarction with nonobstructed coronary arteries (MINOCA) can be triggered by intense emotions. We report 5 cases of emotional…

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.

ObjectiveTo assess the prevalence, characteristics and prognostic value of pulmonary hypertension (PH) and right ventricular dysfunction (RVD) in hospitalised, non-intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19).MethodsThis single-centre, observational, cross-sectional study included 211 patients with COVID-19 admitted to non-ICU departments who underwent a single transthoracic echocardiography (TTE). Patients with poor acoustic window (n=11) were excluded. Clinical, imaging, laboratory and TTE findings were compared in patients with versus without PH (estimated systolic pulmonary artery pressure >35 mm Hg) and with versus without RVD (tricuspid annular plane systolic excursion ResultsA total of 200 patients were included in the final analysis (median age 62 (IQR 52–74) years, 65.5% men). The prevalence of PH and RVD was 12.0% (24/200) and 14.5% (29/200), respectively. Patients with PH were older and had a higher burden of pre-existing cardiac comorbidities and signs of more severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (radiological lung involvement, laboratory findings and oxygenation status) compared with those without PH. Conversely, patients with RVD had a higher burden of pre-existing cardiac comorbidities but no evidence of more severe SARS-CoV-2 infection compared with those without RVD. The presence of PH was associated with a higher rate of in-hospital death or ICU admission (41.7 vs 8.5%, pConclusionsAmong hospitalised non-ICU patients with COVID-19, PH (and not RVD) was associated with signs of more severe COVID-19 and with worse in-hospital clinical outcome.Trial registration numberNCT04318366

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.

Beside obstructive disease of the epicardial coronary arteries dysfunction of the coronary microvasculature has emerged in the past 20 years as an additional mechanism of myocardial ischaemia. The coronary microvasculature cannot be directly visualized in vivo, therefore, both invasive and non-invasive techniques, have been developed to assess parameters that depend directly on coronary microvascular function. Studies at the microcirculatory level entail the use of vasodilators to obtain near-maximal vasodilation. The ratio of the maximal increase of blood flow above its resting value the coronary flow reserve (CFR) allows to gain an insight into the integrated circulatory function. The diagnostic accuracy of imaging techniques can be exploited to detect impairments of myocardial perfusion in asymptomatic subjects with cardiovascular risk factors. The assessment of the coronary microvascular function has provided novel details on the pathophysiological role of coronary microvascular dysfunction in the development of myocardial ischaemia bearing also important prognostic implications.

Background The outcomes of patients presenting with acute myocarditis and life-threatening ventricular tachyarrhythmias (LT-VA) are unclear. The aim of this study was to assess incidence and predictors of recurrence of major arrhythmic events (MAEs) after hospital discharge in such patients. Methods and results We retrospectively analysed 156 patients (median age 44 years; 77% males) discharged with a diagnosis of acute myocarditis and LT-VA from 16 hospitals worldwide. Diagnosis of myocarditis was based on histology or on the combination of increased markers of cardiac injury and cardiac magnetic resonance (CMR) Lake Louise criteria. MAEs were defined as the relapse, after discharge, of sudden cardiac death (SCD) or ventricular fibrillation defibrillated successfully or sustained ventricular tachycardia (sVT) requiring implantable cardioverter-defibrillator therapy or synchronized external cardioversion. Median follow-up period was 23 months (first to third quartile [Q1-Q3] 7-60). Fifty-eight (37.2%) patients experienced MAEs after discharge, at a median time of 8 months (Q1-Q3 2.5-24.0 months; 60.3% of MAEs within the first year). At multivariable Cox analysis, variables independently associated to MAEs were presentation with sVT (hazard ratio [HR] 2.90, 95% confidence interval [CI] 1.38-6.11); late gadolinium enhancement (LGE) involving ≥2 myocardial segments (HR 4.51, 95% CI 2.39-8.53); and absence of positive short-tau inversion recovery (STIR) (HR 2.59, 95% CI 1.40-4.79) at first CMR. Conclusions Among patients discharged with the diagnosis of myocarditis and LT-VA, 37.2% had recurrences of MAEs during follow-up. Initial CMR pattern and sVT at presentation stratify the risk of arrhythmic recurrence.

When acute myocardial injury is found in a clinical setting suggestive of myocardial ischemia, the event is labeled as acute myocardial infarction (MI), and the absence of ≥50% coronary stenosis at angiography or greater leads to the working diagnosis of myocardial infarction with non-obstructed coronary arteries (MINOCA). Determining the mechanism of MINOCA and excluding other possible causes for cardiac troponin elevation has notable implications for tailoring secondary prevention measures aimed at improving the overall prognosis of acute MI. The aim of this review is to increase the awareness that establishing the underlying cause of a MINOCA is possible in the vast majority of cases, and that the proper classification of any MI should be pursued. The initial diagnosis of MINOCA can be confirmed or ruled out based on the results of subsequent investigations. Indeed, a comprehensive clinical evaluation at the time of presentation, followed by a dedicated diagnostic work-up, might lead to the identification of the pathophysiologic abnormality leading to MI in almost all cases initially labeled as MINOCA. When a specific cause of acute MI is identified, cardiologists are urged to transition from the “all-inclusive” term “MINOCA” to the proper classification of any MI, as evidence now exists that MINOCA does not provide conceptual clarity for actionable decision-making in MI with angiographically normal coronary arteries.

Takotsubo syndrome (TTS) is estimated to account for 1–3% of all patients presenting with suspected ST-segment elevation myocardial infarction. A sudden surge in sympathetic nervous system is considered the cause of TTS. Nonetheless, no specific recommendations have been provided regarding β-blocking therapy. Apart from specific contra-indications (severe LV dysfunction, hypotension, bradycardia and corrected QT interval >500 ms), treatment with a β-blocker seems reasonable until full recovery of LV ejection fraction, though evidence is limited to a few animal studies, case reports or observational studies. In this review, we will reappraise the rationale for β-blocker therapy in TTS and speculate on the pathophysiologic basis for preferring non-selective agents with vasodilating activity over β1-selective drugs.

The role of cardiac magnetic resonance (CMR) in identifying mechanisms for myocardial infarction with non-obstructed coronary arteries (MINOCA) is well established. Recent reports have highlighted the potentially key role of invasive management in this diagnostic process. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) allow precise evaluation of coronary anatomy, and assessment of coronary physiology in the catheter laboratory provides information on the hemodynamic significance of sub-critical atherosclerosis and on coronary microvascular dysfunction (CMD). We reviewed the evidence for the contribution of invasive diagnostic techniques in identifying provisional causes for MINOCA. Overall, among 82 studies including 8457 patients were selected. In the acute phase, 16 studies with IVUS or OCT (1207 patients) disclosed that plaque disruption and spontaneous coronary artery dissection had a pooled prevalence of 38% (95% confidence intervals (CI): 29% to 51%) and 16% (95% CI: 9% to 27%), respectively. In 18 studies, coronary function testing (1449 patients) showed a pooled prevalence of spontaneous and/or provoked epicardial coronary spasm of ~28% (95% CI:17% to 41%). In 3 studies (456 patients), the pooled prevalence of CMD was ~32% (95% CI: 20% to 49%). In the subacute phase, 42 CMR studies (5821 patients) showed that a pooled prevalence of myocarditis, takotsubo syndrome and cardiomyopathy of 26% (95% CI: 12% to 40%), 11% (95% CI: 5% to 25%), and 7% (95% CI: 1% to 19%), respectively. In 12 studies on thrombophilia screening (n = 834), the pooled prevalence of thrombotic disorder was ~11% (95% CI: 7%% to 25%). In conclusion, the pathophysiology of MINOCA can be established in the majority of cases using both invasive and non-invasive tools to provide direction for appropriate management.

Background. Myocarditis lacks systematic characterization in COVID-19 patients. Methods. We enrolled consecutive patients with newly diagnosed myocarditis in the context of COVID-19 infection. Diagnostic and treatment strategies were driven by a dedicated multidisciplinary disease unit for myocarditis. Multimodal outcomes were assessed during prospective follow-up. Results. Seven consecutive patients (57% males, age 51 ± 9 y) with acute COVID-19 infection received a de novo diagnosis of myocarditis. Endomyocardial biopsy was of choice in hemodynamically unstable patients (n = 4, mean left ventricular ejection fraction (LVEF) 25 ± 9%), whereas cardiac magnetic resonance constituted the first exam in stable patients (n = 3, mean LVEF 48 ± 10%). Polymerase chain reaction (PCR) analysis revealed an intra-myocardial SARS-CoV-2 genome in one of the six cases undergoing biopsy: in the remaining patients, myocarditis was either due to other viruses (n = 2) or virus-negative (n = 3). Hemodynamic support was needed for four unstable patients (57%), whereas a cardiac device implant was chosen in two of four cases showing ventricular arrhythmias. Medical treatment included immunosuppression (43%) and biological therapy (29%). By the 6-month median follow-up, no patient died or experienced malignant arrhythmias. However, two cases (29%) were screened for heart transplantation. Conclusions. Myocarditis associated with acute COVID-19 infection is a spectrum of clinical manifestations and underlying etiologies. A multidisciplinary approach is the cornerstone for tailored management.

AIMS Coronary microvascular dysfunction (CMD) represents a powerful independent predictor of adverse outcome in hypertrophic cardiomyopathy (HCM). No treatment for CMD exists. The angiotensin-converting enzyme (ACE)-inhibitor perindopril improves myocardial blood flow (MBF) in animal models of cardiac hypertrophy and in hypertensive patients. Whether HCM patients with CMD may benefit is unknown. METHODS Fourteen HCM patients aged 18-60 years with CMD [MBF post 0.56 mg/kg dipyridamole (Dip) infusion

Background Hypertrophic cardiomyopathy (HCM) is characterized by severe alterations of cardiac architecture and function involving cardiomyocytes (CM) and coronary microvessels (MV). Coronary microvascular dysfunction, cardiomyocyte hypertrophy and disarray, sarcomeric alterations and interstitial fibrosis are HCM features. The transcriptome profile associated with coronary MV and CM in HCM patients is presently unknown. Purpose Aim of this study was to improve knowledge of the molecular and biological pahways involved in HCM. To this purpose, the gene expression profile of coronary MV and CM was investigated. Methods Interventricular septum myectomies from patients with obstructive HCM and donors' hearts (CTR) were collected. Coronary MV (HCM=20, CTR=6) and CM (HCM=10, CTR=5) were laser capture microdissected. RNA-seq was performed by Illumina Nextseq 500, with 76 nt long single-reads. Adapter trimming and quality filtering of the sequenced reads were performed before alignment to the human reference genome. Univocally mapped reads estimated gene expression/sample. Normalized expressed gene levels were quantified. Statistical tests compared HCM and CTR to identify differentially expressed genes (DEG), i.e. up- and down-expressed genes in CM and MV samples. Functional enrichment analysis was performed. Biological categories, i.e. KEGG and Reactome pathways, Gene Ontology terms, protein domains in InterPro database, putative interactors collected in the Intact database and protein annotations in UniProt were considered for inter group comparison of DEGs. Results Transcriptome analysis identified 392 genes significantly up-regulated and 514 down-regulated in CM samples of HCM vs. CTR, while in MV 681 genes were up-regulated and 815 down-regulated. Although some DEGs were shared between MV and CM (26 and 146 are up- and down-expressed in both sample types), the majority of DEGs displayed a sample-specific pattern. A comparative functional analysis of DEGs highlighted some statistically enriched biological categories including an enrichment of phosphoproteins, with down-expressed genes both in CM (490) and MV (314). Other biological categories annotated as “ubiquitin-like protein conjugation” or “acetylation” in Uniprot database were enriched in down-regulated genes, both in MV and CM. Interestingly, “ribosomal protein” and “ribonucleoprotein” categories resulted as enriched up-regulated DEGs in MV. Conversely, the “citrullination” category was specifically present in annotations associated to down-regulated DEGs in MV from HCM compared to CTR. Conclusions Our preliminary results support the suitability of RNA-seq analysis to assess: i. the transcriptome profiles and pathways associated to coronary MV and CM; ii. the possible relationship/interplay of MV and CM profiles and HCM disease. The enrichment functional analysis provides preliminary data on candidate DEGs and target proteins for in vitro studies on HCM-related mechanisms. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Ministry of Health

Systemic arterial hypertension is a highly prevalent chronic disease associated with hypertensive cardiomyopathy. One important feature of this condition is remodelling of intramural small coronary arteries and arterioles. Here, we investigated the implications of this remodelling in the downstream vascular organization, in particular at the capillary level. We used Spontaneously Hypertensive Rats (SHR) exhibiting many features of the human hypertensive cardiomyopathy. We generated 3D high-resolution mesoscopic reconstructions of the entire network of SHR hearts combining gel-based fluorescent labelling of coronaries with a CLARITY-based tissue clearing protocol. We performed morphometric quantification of the capillary network over time to assess capillary diameter, linear density, and angular dispersion. In SHRs, we found significant remodelling of the capillary network density and dispersion. SHR capillary density is increased in both ventricles and at all ages, including before the onset of systemic hypertension. This result suggests that remodelling occurs independently from the onset of systemic hypertension and left ventricular hypertrophy. On the contrary, capillary angular dispersion increases with time in SHR. Consistently, our multi-modal imaging underlined a strong correlation between vascular dispersion and cellular disarray. Together our data show that 3D high-resolution reconstruction of the capillary network can unveil anatomic signatures in both physiological and pathological cardiac conditions, thus offering a reliable method for integrated quantitative analyses.

Cardiac and cerebrovascular diseases are currently the leading causes of mortality and disability worldwide. Both the heart and brain display similar vascular anatomy, with large conduit arteries running on the surface of the organ providing tissue perfusion through an intricate network of penetrating small vessels. Both organs rely on fine tuning of local blood flow to match metabolic demand. Blood flow regulation requires adequate functioning of the microcirculation in both organs, with loss of microvascular function, termed small vessel disease (SVD) underlying different potential clinical manifestations. SVD in the heart, known as coronary microvascular dysfunction, can cause chronic or acute myocardial ischemia and may lead to development of heart failure. In the brain, cerebral SVD can cause an acute stroke syndrome known as lacunar stroke or more subtle pathological alterations of the brain parenchyma, which may eventually lead to neurological deficits or cognitive decline in the long term. Coronary microcirculation cannot be visualized in vivo in humans, and functional information can be deduced by measuring the coronary flow reserve. The diagnosis of cerebral SVD is largely based on brain magnetic resonance imaging, with white matter hyperintensities, microbleeds, and brain atrophy reflecting key structural changes. There is evidence that such structural changes reflect underlying cerebral SVD. Here, we review interactions between SVD and cardiovascular risk factors, and we discuss the evidence linking cerebral SVD with large vessel atheroma, atrial fibrillation, heart failure, and heart valve disease.

This consensus document, a summary of the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), appraises the importance of ischaemia with non-obstructive coronary arteries (INOCA). Angina pectoris affects approximately 112 million people globally. Up to 70% of patients undergoing invasive angiography do not have obstructive coronary artery disease, more common in women than in men, and a large proportion have INOCA as a cause of their symptoms. INOCA patients present with a wide spectrum of symptoms and signs that are often misdiagnosed as non-cardiac leading to under-diagnosis/investigation and under-treatment. INOCA can result from heterogeneous mechanism including coronary vasospasm and microvascular dysfunction and is not a benign condition. Compared to asymptomatic individuals, INOCA is associated with increased incidence of cardiovascular events, repeated hospital admissions, as well as impaired quality of life and associated increased health care costs. This consensus document provides a definition of INOCA and guidance to the community on the diagnostic approach and management of INOCA based on existing evidence from research and best available clinical practice; noting gaps in knowledge and potential areas for further investigation.

Myocardial infarction in the absence of obstructive coronary stenosis (MINOCA) is a syndrome with several causes, characterized by clinical evidence of myocardial infarction and coronary angiographically normal or almost normal (stenosis ≤50%). MINOCAs represent about 10% of acute coronary syndromes. The causes of MINOCA are manifold and can be classified on the basis of the mechanism in epicardial (unstable plaque not manifested by angiography, epicardial spasm and coronary dissection) or microvascular. The latter in turn can be divided into intrinsic (microvascular spasm, Takotsubo syndrome and coronary embolization) and extrinsic (myocarditis). In the former, the dysfunctional microcirculation causes myocardial necrosis due to reduction of the lumen due to vasoconstriction and / or obstruction, while in the latter, the compression of the lumen occurs ab extrinsic due to myocardial edema. Note that the prognosis of MINOCA is extremely variable and depends on the underlying cause with high risk clinical subsets. A correct diagnostic procedure includes first level tests (clinical / anamnestic examination, ECG, myocardial necrosis enzyme dosage, trans-thoracic echocardiogram, coronary angiography, ventriculogram) and second level tests (intracoronary imaging, coronary vasomotor test, cardiac nuclear magnetic resonance and trans-esophageal or contrast ultrasound). Through this process, it is possible to identify the cause of MINOCA, fundamental for targeting therapy on the disease mechanism, thus constituting a typical example of precision medicine.

Background The significance of malignancy in patients with myocardial infarction and non-obstructive coronary arteries (MINOCA) is poorly defined. This study aimed at determining the prevalence of malignancy and its association with long-term outcome in MINOCA. Methods We searched the MEDLINE, EMBASE, and CENTRAL databases up to March 31, 2020 to identify studies reporting data on malignancy in full. We performed a random effects meta-analysis of proportions and assessed statistical heterogeneity using the I2 statistic and meta-regression analysis. Results A total of 9 studies including 26,636 patients (11,910 men and 14,726 women) were selected for the meta-analysis. Of them, 655 patients (2.5%) had a diagnosis of malignancy at presentation. Comparison of presenting features and outcome between patients with MINOCA and patients with myocardial infarction and coronary artery disease (MI-CAD) showed that malignancy was significantly more common in the former as compared with the latter (p = 0.019). During a median follow-up of 39 months, 2,081 patients with MINOCA died (7.8%). Meta-regression analysis demonstrated that long-term mortality was associated with left ventricular ejection fraction (p = 0.0001; coefficient: -0.001; 95% CI: from -0.002 to 0.002), malignancy at presentation (p = 0.01; coefficient: 0.001; 95% CI: from -0.001 to 0.001), and use of beta-blockers during follow-up (p = 0.03; coefficient: 0.001; 95% CI: from -0.000 to 0.001). Conclusion This study shows that the prevalence of malignancy in patients with MINOCA is not trivial and is significantly greater than in patients with MI-CAD. Malignancy is significantly associated with an unfavorable long-term prognosis in MINOCA.

Aims Fabry cardiomyopathy is characterized by glycosphingolipid storage and increased myocardial trabeculation has also been demonstrated. This study aimed to explore by cardiac magnetic resonance whether myocardial trabecular complexity, quantified by endocardial border fractal analysis, tracks phenotype evolution in Fabry cardiomyopathy. Methods and results Study population included 20 healthy controls (12 males, age 32±9) and 45 Fabry patients divided into three groups: 15 left ventricular hypertrophy (LVH)-negative patients with normal T1 (5 males, age 28±13; Group 1); 15 LVH-negative patients with low T1 (9 males, age 33±9.6; Group 2); 15 LVH-positive patients (11 males, age 53.5±9.6; Group 3). Trabecular fractal dimensions (Dfs) (total, basal, mid-ventricular, and apical) were evaluated on cine images. Total Df was higher in all Fabry groups compared to controls, gradually increasing from controls to Group 3 (1.27±0.02 controls vs. 1.29±0.02 Group 1 vs. 1.30±0.02 Group 2 vs. 1.34±0.02 Group 3; P Conclusion Fabry cardiomyopathy is characterized by a progressive increase in Df of endocardial trabeculae together with shortening of T1 values. Myocardial trabeculation is increased before the presence of detectable sphingolipid storage, thus representing an early sign of cardiac involvement.

Background: We explored the relation between blood concentrations of monocyte/lymphocyte subsets and carotid artery plaque macrophage content, measured by positron emission tomography (PET) with 11C-PK11195. Methods and results: In 9 patients with carotid plaques we performed 11C-PK11195-PET/computed tomography angiography imaging and measurement of absolute concentrations and frequencies of circulating monocytes and T-cell subsets. Plaque standardized uptake value (SUV) for 11C-PK11195 was negatively correlated with concentrations of total monocytes (r = −0.58, p = 0.05) and CD14++CD16−HLA-DR+ classical subset (r = −0.82, p = 0.005). These correlations hold true also in relation to plaque target to background ratio. No correlation was observed between plaque SUV and CD3+T lymphocytes, CD4+T lymphocytes nor with activated CD3+CD4+T cells expressing HLA-DR. Conclusions: We first demonstrated a reduction in the absolute concentration of monocytes and particularly in classical monocytes expressing HLA-DR in the presence of an increased uptake of 11C-PK11195 in carotid plaques. The present work, despite being a pilot study comprising only a small number of subjects provides new insights in the search for specific cellular biomarkers with potential diagnostic and prognostic value in patients with a known carotid plaque. Keywords: Carotid plaque, 11C-PK11195 uptake, Classical monocytes, Positron emission tomography, Atherosclerosis

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.

In recent years, it has become apparent that coronary microvascular dysfunction plays a pivotal pathogenic role in angina pectoris. Functional and structural mechanisms can affect the physiological function of the coronary microvasculature and lead to myocardial ischemia in people without coronary atheromatous disease and also in individuals with obstructive coronary artery disease. Abnormal dilatory responses of the coronary microvessels, coronary microvascular spasm, and extravascular compressive forces have been identified as pathogenic mechanisms in both chronic and acute forms of ischemic heart disease. The condition characterized by anginal symptoms and evidence of myocardial ischemia triggered by coronary microvascular dysfunction, in the absence of obstructive coronary disease, is known as microvascular angina. The concept of microvascular angina, however, may extend further to include patients with obstructive coronary artery disease and individuals with angina after coronary revascularization or heart transplantation because coronary microvascular dysfunction contributes to myocardial ischemia in many such patients. Patients with microvascular angina constitute a sizeable proportion of all cases of stable angina undergoing diagnostic coronary angiography and of those with persisting angina after successful coronary revascularization. Coronary microvascular dysfunction is also often responsible for angina in individuals with cardiomyopathy and heart valve disease as well as acute coronary syndrome cases such as Takotsubo syndrome and myocardial infarction with no obstructive coronary artery disease. Patients with stable microvascular angina present typically with effort or rest chest pain and a reduced coronary flow reserve or microvascular spasm. This condition, which affects women and men, can markedly impair quality of life and prognosis and represents a substantial cost burden to healthcare systems and individuals alike. In recent years, progress in the diagnosis of myocardial ischemia and the use of tests to investigate functional and structural causes for a reduced coronary flow reserve and microvascular spasm have allowed the identification of an increased number of cases of microvascular angina in everyday clinical practice. Although some of the available anti-anginal drugs may be helpful, treatment of coronary microvascular dysfunction remains a major challenge. The present article discusses the fundamental role that coronary microvascular dysfunction plays in the pathogenesis of ischemic heart disease, the clinical characteristics of patients presenting with microvascular angina, and possible diagnostic and therapeutic strategies.

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.

A range of drugs is available for symptomatic angina, but the optimal choice or combination of therapies is often uncertain, and contemporary guidelines do not necessarily provide definite recommendations. In this Consensus Statement, Ferrari and colleagues propose an individualized approach to angina treatment, which takes into consideration the patient, their comorbidities, and the underlying mechanism of disease.

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.

The Cardiovascular Disease in Women Committee of the American College of Cardiology, in conjunction with interested parties (from the National Heart, Lung, and Blood Institute, American Heart Association, and European Society of Cardiology), convened a working group to develop a consensus on the syndrome of myocardial ischemia with no obstructive coronary arteries. In general, these patients have elevated risk for a cardiovascular event (including acute coronary syndrome, heart failure hospitalization, stroke, and repeat cardiovascular procedures) compared with reference subjects and appear to be at higher risk for development of heart failure with preserved ejection fraction. A subgroup of these patients also has coronary microvascular dysfunction and evidence of inflammation. This document provides a summary of findings and recommendations for the development of an integrated approach for identifying and managing patients with ischemia with no obstructive coronary arteries and outlines knowledge gaps in the area. Working group members critically reviewed available literature and current practices for risk assessment and state-of-the-science techniques in multiple areas, with a focus on next steps needed to develop evidence-based therapies. This report presents highlights of this working group review and a summary of suggested research directions to advance this field in the next decade.

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

Aim: Contemporary survival trends in dilated cardiomyopathy (DCM) are largely unknown. The aim of this study is to investigate clinical descriptors, survival trends and the prognostic impact of aetiological characterization in DCM patients. Methods and results: Dilated cardiomyopathy patients were consecutively enrolled and divided into four groups according to the period of enrolment (1978-1984; 1985-1994; 1995-2004; and 2005-2015). A subset of patients with DCM of specific aetiology, enrolled from 2005 to 2015, was also analysed. Over a mean follow-up of 12 ± 8 years, 1284 DCM patients (52 in the 1978-1984 group, 326 in the 1985-1994 group, 379 in the 1995-2004 group, and 527 in the 2005-2015 group) were evaluated. Despite older age (mean age 51 ± 15, 43 ± 15, 45 ± 14, and 52 ± 15 years for the 1978-1984, 1985-1994, 1995-2004, and 2005-2015 groups, respectively; P < 0.001), most of the baseline clinical characteristics improved in the 2005-2015 group, suggesting a less advanced disease stage at diagnosis. Similarly, at competing risk analysis, the annual incidence of all outcome parameters progressively decreased over time (global P < 0.001). At multivariable analysis, the last period of enrolment emerged as independently associated with a reduction in all-cause mortality/heart transplantation (HTx)/ventricular assist device (VAD) implantation (1.46 events/100 patients/year), cardiovascular death/HTx/VAD implantation (0.82 events/100 patients/year) and sudden cardiac death (0.15 events/100 patients/year). Lastly, in 287 patients with DCM of specific aetiology, patients with environmental, toxic, or removable factors appeared to have different phenotypes and prognosis compared to those with genetic, post-myocarditis, or idiopathic DCM (P < 0.001). Conclusions: Contemporary survival trends in DCM significantly improved, mainly due to a reduction of cardiovascular events. Appropriate aetiological characterization might help in prognostication of DCM patients.

Although current guidelines on the management of stable coronary artery disease acknowledge that multiple mechanisms may precipitate myocardial ischemia, recommended diagnostic, prognostic and therapeutic algorithms are still focused on obstructive epicardial atherosclerotic lesions, and little progress has been made in identifying management strategies for non-atherosclerotic causes of myocardial ischemia. The purpose of this consensus paper is three-fold: 1) to marshal scientific evidence that obstructive atherosclerosis can co-exist with other mechanisms of ischemic heart disease (IHD); 2) to explore how the awareness of multiple precipitating mechanisms could impact on pre-test probability, provocative test results and treatment strategies; and 3) to stimulate a more comprehensive approach to chronic myocardial ischemic syndromes, consistent with the new understanding of this condition.

Supplemental Digital Content is available in the text., Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally

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Highlights • Age and fibrocalcific carotid plaques are associated with lower total brain volume. • Fibrocalcific carotid plaques are associated with lower gray matter volumes. • White matter volumes are associated with the extent of carotid atherosclerosis. • Grey and white matter likely have differential susceptibility to processes., Background and aims Extent of subclinical atherosclerosis has been associated with brain parenchymal loss in community-dwelling aged subjects. Identification of patient-related and plaque-related markers could identify subjects at higher risk of brain atrophy, independent of cerebrovascular accidents. Aim of the study was to investigate the relation between extent and characteristics of carotid plaques and brain atrophy in asymptomatic patients with no indication for revascularization. Methods and results Sixty-four patients (aged 69 ± 8 years, 45% females) with carotid stenosis

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium associated to mutations in sarcomeric genes, but the link between genotype and phenotype remains poorly understood. Magnetic resonance spectroscopy studies have demonstrated impaired cardiac energetics in patients with HCM, and altered mitochondria were described in biopsies, but little is known about possible perturbations of mitochondrial function and adenosine triphosphate (ATP) production/consumption. The aim of this study was to investigate possible abnormalities in mitochondrial enzymes generating/scavenging reactive oxygen species, and changes in the Ca2+-activated ATPases in myocardial tissue from patients with obstructive HCM undergoing surgical myectomy compared to unused donor hearts (CTRL). Methods and Results: Both the amount and activity of mitochondrial Complex I (nicotinamide adenine dinucleotide -reduced form, NADH, dehydrogenase) were upregulated in HCM vs. CTRL, whilst the activity of Complex V (ATP synthase) was not reduced and ATP levels were significantly higher in HCM vs. CTRL. Antioxidant Mn-activated superoxide dismutase (SOD2) and (m)-aconitase activities were increased in HCM vs. CTRL. The Cu/Zn-activated superoxide dismutase (SOD1) amount and mtDNA copy number were unaltered in HCM. Total Ca2+-activated ATPase activity and absolute amount were not different HCM vs. CTRL, but the ratio between ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting type 2 (ATP2A2) and type 1 (ATP2A1), ATP2A2/ATP2A1, was increased in HCM in favor of the slow isoform (ATP2A2). Conclusion: HCM is characterized by mitochondrial Complex I hyperactivity and preserved Ca2+-activated ATPase activity with a partial switch towards slow ATP2A2. This data may give insight into the abnormal cellular energetics observed in HCM cardiomyopathy but other studies would need to be performed to confirm the observations described here.

Left ventricular (LV) hypertrophy (LVH) is a growth in left myocardial mass mainly caused by increased cardiomyocyte size. LVH can be a physiological adaptation to physical exercise or a pathological condition either primary, i.e. genetic, or secondary to LV overload. Patients with both primary and secondary LVH have evidence of coronary microvascular dysfunction (CMD). The latter is mainly due to capillary rarefaction and adverse remodelling of intramural coronary arterioles due to medial wall thickening with an increased wall/lumen ratio. An important feature of this phenomenon is the diffuse nature of this remodelling, which generally affects the coronary microvessels in the whole of the left ventricle. Patients with LVH secondary to arterial hypertension can develop both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). These patients can develop HFrEF via a ‘direct pathway’ with an interval myocardial infarction and also in its absence. On the other hand, patients can develop HFpEF that can then progress to HFrEF with or without interval myocardial infarction. A similar evolution towards LV dysfunction and both HFpEF and HFrEF can occur in patients with hypertrophic cardiomyopathy, the most common genetic cardiomyopathy with a phenotype characterized by massive LVH. In this review article, we will discuss both the experimental and clinical studies explaining the mechanisms responsible for CMD in LVH as well as the evidence linking CMD with HFpEF and HFrEF.

Background: In many genetic and acquired non-ischaemic cardiomyopathies (NICM) there have been frequent reports of involvement of the interventricular septum (IVS) by late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR). However, no studies have investigated the relationship between septal LGE and arrhythmias in different NICM subtypes. Methods: This study enrolled 103 patients with septal LGE at baseline CMR and different NICM: hypertrophic (n=29) or lamin A/C gene (LMNA)-associated (n=23) cardiomyopathy, and acute (n=30) or previous (n=21) myocarditis. During follow-up, the occurrences of malignant ventricular arrhythmias (MVA) and major bradyarrhythmias (BA) were evaluated. Results: At 4.9±0.7 years of follow-up, the occurrence of MVA and major BA in genetic vs acquired NICM were 10 of 52 vs 12 of 51, and 10 of 52 vs 4 of 51, respectively (both p=n.s.). However, MVA occurred more frequently in LMNA-NICM (eight of 23 vs two of 29 hypertrophic, p=0.015) and in previous myocarditis (nine of 21 vs three of 30 acute, p=0.016), while major BAs were particularly common in LMNA-NICM patients only (nine of 23 vs one of 29 hypertrophic, p=0.003). Different patterns of septal LGE were consistently retrospectively identified at baseline CMR: junctional and limited to the base in 79.3% of uneventful hypertrophic NICM; extended and focally transmural in LMNA-NICM with follow-up arrhythmias (both p

[No abstract available]

Background: Coronavirus disease 2019 (COVID-19) pandemic has led to a fast and radical transformation in social, economic, and healthcare networks. COVID-19 outbreak may thus have profound indirect consequences on clinical presentation and management of patients with ST-segment–elevation myocardial infarction (STEMI). Aim of this study was to assess clinical features of patients with STEMI during COVID-19 pandemic. Methods: This single-center, prospective study from a regional public service healthcare hub in Milan included all consecutive patients with STEMI admitted to our institute from February 21 to April 1, 2020 (during COVID-19 pandemic). These patients were compared with a historical cohort of patients admitted for STEMI during the analogous time period (February 21 to April 1) in 2018 and 2019, in terms of time from symptoms onset to hospital admission, clinical characteristics, and in-hospital outcomes. Results: A total of 26 patients were admitted for STEMI during the study period, and 7 (26.9%) of these patients tested positive for severe acute respiratory syndrome coronavirus 2. On admission, medical therapy, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers use, was similar between cohorts. Median (interquartile range) time from symptoms onset to hospital admission was significantly longer in 2020 as compared to the historical cohort (15.0 [2.0–48.0] versus 2.0 [1.0–3.0] hours; P P P =0.06). In-hospital death, thromboembolism, mechanical ventilation, or hemodynamic decompensation needing inotropic or mechanical support were similar between years. Conclusions: These preliminary results from a cardiovascular regional public service healthcare hub demonstrate a significantly longer time from symptoms onset to hospital admission among patients with STEMI during COVID-19 pandemic compared with the same time period in the previous 2 years.