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Heart disease, as well as systemic metabolic alterations, can leave a 'fingerprint' of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy and fatty infiltration, can increase vulnerability to atrial fibrillation (AF), the most relevant manifestation of atrial cardiomyopathy in clinical practice. Atrial cardiomyopathy accompanying AF is associated with thromboembolic events, such as stroke. The interaction between AF and stroke appears to be far more complicated than initially believed. AF and stroke share many risk factors whose underlying pathological processes can reinforce the development and progression of both cardiovascular conditions. In this review, we summarize the main mechanisms by which atrial cardiomyopathy, preceding AF, supports thrombogenic events within the atrial cavity and myocardial interstitial space. Moreover, we report the pleiotropic effects of activated coagulation factors on atrial remodeling, which may aggravate atrial cardiomyopathy. Finally, we address the complex association between AF and stroke, which can be explained by a multidirectional causal relation between atrial cardiomyopathy and hypercoagulability.

Atrial fibrillation (AF) is the most common sustained arrhythmia in the population and is associated with a significant clinical and economic burden. Rigorous assessment of the presence and degree of an atrial arrhythmic substrate is essential for determining treatment options, predicting long-term success after catheter ablation, and as a substrate critical in the pathophysiology of atrial thrombogenesis. Catheter ablation of AF has developed into an essential rhythm-control strategy. Nowadays is one of the most common cardiac ablation procedures performed worldwide, with its success inversely related to the extent of atrial structural disease. Although atrial substrate evaluation remains complex, several diagnostic resources allow for a more comprehensive assessment and quantification of the extent of left atrial structural remodeling and the presence of atrial fibrosis. In this review, we summarize the current knowledge on the pathophysiology, etiology, and electrophysiological aspects of atrial substrates promoting the development of AF. We also describe the risk factors for its development and how to diagnose its presence using imaging, electrocardiograms, and electroanatomic voltage mapping. Finally, we discuss recent data regarding fibrosis biomarkers that could help diagnose atrial fibrotic substrates.

Atrial fibrillation (AF) is the most common sustained arrhythmia in the population and is associated with a significant clinical and economic burden. Rigorous assessment of the presence and degree of an atrial arrhythmic substrate is essential for determining treatment options, predicting long-term success after catheter ablation, and as a substrate critical in the pathophysiology of atrial thrombogenesis. Catheter ablation of AF has developed into an essential rhythm-control strategy. Nowadays is one of the most common cardiac ablation procedures performed worldwide, with its success inversely related to the extent of atrial structural disease. Although atrial substrate evaluation remains complex, several diagnostic resources allow for a more comprehensive assessment and quantification of the extent of left atrial structural remodeling and the presence of atrial fibrosis. In this review, we summarize the current knowledge on the pathophysiology, etiology, and electrophysiological aspects of atrial substrates promoting the development of AF. We also describe the risk factors for its development and how to diagnose its presence using imaging, electrocardiograms, and electroanatomic voltage mapping. Finally, we discuss recent data regarding fibrosis biomarkers that could help diagnose atrial fibrotic substrates. info:eu-repo/semantics/publishedVersion

Atrial fibrillation (AF) contributes to morbidity and mortality of millions of individuals. Its molecular, cellular, neurohumoral, and hemodynamic pathophysiological mechanisms are complex, and there is increasing awareness that a wide range of comorbidities can contribute to AF-promoting atrial remodeling. Moreover, recent research has highlighted that AF risk is not constant and that the temporal variation in concomitant conditions contributes to the complexity of AF dynamics. In this review, we provide an overview of fundamental AF mechanisms related to established and emerging comorbidities or risk factors and their role in the AF-promoting effects. We focus on the accumulating evidence for the relevance of temporally dynamic changes in these risk factors and the consequence for AF initiation and maintenance. Finally, we highlight the important implications for future research and clinical practice resulting from the dynamic interaction between AF risk factors and mechanisms.

Although observational studies have shown positive associations between body mass index (BMI) and the risk of atrial fibrillation (AF), the causal relationship is still uncertain owing to the susceptibility to confounding and reverse causation. This study aimed to examine the potential causality of BMI on AF by conducting a two-sample Mendelian randomization (TSMR) study.METHODS: The independent genetic variants associated with BMI (n = 303) at the genome-wide significant level were derived as instrumental variables (IV) from the Genetic Investigation of Anthropometric Traits (GIANT) consortium consisting of 681,275 individuals of European ancestry. We then derived the outcome data from a GWAS meta-analysis comprised of 60,620 cases and 970,216 controls of European ancestry. The TSMR analyses were performed in five methods, namely inverse variance weighted (IVW) method, MR-Egger regression, the weighted median estimator (WME), the generalized summary data-based Mendelian randomization (GSMR), and the robust adjusted profile score (RAPS), to investigate whether BMI was causally associated with the risk of AF.RESULTS: We found a genetically determined 1-standard deviation (SD) increment of BMI causally increased a 42.5% risk of AF (OR = 1.425; 95% CI, 1.346 to 1.509) based on the IVW method, which was consistent with the results of MR-Egger regression, WME, GSMR, as well as RAPS. The Mendelian randomization assumptions did not seem to be violated.CONCLUSION: This study provides evidence that higher BMI causally increased the risk of AF, suggesting control of BMI and obesity for prevention of AF.

Accumulating evidence points to the existence of an inflammatory-metabolic phenotype of heart failure with a preserved ejection fraction (HFpEF), which is characterized by biomarkers of inflammation, an expanded epicardial adipose tissue mass, microvascular endothelial dysfunction, normal-to-mildly increased left ventricular volumes and systolic blood pressures, and possibly, altered activity of adipocyte-associated inflammatory mediators. A broad range of adipogenic metabolic and systemic inflammatory disorders - e.g. obesity, diabetes and metabolic syndrome as well as rheumatoid arthritis and psoriasis - can cause this phenotype, independent of the presence of large vessel coronary artery disease. Interestingly, when compared with men, women are both at greater risk of and may suffer greater cardiac consequences from these systemic inflammatory and metabolic disorders. Women show disproportionate increases in left ventricular filling pressures following increases in central blood volume and have greater arterial stiffness than men. Additionally, they are particularly predisposed to epicardial and intramyocardial fat expansion and imbalances in adipocyte-associated proinflammatory mediators. The hormonal interrelationships seen in inflammatory-metabolic phenotype may explain why mineralocorticoid receptor antagonists and neprilysin inhibitors may be more effective in women than in men with HFpEF. Recognition of the inflammatory-metabolic phenotype may improve an understanding of the pathogenesis of HFpEF and enhance the ability to design clinical trials of interventions in this heterogeneous syndrome.

Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing incidence, leading to a health care problem of epidemic proportions for which no curative treatments exist. Consequently, an urge exists to better understand the pathophysiology of HFpEF. Accumulating evidence suggests a key pathophysiological role for coronary microvascular dysfunction (MVD), with an underlying mechanism of low-grade pro-inflammatory state caused by systemic comorbidities. The systemic entity of comorbidities and inflammation in HFpEF imply that patients develop HFpEF due to systemic mechanisms causing coronary MVD, or systemic MVD. The absence or presence of peripheral MVD in HFpEF would reflect HFpEF being predominantly a cardiac or a systemic disease. Here, we will review the current state of the art of cardiac and systemic microvascular dysfunction in HFpEF (Graphical Abstract), resulting in future perspectives on new diagnostic modalities and therapeutic strategies.

Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing incidence, leading to a health care problem of epidemic proportions for which no curative treatments exist. Consequently, an urge exists to better understand the pathophysiology of HFpEF. Accumulating evidence suggests a key pathophysiological role for coronary microvascular dysfunction (MVD), with an underlying mechanism of low-grade pro-inflammatory state caused by systemic comorbidities. The systemic entity of comorbidities and inflammation in HFpEF imply that patients develop HFpEF due to systemic mechanisms causing coronary MVD, or systemic MVD. The absence or presence of peripheral MVD in HFpEF would reflect HFpEF being predominantly a cardiac or a systemic disease. Here, we will review the current state of the art of cardiac and systemic microvascular dysfunction in HFpEF (Graphical Abstract), resulting in future perspectives on new diagnostic modalities and therapeutic strategies.

In type 2 diabetes mellitus (T2DM), there is an increased prevalence of cardiovascular disease (CVD), even when corrected for atherosclerosis and other CVD risk factors. Diastolic dysfunction is one of the early changes in cardiac function that precedes the onset of cardiac failure, and it occurs already in the prediabetic state. It is clear that these changes are closely linked to alterations in cardiac metabolism; however, the exact etiology is unknown. In this narrative review, we provide an overview of the early cardiac changes in fatty acid and glucose metabolism in prediabetes and its consequences on cardiac function. A better understanding of the relationship between metabolism, mitochondrial function, and cardiac function will lead to insights into the etiology of the declined cardiac function in prediabetes.

In type 2 diabetes mellitus (T2DM), there is an increased prevalence of cardiovascular disease (CVD), even when corrected for atherosclerosis and other CVD risk factors. Diastolic dysfunction is one of the early changes in cardiac function that precedes the onset of cardiac failure, and it occurs already in the prediabetic state. It is clear that these changes are closely linked to alterations in cardiac metabolism; however, the exact etiology is unknown. In this narrative review, we provide an overview of the early cardiac changes in fatty acid and glucose metabolism in prediabetes and its consequences on cardiac function. A better understanding of the relationship between metabolism, mitochondrial function, and cardiac function will lead to insights into the etiology of the declined cardiac function in prediabetes.

Summary Coronaviruses are constantly circulating in humans, causing common colds and mild respiratory infections. In contrast, infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), responsible for coronavirus disease‐2019 (COVID‐19), can cause additional severe complications, particularly in patients with obesity and associated metabolic disturbances. Obesity is a principal causative factor in the development of the metabolic syndrome; a series of physiological, biochemical, clinical, and metabolic factors that increase the risk of obesity‐associated diseases. “Metabolically unhealthy” obesity is, in addition to metabolic disturbances, also associated with immunological disturbances. As such, patients with obesity are more prone to develop serious complications from infections, including those from SARS‐CoV‐2. In this review, we first describe how obesity and related metabolic disturbances increase the risk of SARS‐CoV‐2 infection. Then, mechanisms contributing to COVID‐19 complications and poor prognosis in these patients are discussed. Finally, we discuss how obesity potentially reduces long‐term COVID‐19 vaccination efficacy. Despite encouraging COVID‐19 vaccination results in patients with obesity and related metabolic disturbances in the short‐term, it is becoming increasingly evident that long‐term COVID‐19 vaccination efficacy should be closely monitored in this vulnerable group.

Objective: Tissue Inhibitor of Metalloproteinase-3 human (TIMP3) is one of tissue inhibitors of metalloproteinases (TIMPs), which binds to the components of the extracellular matrix, and has crucial roles in atherosclerogenesis and adipose tissue differentiation. In this study, it was aimed to determine the effects of TIMP3 gene expression levels on severity of atherosclerosis in different tissues. Material and Methods: The first group of the study (evaluated for coronary artery disease) were cases classified as high and low plaque scores according to the degree and location of atherosclerotic lesions. In the second group (post-mortem cases) were male cadavers who died due to coronary heart disease (CHD, n=26) and non-cardiac trauma (T-nonP, n=4). The TIMP3 expression levels were examined in leukocyte and peri-coronary epicardial adipose tissues (EAT) samples (n=69 and n=34, respectively) of the first group and EAT and coronary artery samples (n=12 and n=30, respectively) of the second group using quantitative RT-PCR. In addition, the protein expressions of TIMP3 were analysed on artery sections by immunofluorestaining. Results: In the post-mortem study group, the TIMP3 expression levels were found to increase in no plaque segments of arteries of cases with CHD (CHD-nonP) compared to advanced atherosclerotic arteries (CHD-P) and normal arteries of T-nonP cases (p=0.01 and p=0.05, respectively). The TIMP3 expressions in EATs and leukocytes were not statistically significant between the study groups. In addition, TIMP3 protein was detected in normal arteries, peri-coronary EATs and mostly in macrophages- rich areas in advanced atherosclerotic arteries. Conclusion: Tissue Inhibitor of Metalloproteinase-3 human (TIMP3) expression levels increase in normal coronary arterial segments of cases with CHD, which depict a protective role of TIMP3 in development of atherosclerosis., Amaç: Hücre dışı matriksin bileşenlerine bağlanan TIMP3, metaloproteinazların doku inhibitörlerinden (TIMP’ler) biridir ve ateroskleroz gelişimi ile yağ dokusu farklılaşmasında rol oynamaktadır. Bu çalışmada, farklı dokulardaki TIMP3 gen ifade düzeylerinin ateroskleroz şiddeti üzerine olan etkisinin belirlenmesi amaçlandı. Gereç ve Yöntemler: Çalışmanın ilk grubu (koroner arter hastalığı için değerlendirilen), aterosklerotik lezyonların derecesine ve yerine göre yüksek ve düşük plak skoru olarak sınıflandırılan vakalardı. İkinci grup (post-mortem vakalar), koroner kalp hastalığı (CHD, n=26) ve kardiyak olmayan travma (T-nonP, n=4) nedeniyle ölen erkek kadavralardı. Birinci grubun lökosit ve peri-koroner epikardiyal yağ doku (EYD) örnekleri (sırasıyla, n=69 ve n=34) ile ikinci grubun EYD ve koroner arter örneklerinde (sırasıyla, n=12 ve n=30) TIPM3 ifade düzeyleri kantitatif RT-PCR ile incelendi. Ek olarak, TIMP3 protein lokalizasyonları, immunfluoresans tekniği ile belirlendi. Bulgular: Post-mortem çalışma grubunda, TIMP3 ifade düzeylerinin CHD’li vakaların plaksız arter segmentlerinde (CHD-nonP), ileri aterosklerotik arterlere (CHD-P) ve T-nonP vakaların normal arterlere kıyasla arttığı bulundu (sırasıyla, p=0.01 ve p=0.05). Lökosit ve EYD’lerdeki TIMP3 gen ifadeleri, çalışma grupları arasında istatistiksel olarak anlamlı fark göstermedi. Ek olarak, TIMP3 proteini normal arter, peri-koroner EYD ve ileri aterosklerotik arterde makrofajların yoğun olduğu alanlarda tespit edildi. Sonuç: CHD’li vakaların normal koroner arteriyel segmentlerinde TIMP3 ifadesindeki artışın ateroskleroz gelişimine karşı koruyucu bir etkisi olabileceğini göstermektedir

Heart disease, as well as systemic metabolic alterations, can leave a ‘fingerprint’ of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy and fatty infiltration, can increase vulnerability to atrial fibrillation (AF), the most relevant manifestation of atrial cardiomyopathy in clinical practice. Atrial cardiomyopathy accompanying AF is associated with thromboembolic events, such as stroke. The interaction between AF and stroke appears to be far more complicated than initially believed. AF and stroke share many risk factors whose underlying pathological processes can reinforce the development and progression of both cardiovascular conditions. In this review, we summarize the main mechanisms by which atrial cardiomyopathy, preceding AF, supports thrombogenic events within the atrial cavity and myocardial interstitial space. Moreover, we report the pleiotropic effects of activated coagulation factors on atrial remodeling, which may aggravate atrial cardiomyopathy. Finally, we address the complex association between AF and stroke, which can be explained by a multidirectional causal relation between atrial cardiomyopathy and hypercoagulability.

Background Pericardial fat (PF) has been suggested to directly act on cardiomyocytes, leading to diastolic dysfunction. The aim of this study was to investigate whether a higher PF volume is associated with a lower diastolic function in healthy subjects. Methods 254 adults (40–70 years, BMI 18–35 kg/m2, normal left ventricular ejection fraction), with (a)typical chest pain (otherwise healthy) from the cardiology outpatient clinic were retrospectively included in this study. All patients underwent a coronary computed tomographic angiography for the measurement of pericardial fat volume, as well as a transthoracic echocardiography for the assessment of diastolic function parameters. To assess the independent association of PF and diastolic function parameters, multivariable linear regression analysis was performed. To maximize differences in PF volume, the group was divided in low (lowest quartile of both sexes) and high (highest quartile of both sexes) PF volume. Multivariable binary logistic analysis was used to study the associations within the groups between PF and diastolic function, adjusted for age, BMI, and sex. Results Significant associations for all four diastolic parameters with the PF volume were found after adjusting for BMI, age, and sex. In addition, subjects with high pericardial fat had a reduced left atrial volume index (p = 0.02), lower E/e (p Conclusion These findings confirm that pericardial fat volume, even in healthy subjects with normal cardiac function, is associated with diastolic function. Our results suggest that the mechanical effects of PF may limit the distensibility of the heart and thereby directly contribute to diastolic dysfunction. Trial registration NCT01671930

Accumulating evidence points to the existence of an inflammatory‐metabolic phenotype of heart failure with a preserved ejection fraction (HFpEF), which is characterized by biomarkers of inflammation, an expanded epicardial adipose tissue mass, microvascular endothelial dysfunction, normal‐to‐mildly increased left ventricular volumes and systolic blood pressures, and possibly, altered activity of adipocyte‐associated inflammatory mediators. A broad range of adipogenic metabolic and systemic inflammatory disorders – e.g. obesity, diabetes and metabolic syndrome as well as rheumatoid arthritis and psoriasis – can cause this phenotype, independent of the presence of large vessel coronary artery disease. Interestingly, when compared with men, women are both at greater risk of and may suffer greater cardiac consequences from these systemic inflammatory and metabolic disorders. Women show disproportionate increases in left ventricular filling pressures following increases in central blood volume and have greater arterial stiffness than men. Additionally, they are particularly predisposed to epicardial and intramyocardial fat expansion and imbalances in adipocyte‐associated proinflammatory mediators. The hormonal interrelationships seen in inflammatory‐metabolic phenotype may explain why mineralocorticoid receptor antagonists and neprilysin inhibitors may be more effective in women than in men with HFpEF. Recognition of the inflammatory‐metabolic phenotype may improve an understanding of the pathogenesis of HFpEF and enhance the ability to design clinical trials of interventions in this heterogeneous syndrome.

Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVDs), is a lipid-driven, inflammatory disease of the large arteries. Gold standard therapy with statins and the more recently developed proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have improved health conditions among CVD patients by lowering low density lipoprotein (LDL) cholesterol. Nevertheless, a substantial part of these patients is still suffering and it seems that 'just' lipid lowering is insufficient. The results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) have now proven that inflammation is a key driver of atherosclerosis and that targeting inflammation improves CVD outcomes. Therefore, the identification of novel drug targets and development of novel therapeutics that block atherosclerosis-specific inflammatory pathways have to be promoted. The inflammatory processes in atherosclerosis are facilitated by a network of immune cells and their subsequent responses. Cell networking is orchestrated by various (inflammatory) mediators which interact, bind and induce signaling. Over the last years, G-protein coupled receptors (GPCRs) emerged as important players in recognizing these mediators, because of their diverse functions in steady state but also and specifically during chronic inflammatory processes - such as atherosclerosis. In this review, we will therefore highlight a selection of these receptors or receptor sub-families mainly expressed on myeloid cells and their role in atherosclerosis. More specifically, we will focus on chemokine receptors, both classical and atypical, formyl-peptide receptors, the chemerin receptor 23 and the calcium-sensing receptor. When information is available, we will also describe the consequences of their targeting which may hold promising options for future treatment of CVD.

Purpose: To prospectively assess the effects of an exercise intervention on organ-specific fat accumulation and cardiac function in type 2 diabetes mellitus.Materials and Methods: Written informed consent was obtained from all participants, and the study protocol was approved by the medical ethics committee. The study followed 12 patients with type 2 diabetes mellitus (seven men; mean age, 46 years 6 2 [standard error]) before and after 6 months of moderate-intensity exercise, followed by a high-altitude trekking expedition with exercise of long duration. Abdominal, epicardial, and paracardial fat volume were measured by using magnetic resonance (MR) imaging. Cardiac function was quantified with cardiac MR, and images were analyzed by a researcher who was supervised by a senior researcher (4 and 21 years of respective experience in cardiac MR). Hepatic, myocardial, and intramyocellular triglyceride (TG) content relative to water were measured with proton MR spectroscopy at 1.5 and 7 T. Two-tailed paired t tests were used for statistical analysis.Results: Exercise reduced visceral abdominal fat volume from 348 mL +/- 57 to 219 mL +/- 33 (P Conclusion: A 6-month exercise intervention in type 2 diabetes mellitus decreased hepatic TG content and visceral abdominal and paracardial fat volume, which are associated with increased cardiovascular risk, but cardiac function was unaffected. Tissue-specific exercise-induced changes in body fat distribution in type 2 diabetes mellitus were demonstrated in this study. (C) RSNA, 2013

Atrial fibrillation (AF) is the most common cardiac arrhythmia; the lifetime risk is 1 in 4 for persons over the age of 40 years in the United States.1 AF is associated with an increased risk of death, dementia, heart failure, and stroke.2–5 AF leads to high healthcare system utilization rates.6 Based on current US age- and sex-specific prevalence data, the national incremental AF cost in 2010 is estimated to range from $6.0 to $26.0 billion.7 Risk factors for AF are diverse8 and include advancing age, male sex, diabetes mellitus, hypertension, valvular disease, myocardial infarction, heart failure, obesity, elevated inflammatory marker concentrations, and PR-interval prolongation, as recently reviewed elsewhere.9 Risk prediction models are important to define individual risk for AF, to identify novel risk factors for AF, to identify and assess potential targets of therapy, and to enhance the cost-effective implementation of therapies for both primary and secondary prevention of AF.10 A recently published risk score for the development of AF based on the established cardiovascular risk factors accounted for only part of the AF risk (C-statistic 0.76).11 Thus, although many risk factors for AF have been described, a substantial proportion of AF risk still remains unexplained. In the past years, multiple novel AF risk factors have been studied. In the present review, we aim to describe recently described risk factors and will underscore that substantial efforts are needed to incorporate novel markers of AF into risk prediction models. Efforts to optimize risk prediction models and prevention algorithms are useful for risk communication, patient motivation, and clinical decision making.10 ### Familial Aggregation In recent years, increasing data have been reported supporting the notion that AF in the general population is heritable. Diverse population-based studies have demonstrated that familial clustering of AF is common. …

As obesity and type 2 diabetes are becoming an epidemic in westernized countries, the incidence and prevalence of obesity- and diabetes-related co-morbidities are increasing. In type 2 diabetes ectopic lipid accumulation in the heart has been associated with cardiac dysfunction and apoptosis, a process termed lipotoxicity. Since cardiovascular diseases are the main cause of death in diabetic patients, diagnosis and treatment become increasingly important. Although ischaemic heart disease is a major problem in diabetes, non-ischaemic heart disease (better known as diabetic cardiomyopathy) becomes increasingly important with respect to the impairment of cardiac function and mortality in type 2 diabetes. The underlying aetiology of diabetic cardiomyopathy is incompletely understood but is beginning to be elucidated. Various mechanisms have been proposed that may lead to lipotoxicity. Therefore, this review will focus on the mechanisms of cardiac lipid accumulation and its relation to the development of cardiomyopathy.