Imagenetics for Precision Medicine in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a common heart muscle disorder of nonischemic etiology associated with heart failure development and the risk of malignant ventricular arrhythmias and sudden cardiac death. A tailored approach to risk stratification and prevention of sudden cardiac death is required in genetic DCM given its variable presentation and phenotypic severity. Currently, advances in cardiogenetics have shed light on disease mechanisms, the complex genetic architecture of DCM, polygenic contributors to disease susceptibility and the role of environmental triggers. Parallel advances in imaging have also enhanced disease recognition and the identification of the wide spectrum of phenotypes falling under the DCM umbrella. Genotype-phenotype associations have been also established for specific subtypes of DCM, such as DSP (desmoplakin) or FLNC (filamin-C) cardiomyopathy but overall, they remain elusive and not readily identifiable. Also, despite the accumulated knowledge on disease mechanisms, certain aspects remain still unclear, such as which patients with DCM are at risk for disease progression or remission after treatment. Imagenetics, that is, the combination of imaging and genetics, is expected to further advance research in the field and contribute to precision medicine in DCM management and treatment. In the present article, we review the existing literature in the field, summarize the established knowledge and emerging data on the value of genetics and imaging in establishing genotype-phenotype associations in DCM and in clinical decision making for DCM patients.

Silent Myocardial Ischemia: From Pathophysiology to Diagnosis and Treatment.

Silent myocardial ischemia (SMI), characterized by a lack of overt symptoms despite an inadequate blood supply to the myocardium, remains a challenging entity in cardiovascular medicine. The pathogenesis involves intricate interactions of vascular, neurohormonal, and metabolic factors, contributing to perfusion deficits without the characteristic chest pain. Understanding these mechanisms is pivotal for recognizing diverse clinical presentations and designing targeted interventions. Diagnostic strategies for SMI have evolved from traditional electrocardiography to advanced imaging modalities, including stress echocardiography, single-photon emission computed tomography (SPECT), positron emission tomography (PET), and cardiac magnetic resonance imaging (MRI). Treating SMI is a matter of ongoing debate, as the available evidence on the role of invasive versus medical management is controversial. This comprehensive review synthesizes current knowledge of silent myocardial ischemia, addressing its pathophysiology, diagnostic modalities, and therapeutic interventions.

A "Snake-Like" Vessel in the Thorax.

We report a congenital extracardiac arteriovenous fistula revealed incidentally in a patient undergoing computed tomographic coronary angiography for angina. This clinical vignette panel describes the origin and the trajectory of this rare vascular lesion.

An overview of systematic reviews on imaging tests for diagnosis of pulmonary embolism applying different network meta-analytic methods.

PURPOSE: This study aimed to apply different methods of diagnostic test accuracy network meta-analysis (DTA-NMA) for studies reporting results of five imaging tests for the diagnosis of suspected pulmonary embolism (PE): pulmonary angiography (PA), computed tomography angiography (CTPA), magnetic resonance angiography (MRA), planar ventilation/perfusion (V/Q) scintigraphy and single-photon emission computed tomography ventilation/perfusion (SPECT V/Q). METHODS: We searched four databases (MEDLINE [via PubMed], Cochrane CENTRAL, Scopus, and Epistemonikos) from inception until June 2, 2022 to identify systematic reviews (SRs) describing diagnostic accuracy of PA, CTPA, MRA, V/Q scan and SPECT V/Q for suspected PE. Study-level data were extracted and pooled using a hierarchical summary receiver operating characteristic (HSROC) meta-regression approach and two DTA-NMA models to compare accuracy estimates of different imaging tests. Risk of bias was assessed using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool and certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. RESULTS: We identified 13 SRs, synthesizing data from 33 primary studies and for four imaging tests (PA, CTPA, MRA and V/Q scan). The HSROC meta-regression model using PA as the reference standard showed that MRA had the best overall diagnostic performance with sensitivity of 0.93 (95% confidence interval [CI]: 0.76, 1.00) and specificity of 0.94 (95% CI: 0.84, 0.99). However, DTA-NMA models indicated that V/Q scan had the highest sensitivity, while CTPA was most specific. CONCLUSION: Selecting a different DTA-NMA method to assess multiple diagnostic tests can affect estimates of diagnostic accuracy. There is no established method, but the choice depends on the data and familiarity with Bayesian statistics.

Direct Oral Anticoagulants use in Patients with Stable Coronary Artery Disease, Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention.

The investigation for the optimal anticoagulation strategy for patients with stable coronary artery disease, acute coronary syndromes, and undergoing percutaneous coronary intervention constitutes a great challenge for physicians and is a field of extensive research. Although aspirin is commonly recommended as a protective measure for all patients with coronary artery disease and dual antiplatelet therapy for those undergoing procedures, such as percutaneous coronary intervention or coronary artery bypass graft surgery, the risk of recurrent cardiovascular events remains significant. In this context, the shortcomings associated with the use of vitamin K antagonists have led to the assessment of direct oral anticoagulants as promising alternatives. This review will explore and provide a comprehensive analysis of the existing data regarding the use of direct oral anticoagulants in patients with stable coronary artery disease or acute coronary syndrome, as well as their effectiveness in those undergoing percutaneous coronary intervention or coronary artery bypass graft surgery.

Preventative Imaging with Coronary Computed Tomography Angiography.

PURPOSE OF REVIEW: Coronary computed tomography angiography (CCTA) is the diagnostic modality of choice for patients with stable chest pain. In this review, we scrutinize the evidence on the use of CCTA for the screening of asymptomatic patients. RECENT FINDINGS: Clinical evidence suggests that CCTA imaging enhances cardiovascular risk stratification and prompts the timely initiation of preventive treatment leading to reduced risk of major adverse coronary events. Visualization of coronary plaques by CCTA also helps patients to comply with preventive medications. The presence of non-obstructive plaques and total plaque burden are prognostic for cardiovascular events. High-risk plaque features and pericoronary fat attenuation index, enrich the prognostic output of CCTA on top of anatomical information by capturing information on plaque vulnerability and coronary inflammatory burden. Timely detection of atherosclerotic disease or coronary inflammation by CCTA can assist in the deployment of targeted preventive strategies and novel therapeutics to prevent cardiovascular disease.

The cardiovascular consequences of electronic cigarette smoking: a narrative review.

INTRODUCTION: E-cigarettes have emerged as a popular alternative to traditional tobacco smoking in recent years. Despite their growing popularity, concerns have arisen regarding the cardiovascular implications of e-cigarette use. AREAS COVERED: This narrative review aims to highlight the latest evidence on the impact of e-cigarettes on cardiovascular health. EXPERT OPINION: Numerous studies have demonstrated that e-cigarette use can lead to acute adverse cardiovascular effects. Inhalation of e-cigarette aerosols exposes users to a wide range of potentially harmful substances that have been implicated in critical pathophysiologic pathways of cardiovascular disease, namely endothelial dysfunction, oxidative stress, inflammation, sympathetic overdrive, and arterial stiffness. While long-term epidemiological studies specifically focusing on the cardiovascular effects of e-cigarettes are still relatively scarce, early evidence suggests a potential association between e-cigarette use and an increased risk of adverse cardiovascular events. However, it is essential to recognize that e-cigarettes are relatively new products, and the full extent of their long-term cardiovascular impact has not been fully elucidated. In the meantime, promoting tobacco cessation strategies that are evidence-based and regulated, along with rigorous monitoring of e-cigarette use patterns and associated health outcomes, are essential steps in safeguarding cardiovascular health in the face of this emerging public health challenge.

Perivascular adipose tissue as a source of therapeutic targets and clinical biomarkers.

Obesity is a modifiable cardiovascular risk factor, but adipose tissue (AT) depots in humans are anatomically, histologically, and functionally heterogeneous. For example, visceral AT is a pro-atherogenic secretory AT depot, while subcutaneous AT represents a more classical energy storage depot. Perivascular adipose tissue (PVAT) regulates vascular biology via paracrine cross-talk signals. In this position paper, the state-of-the-art knowledge of various AT depots is reviewed providing a consensus definition of PVAT around the coronary arteries, as the AT surrounding the artery up to a distance from its outer wall equal to the luminal diameter of the artery. Special focus is given to the interactions between PVAT and the vascular wall that render PVAT a potential therapeutic target in cardiovascular diseases. This Clinical Consensus Statement also discusses the role of PVAT as a clinically relevant source of diagnostic and prognostic biomarkers of vascular function, which may guide precision medicine in atherosclerosis, hypertension, heart failure, and other cardiovascular diseases. In this article, its role as a 'biosensor' of vascular inflammation is highlighted with description of recent imaging technologies that visualize PVAT in clinical practice, allowing non-invasive quantification of coronary inflammation and the related residual cardiovascular inflammatory risk, guiding deployment of therapeutic interventions. Finally, the current and future clinical applicability of artificial intelligence and machine learning technologies is reviewed that integrate PVAT information into prognostic models to provide clinically meaningful information in primary and secondary prevention.

Stem Cell-based Therapies in Cardiovascular Diseases: From Pathophysiology to Clinical Outcomes.

Over 20 years of intensified research in the field of stem cells brought about unprecedented possibilities in treating heart diseases. The investigators were initially fascinated by the idea of regenerating the lost myocardium and replacing it with new functional cardiomyocytes, but this was extremely challenging. However, the multifactorial effects of stem cell-based therapies beyond mere cardiomyocyte generation, caused by paracrine signaling, would open up new possibilities in treating cardiovascular diseases. To date, there is a strong body of evidence that the anti-inflammatory, anti-apoptotic, and immunomodulatory effects of stem cell therapy may alleviate atherosclerosis progression. In the present review, our objective is to provide a brief overview of the stem cell-based therapeutic options. We aim to delineate the pathophysiological mechanisms of their beneficial effects in cardiovascular diseases especially in coronary artery disease and to highlight some conclusions from important clinical studies in the field of regenerative medicine in cardiovascular diseases and how we could further move onwards.

Interleukin-6 Signaling in Atherosclerosis: From Molecular Mechanisms To Clinical Outcomes.

Interleukin-6 (IL-6) is a cytokine centrally involved in several immune responses and it has been recognized as a driver of enhanced atherothrombotic risk. Immunity and inflammation are intrinsically involved in atherosclerosis progression. This generated 'inflammation hypothesis', which is now validated in large-scale clinical trials. Abundant evidence supports the distinctive role of IL-6 in coronary artery disease. The focus on this cytokine stems from epidemiological studies linking high plasma concentrations of IL-6 with greater risk for adverse cardiovascular events, genetic studies which implicate a causative role of IL-6 in atherosclerosis and murine data which support the involvement of IL-6 in various pathophysiological cascades of atherothrombosis. The fact that high IL-6 levels are equivalent to increased cardiovascular risk created an unmet need to address those who are at 'residual inflammatory risk'. Moreover, the opposing effects of IL-6 underlined the importance of deciphering specific signaling cascades, which may be responsible for different effects. Finally, murine data and some small clinical trials highlighted the possibility of reversing the pro-atherogenic effects of IL-6 by directly targeting it. While IL-1 blockage was proved effective, it is reasonable to examine if moving more downstream in the inflammation cascade could be more selective and effective than other anti-inflammatory therapies. In the present review, we examine the role of IL-6 as a biomarker of 'residual inflammatory risk', its vital role in the pathophysiology of atherosclerosis progression and the possibility of targeting it to stall coronary artery disease progression.

The Role of Right Ventriculo-Arterial Coupling in Symptoms Presentation of Patients with Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. The hallmark of HCM is myocardial fibrosis which contributes to heart failure, arrhythmias, and sudden cardiac death (SCD). OBJECTIVE: To identify the factors implicated in heart failure symptoms and functional capacity of patients with HCM. METHODS: In this cohort study, 43 patients with HCM were recruited. According to functional capacity and symptoms presentation, patients were categorized according to New York Heart Association (NYHA) classification, and echocardiographic measurements of left ventricle systolic and diastolic function were conducted. The echocardiographic assessment of right ventriculo-arterial coupling (RVAC) was made by calculating the tricuspid annular peak systolic tissue Doppler velocity (TASV)/estimated RV systolic pressure (RVSP) ratio. RESULTS: Almost half (51%) of our study population present symptoms of heart failure and were categorized as the symptomatic group-NYHA 2 or higher. Maximum LVOT gradient, RVSP, and the ratio of E/e' were higher in the symptomatic group compared with the asymptomatic group. TASV was lower in the symptomatic group compared with the asymptomatic group (11 ± 1 cm/s vs. 13 ± 2 cm/s, p = 0.04). However, there was no difference in other potentially influential factors, such as heart rate or systemic blood pressure. The SCD risk score does not differ between the two studied groups. The RVAC (estimated with the TASV/RVSP ratio) was lower in the symptomatic group compared with the asymptomatic group (0.32 ± 0.09 vs. 0.46 ± 0.11, p < 0.001). CONCLUSION: A low RVAC (as estimated with TASV/RVSP ratio) value could represent an echocardiographic marker of right ventricular-arterial uncoupling in patients with HCM and impaired functional status.

Role of Human Epicardial Adipose Tissue-Derived miR-92a-3p in Myocardial Redox State.

BACKGROUND: Visceral obesity is directly linked to increased cardiovascular risk, including heart failure. OBJECTIVES: This study explored the ability of human epicardial adipose tissue (EAT)-derived microRNAs (miRNAs) to regulate the myocardial redox state and clinical outcomes. METHODS: This study screened for miRNAs expressed and released from human EAT and tested for correlations with the redox state in the adjacent myocardium in paired EAT/atrial biopsy specimens from patients undergoing cardiac surgery. Three miRNAs were then tested for causality in an in vitro model of cardiomyocytes. At a clinical level, causality/directionality were tested using genome-wide association screening, and the underlying mechanisms were explored using human biopsy specimens, as well as overexpression of the candidate miRNAs and their targets in vitro and in vivo using a transgenic mouse model. The final prognostic value of the discovered targets was tested in patients undergoing cardiac surgery, followed up for a median of 8 years. RESULTS: EAT miR-92a-3p was related to lower oxidative stress in human myocardium, a finding confirmed by using genetic regulators of miR-92a-3p in the human heart and EAT. miR-92a-3p reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase-derived superoxide (O2.-) by targeting myocardial expression of WNT5A, which regulated Rac1-dependent activation of NADPH oxidases. Finally, high miR-92a-3p levels in EAT were independently related with lower risk of adverse cardiovascular events. CONCLUSIONS: EAT-derived miRNAs exert paracrine effects on the human heart. Indeed miR-92a-3p suppresses the wingless-type MMTV integration site family, member 5a/Rac1/NADPH oxidase axis and improves the myocardial redox state. EAT-derived miR-92a-3p is related to improved clinical outcomes and is a rational therapeutic target for the prevention and treatment of obesity-related heart disease.

Fabry disease due to D313Y variant with renal failure and possible cardiac involvement: a case report.

Background: This is a case report of a patient with Anderson-Fabry disease (AFD) due to the D313Y variant on the a-galactosidase A (GLA) gene on migalastat treatment and severe chronic kidney disease referred to our unit to assess possible cardiac involvement. Case summary: A 53-year-old man with chronic kidney disease due to AFD and a medical history of revascularized coronary artery disease, chronic atrial fibrillation, and arterial hypertension was referred to our unit for evaluation of possible cardiac involvement in the context of AFD. Biochemical evaluation reported reduced serum alpha-galactosidase A activity and borderline abnormal serum lyso-Gb3 enzyme activity. The patient had also history of acroparesthesias, dermatological presentation of multiple angiokeratomas, severe kidney impairment with an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73m² by the age of 16, and microalbuminuria that cumulatively set the diagnosis of AFD. Transthoracic echocardiogram showed left ventricular concentric hypertrophy with left ventricular ejection fraction of 45%. Cardiac magnetic resonance showed findings in keeping with ischaemic heart disease (IHD), i.e. akinesia and subendocardial scarring of the basal anterior and the entirety of the septum and the true apex; in addition, there was severe asymmetrical hypertrophy of the basal anteroseptum (max 18 mm), evidence of low-grade myocardial inflammation, and mid-wall fibrosis of the basal inferior and inferolateral wall, suggesting a cardiomyopathic process-myocardial disease which could not be explained solely by IHD or well-controlled hypertension. Discussion: This is the first case of possible cardiac involvement in a patient with AFD due to the D313Y variant. This case demonstrates the diagnostic challenges of cardiac involvement in AFD, especially in the presence of a concomitant underlying pathology.

Epicardial Adipose Tissue in Myocardial Disease: From Physiology to Heart Failure Phenotypes.

Epicardial adipose tissue (EAT) is increasingly being recognized as a determinant of myocardial biology. The EAT-heart crosstalk suggests causal links between dysfunctional EAT and cardiomyocyte impairment. Obesity promotes EAT dysfunction and shifts in secreted adipokines which adversely affect cardiac metabolism, induce cardiomyocyte inflammation, redox imbalance and myocardial fibrosis. Thus, EAT determines cardiac phenotype via effects on cardiac energetics, contractility, diastolic function, and atrial conduction. Vice-versa the EAT is altered in heart failure (HF), and such phenotypic changes can be detected by noninvasive imaging or incorporated in Artificial Intelligence-enhanced tools to aid the diagnosis, subtyping or risk prognostication of HF. In the present article, we summarize the links between EAT and the heart, explaining how the study of epicardial adiposity can improve the understanding of cardiac disease, serve as a source of diagnostic and prognostic biomarkers, and as a potential therapeutic target in HF to improve clinical outcomes.

Oxidative Stress Biomarkers in Coronary Artery Disease.

Oxidative stress plays a central role in atherogenesis, implicated in endothelial dysfunction, coronary plaque formation, and destabilization. Therefore, identifying oxidative stress in the vascular wall by reliable biomarkers could aid in early diagnosis and better coronary artery disease (CAD) prognostication. Because of the short half-life of reactive oxygen species, the current approach is to measure stable products generated by the oxidation of macromolecules in plasma or urine. Most popular oxidative stress biomarkers are oxidized low-density lipoprotein, myeloperoxidase and lipid peroxidation biomarkers, such as malondialdehyde and F2-isoprostanes. Oxidative protein modification biomarkers and oxidized phospholipids have also been studied and discussed in the present review. Most of these biomarkers are associated with the presence and extent of CAD, are elevated in patients with acute coronary syndromes, and may predict outcomes independent of traditional CAD risk factors. However, further standardization of measurement methods and assessment in large randomized clinical trials are required to integrate these biomarkers into clinical practice. In addition, evidence that these biomarkers detect oxidative stress in the vascular wall lacks and more specific biomarkers should be developed to identify vascular oxidative stress. Consequently, several oxidative stress biomarkers have been developed, most of which can be associated with the presence and extent of CAD and event prognosis. However, they still have significant limitations that hinder their integration into clinical practice.

Cardiac magnetic resonance imaging of pericardial diseases: a comprehensive guide.

Cardiac magnetic resonance (CMR) imaging has been established as a valuable diagnostic tool in the assessment of pericardial diseases by providing information on cardiac anatomy and function, surrounding extra-cardiac structures, pericardial thickening and effusion, characterization of pericardial effusion, and the presence of active pericardial inflammation from the same scan. In addition, CMR imaging has excellent diagnostic accuracy for the non-invasive detection of constrictive physiology evading the need for invasive catheterization in most instances. Growing evidence in the field suggests that pericardial enhancement on CMR is not only diagnostic of pericarditis but also has prognostic value for pericarditis recurrence, although such evidence is derived from small patient cohorts. CMR findings could also be used to guide treatment de-escalation or up-titration in recurrent pericarditis and selecting patients most likely to benefit from novel treatments such as anakinra and rilonacept. This article is an overview of the CMR applications in pericardial syndromes as a primer for reporting physicians. We sought to provide a summary of the clinical protocols used and an interpretation of the major CMR findings in the setting of pericardial diseases. We also discuss points that are less well clear and delineate the strengths and weak points of CMR in pericardial diseases.

Lipoprotein(a) and calcific aortic valve disease initiation and progression: a systematic review and meta-analysis.

Although evidence indicates the association of lipoprotein(a) [Lp(a)] with atherosclerosis, the link with calcific aortic valve disease (CAVD) is unclear. This systematic review and meta-analysis explores the connection between Lp(a) and aortic valve calcification and stenosis (AVS). We included all relevant studies, indexed in eight databases, up to February 2023. A total of 44 studies (163 139 subjects) were included, with 16 of them being further meta-analysed. Despite considerable heterogeneity, most studies support the relationship between Lp(a) and CAVD, especially in younger populations, with evidence of early aortic valve micro-calcification in elevated-Lp(a) populations. The quantitative synthesis showed higher Lp(a) levels, by 22.63 nmol/L (95% CI: 9.98-35.27), for patients with AVS, while meta-regressing the data revealed smaller Lp(a) differences for older populations with a higher proportion of females. The meta-analysis of eight studies providing genetic data, revealed that the minor alleles of both rs10455872 and rs3798220 LPA gene loci were associated with higher risk for AVS (pooled odds ratio 1.42; 95% CI: 1.34-1.50 and 1.27; 95% CI: 1.09-1.48, respectively). Importantly, high-Lp(a) individuals displayed not only faster AVS progression, by a mean difference of 0.09 m/s/year (95% CI: 0.09-0.09), but also a higher risk of serious adverse outcomes, including death (pooled hazard ratio 1.39; 95% CI: 1.01-1.90). These summary findings highlight the effect of Lp(a) on CAVD initiation, progression and outcomes, and support the early onset of Lp(a)-related subclinical lesions before clinical evidence.

High-Sensitivity Troponin (hs-Tn) for Cardiovascular Risk Prognostication: A Systematic Review and Meta-Analysis.

BACKGROUND: Chronic low-grade inflammation is involved in coronary atherosclerosis progression whereas recent research efforts suggest that preventative methods should be tailored to the "residual inflammatory risk". As such, modalities for the early identification of the risk have to be investigated. METHODS: We performed a systematic review and meta-analysis according to the PRISMA guidelines. Any study that presented the prognostic value of high sensitivity troponin (hs-cTn) of vascular inflammation in stable patients without known cardiac heart disease was considered to be potentially eligible. The Medline (PubMed) database was searched up to April 22, 2021. The main endpoint was the difference in c-index (Δ[c-index]) with the use of hs-cTn for major adverse cardiovascular events (MACEs), cardiovascular and all-cause mortality. We calculated I² to test heterogeneity. RESULTS: In total, 44 studies and 112,288 stable patients without known coronary heart disease were included in this meta-analysis. The mean follow-up duration of the whole cohort was 6.8 ± 1.1 years. 77,004 (68.5%) of the patients presented with low cardiovascular risk while 35,284 (31.5%) in high. The overall pooled estimate of Δ[c-index] for MACE was 1.4% (95%CI: 0.7-2.1, I2=0%) and for cardiovascular death 1.3% (95%CI: 0.3-2.3, I2=0%). Finally, the overall pooled estimate of Δ[c-index] for all-cause mortality was 3% (95%CI: 1.9-3.9, I2=86%), while high heterogeneity was observed between the studies. CONCLUSION: The predictive usefulness of changes in hs-cTn measures in stable individuals with either high or low cardiovascular risk, demonstrates that assessing vascular inflammation in addition to clinical risk factors enhances risk prediction for cardiovascular events and all-cause mortality. Further prospective studies are necessary to confirm these findings and assist clinical decision-making regarding the most optimal prevention strategy.