Stable coronary syndromes: pathophysiology, diagnostic advances and therapeutic need

The diagnostic management of patients with angina pectoris typically centres on the detection of obstructive epicardial CAD, which aligns with evidence-based treatment options that include medical therapy and myocardial revascularisation. This clinical paradigm fails to account for the considerable proportion (approximately one-third) of patients with angina in whom obstructive CAD is excluded. This common scenario presents a diagnostic conundrum whereby angina occurs but there is no obstructive CAD (ischaemia and no obstructive coronary artery disease—INOCA). We review new insights into the pathophysiology of angina whereby myocardial ischaemia results from a deficient supply of oxygenated blood to the myocardium, due to various combinations of focal or diffuse epicardial disease (macrovascular), microvascular dysfunction or both. Macrovascular disease may be due to the presence of obstructive CAD secondary to atherosclerosis, or may be dynamic due to a functional disorder (eg, coronary artery spasm, myocardial bridging). Pathophysiology of coronary microvascular disease may involve anatomical abnormalities resulting in increased coronary resistance, or functional abnormalities resulting in abnormal vasomotor tone. We consider novel clinical diagnostic techniques enabling new insights into the causes of angina and appraise the need for improved therapeutic options for patients with INOCA. We conclude that the taxonomy of stable CAD could improve to better reflect the heterogeneous pathophysiology of the coronary circulation. We propose the term ‘stable coronary syndromes’ (SCS), which aligns with the well-established terminology for ‘acute coronary syndromes’. SCS subtends a clinically relevant classification that more fully encompasses the different diseases of the epicardial and microvascular coronary circulation

Boosting autophagy in the diabetic heart: a translational perspective

Diabetes, obesity, and dyslipidemia are main risk factors that promote the development of cardiovascular diseases. These metabolic abnormalities are frequently found to be associated together in a highly morbid clinical condition called metabolic syndrome. Metabolic derangements promote endothelial dysfunction, atherosclerotic plaque formation and rupture, cardiac remodeling and dysfunction. This evidence strongly encourages the elucidation of the mechanisms through which obesity, diabetes, and metabolic syndrome induce cellular abnormalities and dysfunction in order to discover new therapeutic targets and strategies for their prevention and treatment. Numerous studies employing both dietary and genetic animal models of obesity and diabetes have demonstrated that autophagy, an intracellular system for protein degradation, is impaired in the heart under these conditions. This suggests that autophagy reactivation may represent a future potential therapeutic intervention to reduce cardiac maladaptive alterations in patients with metabolic derangements. In fact, autophagy is a critical mechanism to preserve cellular homeostasis and survival. In addition, the physiological activation of autophagy protects the heart during stress, such as acute ischemia, starvation, chronic myocardial infarction, pressure overload, and proteotoxic stress. All these aspects will be discussed in our review article together with the potential ways to reactivate autophagy in the context of obesity, metabolic syndrome, and diabetes

Pregnancy-associated cardiac dysfunction and the regulatory role of microRNAs.

Many crucial cardiovascular adaptations occur in the body during pregnancy to ensure successful gestation. Maladaptation of the cardiovascular system during pregnancy can lead to complications that promote cardiac dysfunction and may lead to heart failure (HF). About 12% of pregnancy-related deaths in the USA have been attributed to HF and the detrimental effects of cardiovascular complications on the heart can be long-lasting, pre-disposing the mother to HF later in life. Indeed, cardiovascular complications such as gestational diabetes mellitus, preeclampsia, gestational hypertension, and peripartum cardiomyopathy have been shown to induce cardiac metabolic dysfunction, oxidative stress, fibrosis, apoptosis, and diastolic and systolic dysfunction in the hearts of pregnant women, all of which are hallmarks of HF. The exact etiology and cardiac pathophysiology of pregnancy-related complications is not yet fully deciphered. Furthermore, diagnosis of cardiac dysfunction in pregnancy is often made only after clinical symptoms are already present, thus necessitating the need for novel diagnostic and prognostic biomarkers. Mounting data demonstrates an altered expression of maternal circulating miRNAs during pregnancy affected by cardiovascular complications. Throughout the past decade, miRNAs have become of growing interest as modulators and biomarkers of pathophysiology, diagnosis, and prognosis in cardiac dysfunction. While the association between pregnancy-related cardiovascular complications and cardiac dysfunction or HF is becoming increasingly evident, the roles of miRNA-mediated regulation herein remain poorly understood. Therefore, this review will summarize current reports on pregnancy-related cardiovascular complications that may lead to cardiac dysfunction and HF during and after pregnancy in previously healthy women, with a focus on the pathophysiological role of miRNAs

Early diagnosis of cardiovascular diseases in workers: role of standard and advanced echocardiography

Cardiovascular disease (CVD) still remains the main cause of morbidity and mortality and consequently early diagnosis is of paramount importance. Working conditions can be regarded as an additional risk factor for CVD. Since different aspects of the job may affect vascular health differently, it is important to consider occupation from multiple perspectives to better assess occupational impacts on health. Standard echocardiography has several targets in the cardiac population, as the assessment of myocardial performance, valvular and/or congenital heart disease, and hemodynamics. Three-dimensional echocardiography gained attention recently as a viable clinical tool in assessing left ventricular (LV) and right ventricular (RV), volume, and shape. Two-dimensional (2DSTE) and, more recently, three-dimensional speckle tracking echocardiography (3DSTE) have also emerged as methods for detection of global and regional myocardial dysfunction in various cardiovascular diseases, and applied to the diagnosis of subtle LV and RV dysfunction. Although these novel echocardiographic imaging modalities have advanced our understanding of LV and RV mechanics, overlapping patterns often show challenges that limit their clinical utility. This review will describe the current state of standard and advanced echocardiography in early detection (secondary prevention) of CVD and address future directions for this potentially important diagnostic strategy

Cardiotoxicity with vascular endothelial growth factor inhibitor therapy

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway (VSP) have been important additions in the therapy of various cancers, especially renal cell carcinoma and colorectal cancer. Bevazicumab, the first VSP to receive FDA approval in 2004 targeting all circulating isoforms of VEGF-A, has become one of the best-selling drugs of all times. The second wave of tyrosine kinase inhibitors (TKIs), which target the intracellular site of VEGF receptor kinases, began with the approval of sorafenib in 2005 and sunitinib in 2006. Heart failure was subsequently noted, in 2–4% of patients on bevacizumab and in 3–8% of patients on VSP-TKIs. The very fact that the single-targeted monoclonal antibody bevacizumab can induce cardiotoxicity supports a pathomechanistic role for the VSP and the postulate of the “vascular” nature of VSP inhibitor cardiotoxicity. In this review we will outline this scenario in greater detail, reflecting on hypertension and coronary artery disease as risk factors for VSP inhibitor cardiotoxicity, but also similarities with peripartum and diabetic cardiomyopathy. This leads to the concept that any preexisting or coexisting condition that reduces the vascular reserve or utilizes the vascular reserve for compensatory purposes may pose a risk factor for cardiotoxicity with VSP inhibitors. These conditions need to be carefully considered in cancer patients who are to undergo VSP inhibitor therapy. Such vigilance is not to exclude patients from such prognostically extremely important therapy but to understand the continuum and to recognize and react to any cardiotoxicity dynamics early on for superior overall outcomes

Diagnostic accuracy of myocardial perfusion imaging with czt technology. Systemic review and meta-analysis of comparison with invasive coronary angiography

OBJECTIVES: This study sought to summarize the evidence on stress myocardial perfusion imaging (MPI) using cadmium-zinc-telluride (CZT) technology for the diagnosis of obstructive coronary artery disease (CAD). The CZT cameras are newly introduced, and comparative data with the conventional Anger technology (Anger-MPI) are lacking. BACKGROUND: The diagnostic accuracy of Anger-MPI for detection of angiographically significant CAD is well established; however, less evidence is available on the diagnostic accuracy of CZT-MPI. METHODS: Clinical studies comparing CZT-MPI and invasive coronary angiography were systematically searched and abstracted. Calculations of diagnostic accuracy, including sensitivity, specificity, likelihood ratios, and diagnostic odds ratio, were obtained with fixed and random effects, reporting point estimates and 95% confidence intervals. RESULTS: Based on our search, a total of 16 studies (N = 2,092) were included. The sensitivity of CZT-MPI was 0.84 (95% confidence interval [CI]: 0.78 to 0.89), whereas the specificity of 0.69 (95% CI: 0.62 to 0.76) was significantly reduced. The positive likelihood ratio was 2.73 (95% CI: 2.21 to 3.39), the negative likelihood ratio was 0.24 (95% CI: 0.17 to 0.31), and the diagnostic odds ratio was 11.93 (95% CI: 7.84 to 17.42). At subgroup and meta-regression analyses, the diagnostic accuracy between D-SPECT and Discovery cameras was similar (p = 0.711) and not impacted upon by smaller sample size studies (p = 0.573). CONCLUSIONS: CZT-MPI has satisfactory sensitivity for angiographically significant CAD, but its suboptimal specificity warrants further development and research

Investigating the protective role of the natural hormone Melatonin, in reducing drug-induced cardiotoxicity in the therapy of chronic diseases

Heart failure (HF) is a highly complex disorder and a major end-point of cardiovascular diseases (CVD). The pathogenesis of HF is mostly unresolved but involves interplay between cardiac structural and electrical remodelling, metabolic alterations, cell death and altered gene expression. Mitochondrial dysfunction and HF are common complications of chronic treatment from diverse groups of drugs, in particular anticancer drugs such as doxorubicin (DOX). Treatment of animals and cardiomyocytes with cardiotoxic chemicals such as β-adrenergic receptor agonists (such as isoproterenol) induces cardiac dysfunction and HF. Previous work done by the group have identified the pineal hormone melatonin was protective against stress-induced cardiac arrhythmias and simulated heart failure in cardiomyocytes in vitro. Melatonin synthesis is also dramatically decreased with age and in patients with CVD. The aim of the present project was to better understand the pathogenesis of druginduced cardiac dysfunction and delineate the role of melatonin in cardioprotection in H9c2, a model rat cell line in vitro. Using the Seahorse XF analyser method, it was demonstrated that commonly used medication for chronic diseases such as amiodarone, amitriptyline, and statins all caused altered mitochondrial dysfunction. In addition, cardiotoxic chemicals (isoproterenol, hydrogen peroxide, DOX) altered oxidative phosphorylation and glycolysis in living cardiomyocyte-derived H9c2 cells; these deleterious metabolic changes were ameliorated by melatonin. Flowcytometry and Alamar Blue staining methods demonstrated that DOX robustly induced apoptosis in H9c2 cells (~30%) which was reversed by melatonin. Doxorubicin-induced stress in H9c2 cells dramatically altered gene expression in several key signalling pathways integral in cardiac function and disease. These included mitochondrial metabolism (UCP2, PPARɣ, Drp1, Mfn1, Parp 1, Parp2, Sirt3 and Cav3), apoptosis (Bcl2 and Bcl-xL), cardiac electrophysiology and arrhythmia (Scn5a, SERCA2a), calcium handling (SERCA2a) and cardiac remodelling (Myh7, ms1). Melatonin pre-treatment attenuated or completely blocked this DOX-induced alteration in gene expression in cardiomyocytes. In conclusion, the present result demonstrated for the first time that melatonin is cardioprotective against drug-induced cardiotoxicity and apoptosis via modifying diverse heart failure-related signalling pathways. This provides novel insight on the possible use of melatonin as an adjunct intervention in several therapies including anti-cancer