Hearts, Volume 1, Issue 2 (September 2020) – 9 articles

Vitamin A is a micronutrient and signaling molecule that regulates transcription, cellular differentiation, and organ homeostasis. Additionally, metabolites of Vitamin A are utilized as differentiation agents in the treatment of hematological cancers and skin disorders, necessitating further study into the effects of both nutrient deficiency and the exogenous delivery of Vitamin A and its metabolites on cardiovascular phenotypes. Though vitamin A/retinoids are well-known regulators of cardiac formation, recent evidence has emerged that supports their role as regulators of cardiac regeneration, postnatal cardiac function, and cardiovascular disease progression. We here review findings from genetic and pharmacological studies describing the regulation of both myocyte- and vascular-driven cardiac phenotypes by vitamin A signaling. We identify the relationship between retinoids and maladaptive processes during the pathological hypertrophy of the heart, with a focus on the activation of neurohormonal signaling and fetal transcription factors (Gata4, Tbx5). Finally, we assess how this information might be leveraged to develop novel therapeutic avenues. Full article

The role of NADPH oxidase subunit, gp91^phox (NOX2) in development of oxidative stress and cardiac dysfunction due to iron (Fe)-overload was assessed. Control (C57BL/6J) and gp91^phox knockout (KO) mice were treated for up to 8 weeks with Fe (2.5 mg/g/wk, i.p.) or Na-dextran; echocardiography, plasma 8-isoprostane (lipid peroxidation marker), cardiac Fe accumulation (Perl’s staining), and CD11b+ (WBCs) infiltrates were assessed. Fe caused no adverse effects on cardiac function at 3 weeks. At 6 weeks, significant declines in left ventricular (LV) ejection fraction (14.6% lower), and fractional shortening (19.6% lower) occurred in the Fe-treated control, but not in KO. Prolonging Fe treatment (8 weeks) maintained the depressed LV systolic function with a trend towards diastolic dysfunction (15.2% lower mitral valve E/A ratio) in controls but produced no impact on the KO. Fe-treatment (8 weeks) caused comparable cardiac Fe accumulation in both strains, but a 3.3-fold elevated plasma 8-isoprostane, and heightened CD11b+ staining in controls. In KO mice, lipid peroxidation and CD11b+ infiltration were 50% and 68% lower, respectively. Thus, gp91^phox KO mice were significantly protected against oxidative stress, and systolic and diastolic dysfunction, supporting an important role of NOX2-mediated oxidative stress in causing cardiac dysfunction during Fe overload. Full article

Hypomagnesemia occurs clinically as a result of restricted dietary intake, Mg-wasting drug therapies, chronic disease status and may be a risk factor in patients with cardiovascular disorders. Dietary restriction of magnesium (Mg deficiency) in animal models produced a pro-inflammatory/pro-oxidant condition, involving hematopoietic, neuronal, cardiovascular, renal and other systems. In Mg-deficient rodents, early elevations in circulating levels of the neuropeptide, substance P (SP) may trigger subsequent deleterious inflammatory/oxidative/nitrosative stress events. Evidence also suggests that activity of neutral endopeptidase (NEP, neprilysin), the major SP-degrading enzyme, may be impaired during later stages of Mg deficiency, and this may sustain the neurogenic inflammatory response. In this article, experimental findings using substance P receptor blockade, NEP inhibition, and N-methyl-D-aspartate (NMDA) receptor blockade demonstrated the connection between hypomagnesemia, neurogenic inflammation, oxidative stress and enhanced cardiac dysfunction. Proof of concept concerning neurogenic inflammation is provided using an isolated perfused rat heart model exposed to acute reductions in perfusate magnesium concentrations. Full article

Taurine is a ubiquitous β-amino acid that plays an essential role in ensuring normal mitochondrial and myocardial function. In the mitochondria, taurine reacts with a tRNA forming a 5-taurinomethyluridine conjugate that primarily regulates the biosynthesis of the mitochondria encoded protein, ND6, which serves as a subunit of complex I of the respiratory chain. Impaired formation of the taurine conjugate reduces activity of complex I and plays a central role in the pathophysiology of the mitochondrial disease MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The restoration of mitochondrial levels of the taurine conjugate enhances electron flux through the respiratory chain, thereby preventing at least some of the symptoms of MELAS. Taurine therapy also diminishes the severity of congestive heart failure, an observation that led to its approval for the treatment of congestive heart failure in Japan. The review article discusses the role of defective calcium handling, reduced ATP generation, enhanced oxidative stress and apoptosis in the development of taurine-deficient cardiomyopathy. Some patients suffering from congestive heart failure are taurine-deficient, an observation supporting the hypothesis that low taurine levels contribute to the severity of heart failure. Thus, mishandling of taurine leads to mitochondrial dysfunction, which is involved in the development of both MELAS and congestive heart failure. Full article

Takayasu arteritis is a large vessel vasculitis which commonly affects the aorta and its major branches. Active arterial inflammation is characterised by the presence of T and B lymphocytes, natural killer cells, macrophages and occasional multinucleate giant cells. Uncontrolled vascular inflammation can progress to cause arterial stenosis, occlusion or aneurysmal dilatation. Medical treatment involves combination immunosuppression and more recently biologic therapies targeting TNF-α and IL-6. Due to the typical delays in diagnosis and accumulation of arterial injury, open and endovascular surgical intervention are important and potentially life-saving treatment options for Takayasu arteritis. Common indications for surgery include aortic coarctation and ascending aortic dilatation ± aortic valve regurgitation, renal artery stenosis, ischaemic heart disease, supra-aortic disease, mesenteric ischaemia, severe limb-threatening claudication and aneurysm repair. Surgical outcomes are markedly improved in patients with clinically inactive disease and those who receive adequate periprocedural immunosuppression. Decisions regarding surgical approaches are best made as part of a multi-disciplinary team. Full article

Thoracic aortic aneurysms are prevalent in the Western population and are often caused by genetic defects. If undetected, aneurysms can dissect or rupture, which are events associated with a high mortality rate. Hitherto no cure exists other than elective surgery if aneurysm dimensions reach a certain threshold. In the past decades, genotype-phenotype associations have emerged that enable clinicians to start stratifying patients according to risk for dissection. Nonetheless, risk assessment is—to this day—confounded by the lack of full comprehension of underlying genetics and modifying genetic risk factors that complicate the yet established genotype-phenotype correlations. Further research that focuses on identifying these additional risk markers is crucial. Full article

Background: Pulmonary hypertension is observed in 70% of patients with left ventricular (LV) dysfunction. Right heart catheterization is the gold standard for a complete evaluation of Pulmonary Hypertension (PH); however, echocardiography represents a powerful initial diagnostic tool. The aim of our study was to evaluate the accuracy of echocardiography for the diagnosis of postcapillary PH, i.e., due to increased left ventricular filling pressures. Methods and Results: We recruited patients with a diagnosis of PH from the RIGHT1 study (Right heart invasive and echocardiographic hemodynamic evaluation in Turin 1). Transthoracic echocardiography was performed within 60 min of cardiac catheterization. High LV filling pressures were defined by a pulmonary arterial wedge pressure (PAWP) greater than 15 mmHg. We assessed numerous morphological and functional features of LV, and their association with PAWP. 128 patients were diagnosed with PH. We observed a significant association between PAWP, the left atrial volume indexed by BSA (LAVi, R2 = 0.27; p < 0.0001) and the E/e’ ratio (R2 = 0.27; p < 0.0001). With these parameters, we implemented a diagnostic algorithm to identify high ventricular filling pressures in PH patients. The application of this algorithm could help identify patients with a diagnosis of postcapillary PH due to high ventricular filling pressures (E/E’ > 15). Conclusions: The echocardiographic parameters with the best association with PAWP in PH patients are E/e’ and LAVi. For these patients, our diagnostic algorithm could improve the diagnostic precision for the definition of subgroups. Full article

Neurological brain injury (NBI) remains the most feared complication following thoracic endovascular aortic repair (TEVAR), and can manifest as clinically overt stroke and/or more covert injury, detected only on explicit neuropsychological testing. Microembolic signals (MES) detected on transcranial Doppler (TCD) monitoring of the cerebral arteries during TEVAR and the high prevalence and incidence of new ischaemic infarcts on diffusion-weighted magnetic resonance imaging (DW-MRI) suggests procedure-related solid and gaseous cerebral microembolisation to be an important cause of NBI. Any intervention that can reduce the embolic burden during TEVAR may, therefore, help mitigate the risk of stroke and the covert impact of ischaemic infarcts to the function of the brain. This perspective article provides an understanding of the mechanism of stroke and reviews the available evidence regarding potential neuroprotective strategies that target high-risk procedural steps of TEVAR to reduce periprocedural cerebral embolisation. Full article