Massive Parallel DNA Sequencing of Patients with Inherited Cardiomyopathies in Cyprus and Suggestion of Digenic or Oligogenic Inheritance.

Inherited cardiomyopathies represent a highly heterogeneous group of cardiac diseases. DNA variants in genes expressed in cardiomyocytes cause a diverse spectrum of cardiomyopathies, ultimately leading to heart failure, arrythmias, and sudden cardiac death. We applied massive parallel DNA sequencing using a 72-gene panel for studying inherited cardiomyopathies. We report on variants in 25 families, where pathogenicity was predicted by different computational approaches, databases, and an in-house filtering analysis. All variants were validated using Sanger sequencing. Familial segregation was tested when possible. We identified 41 different variants in 26 genes. Analytically, we identified fifteen variants previously reported in the Human Gene Mutation Database: twelve mentioned as disease-causing mutations (DM) and three as probable disease-causing mutations (DM?). Additionally, we identified 26 novel variants. We classified the forty-one variants as follows: twenty-eight (68.3%) as variants of uncertain significance, eight (19.5%) as likely pathogenic, and five (12.2%) as pathogenic. We genetically characterized families with a cardiac phenotype. The genetic heterogeneity and the multiplicity of candidate variants are making a definite molecular diagnosis challenging, especially when there is a suspicion of incomplete penetrance or digenic-oligogenic inheritance. This is the first systematic study of inherited cardiac conditions in Cyprus, enabling us to develop a genetic baseline and precision cardiology.

Improved indoor air quality during desert dust storms: The impact of the MEDEA exposure-reduction strategies.

Desert dust storms (DDS) are natural events that impact not only populations close to the emission sources but also populations many kilometers away. Countries located across the main dust sources, including countries in the Eastern Mediterranean, are highly affected by DDS. In addition, climate change is expanding arid areas exacerbating DDS events. Currently, there are no intervention measures with proven, quantified exposure reduction to desert dust particles. As part of the wider "MEDEA" project, co-funded by LIFE 2016 Programme, we examined the effectiveness of an indoor exposure-reduction intervention (i.e., decrease home ventilation during DDS events and continuous use of air purifier during DDS and non-DDS days) across homes and/or classrooms of schoolchildren with asthma and adults with atrial fibrillation in Cyprus and Crete-Greece. Participants were randomized to a control or intervention groups, including an indoor intervention group with exposure reduction measures and the use of air purifiers. Particle sampling, PM10 and PM2.5, was conducted in participants' homes and/or classrooms, between 2019 and 2022, during DDS-free weeks and during DDS days for as long as the event lasted. In indoor and outdoor PM10 and PM2.5 samples, mass and content in main and trace elements was determined. Indoor PM2.5 and PM10 mass concentrations, adjusting for premise type and dust conditions, were significantly lower in the indoor intervention group compared to the control group (PM2.5-intervention/PM2.5-control = 0.57, 95% CI: 0.47, 0.70; PM10-intervention/PM10-control = 0.59, 95% CI: 0.49, 0.71). In addition, the PM2.5 and PM10 particles of outdoor origin were significantly lower in the intervention vs. the control group (PM2.5 infiltration intervention-to-control ratio: 0.49, 95% CI: 0.42, 0.58; PM10 infiltration intervention-to-control ratio: 0.68, 95% CI: 0.52, 0.89). Our findings suggest that the use of air purifiers alongside decreased ventilation measures is an effective protective measure that reduces significantly indoor exposure to particles during DDS and non-DDS in high-risk population groups.

The Conjunction Conundrum in Transcatheter Aortic Valve Implantation.

A continuous discussion regarding the predictors for permanent pacemaker implantation (PPI) following transcatheter aortic valve implantation (TAVI) is ongoing, especially in the era of low and medium risk patients. The aim of this article is to review the data so far regarding the pathophysiology, risk factors, and the indications for permanent pacemaker implantation after TAVI. The factors that contribute to rhythm abnormalities post TAVI can be divided into pre-existing conduction abnormalities, patient-related anatomical factors, and peri-procedural technical factors. The latter components are potentially modifiable, and this is where attention should be directed, particularly now that in an era of TAVI expansion towards lower-risk patients.

Syncope in a Patient With Giant Left Main Coronary Aneurysm: Is There a Link With Ventricular Arrhythmias?

Giant aneurysm of the left main coronary artery is exceedingly rare and accounts for less than 2% of patients undergoing coronary angiography. The etiology varies depending on the patient's age and geographic area, but half are of atherosclerotic origin. In most cases, coronary aneurysms are asymptomatic, however, symptomatic patients present with symptoms characteristic of coronary artery disease such as chest pain (angina pectoris), myocardial infarction, congestive heart failure, and even sudden death. Coronary angiography is considered the gold standard tool to determine the presence or absence of coronary artery disease, and if present, its size and location. Herein, we report a case of giant aneurysm of the left main coronary artery presenting as syncope and documented nonsustained ventricular tachycardia.

New Drugs and Interventional Strategies for the Management of Hypertension.

Essential hypertension is an important cause of cardiovascular morbidity and mortality worldwide with significant clinical and economic implications. The field of antihypertensive treatment already numbers numerous agents and classes of drugs. However, patients are still developing uncontrolled hypertension. Hence there is a continuous need for novel agents with good tolerability. Advances in this field are focusing both on pharmacotherapy, with the developments in traditional and non-traditional targets, as well as interventional techniques such as renal denervation and baroreflex activation therapy. It is likely that future strategies may involve a tailored approach to the individual patient, with genetic modulation playing a key role.

Cardiac Effects of Lightning Strikes.

Lightning strikes are a common and leading cause of morbidity and mortality. Multiple organ systems can be involved, though the effects of the electrical current on the cardiovascular system are one of the main modes leading to cardiorespiratory arrest in these patients. Cardiac effects of lightning strikes can be transient or persistent, and include benign or life-threatening arrhythmias, inappropriate therapies from cardiac implantable electronic devices, cardiac ischaemia, myocardial contusion, pericardial disease, aortic injury, as well as cardiomyopathy with associated ventricular failure. Prolonged resuscitation can lead to favourable outcomes especially in young and previously healthy victims.

CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver.

Natural killer cells (NK) are highly enriched in the human liver, where they can regulate immunity and immunopathology. We probed them for a liver-resident subset, distinct from conventional bone-marrow-derived NK. CXCR6+ NK were strikingly enriched in healthy and diseased liver compared to blood (p < 0.0001). Human hepatic CXCR6+ NK had an immature phenotype (predominantly CD56(bright)CD16-CD57-), and expressed the tissue-residency marker CD69. CXCR6+ NK produced fewer cytotoxic mediators and pro-inflammatory cytokines than the non-liver-specific CXCR6- fraction. Instead CXCR6+ NK could upregulate TRAIL, a key death ligand in hepatitis pathogenesis. CXCR6 demarcated liver NK into two transcriptionally distinct populations: T-bet(hi)Eomes(lo)(CXCR6-) and T-bet(lo)Eomes(hi)(CXCR6+); the latter was virtually absent in the periphery. The small circulating CXCR6+ subset was predominantly T-bet(hi)Eomes(lo), suggesting its lineage was closer to CXCR6- peripheral than CXCR6+ liver NK. These data reveal a large subset of human liver-resident T-bet(lo)Eomes(hi) NK, distinguished by their surface expression of CXCR6, adapted for hepatic tolerance and inducible anti-viral immunity.

The role of inflammation and cell death in the pathogenesis, progression and treatment of heart failure.

Chronic inflammation underlies a variety of seemingly unrelated conditions including coronary artery disease. The interest in exploring the role of inflammation in heart failure (CHF) arises from earlier observations that circulating pro-inflammatory biomarker levels are elevated in patients with both ischaemic and non-ischaemic cardiomyopathies and correlate with severity of disease and prognosis (McMurray et al. in Eur Heart J 33:1787-1847, 2012; Mosterd and Hoes in Heart 93:1137-1146, 2007; Owan et al. in New Engl J Med 355:251-259, 2006). In acute decompensated HF, pro-inflammatory biomarker levels have been associated with mortality and readmission rates (Cowie et al. in Heart 83:505-510, 2000). Similar to neurohormonal activation and inflammation, production of pro-inflammatory cytokines is a response to stress in an attempt to restore cellular function. However, sustained expression and exposure to cytokines can lead to left ventricular dysfunction, negative inotropic effects, altered cardiac metabolism, myocardial remodelling and HF progression. However, it is unclear whether elevated levels of pro-inflammatory biomarkers, such as high-sensitivity C-reactive protein, signify an ongoing inflammatory process that leads to HF progression, or are merely markers of advanced disease. Beta-blockers, renin-angiotensin-aldosterone axis antagonists, statins and immunosuppressants have been found to decrease the levels of cytokines in small clinical studies of patients with HF (Hobbs et al. in Heart J 28:1128-1134, 2007). However, 'immunomodulatory' approaches applied in the RECOVER, RENAISSANCE, ATTACH, IMAC and ACCLAIM double-blind, placebo-controlled studies had neutral or negative effects on outcomes of patients with HF. In the present review, we focus on the role of inflammation in pathogenesis and progression of the HF, the value of pro-inflammatory cytokines as biomarkers and the potential therapeutic applications of immunomodulation in HF patients.

Chronic thromboembolic pulmonary arterial hypertension: a review of the literature and novel therapeutic approaches.

Chronic thromboembolic pulmonary hypertension is defined as pulmonary hypertension (PH) caused by single or recurrent pulmonary emboli and is characterized by chronic obstruction of the pulmonary arteries leading to increased vascular resistance and PH. Also, progressive remodeling may occur in occluded and nonoccluded territories. Better understanding of the underlying mechanisms and risk factors could improve diagnosis and allow appropriate interventions. Pulmonary endarterectomy is an established approach and is considered the definitive treatment for chronic PH, resulting from thromboembolic disease. Furthermore, percutaneous transluminal pulmonary angioplasty is technically feasible, especially for those with peripheral-type of the disease. In addition, several agents, including prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors, have been tested in selected patients yielding promising results. Several novel agents are under investigation, and extensive research is currently in progress aiming to resolve uncertainties in the understanding and treatment of the disease.

Coronary artery disease and HIV; getting to the HAART of the matter.

Premature coronary disease is an important emerging paradigm affecting contemporary HIV patients. Through immune reconstruction HIV causes multisystem pathology. Recent advances in the treatment of AIDS, mainly highly active retroviral therapy (HAART), have transformed this previously terminal illness to a chronic disease. However, an interplay between traditional risk factors in a high risk predominantly male population together with the effect of the long term use of HAART in inducing a metabolic syndrome is leading to a premature and aggressive coronary artery disease phenotype not previously recognised. An association between HAART and increased cardiovascular events appears to exist. However, currently this risk appears to be low, and HAART is vital to maintain adequate viral suppression and disease control. HAART- and viral-associated dyslipidaemia can pose a significant challenge to the clinician as drug interactions may precipitate drug toxicity. In our institution a varied phenotypic pattern of coronary disease is seen angiographically from severe atherosclerotic calcific disease through to aneurysm formation and thrombotic occlusion. This is illustrated by case studies. There is a need for aggressive primary and secondary prevention strategies in this important sub-group of patients with a multi-disciplinary approach required in the management including cardiologists, metabolic physicians and lipidologists.

Angiographic segmental narrowing of a saphenous vein bypass graft during diastole.

Dynamic narrowing of native coronary vessels is widely known to occur during the systolic phase of the cardiac cycle. This phenomenon has also been reported to occur in coronary artery bypass grafts. However, to the best of our knowledge, only one case report exists of this event taking place in bypass grafts during diastole. We discuss the angiographic findings of a 73-year-old male who had undergone coronary artery bypass grafting surgery twice and experienced diastolic compression of his saphenous vein graft to the right posterior descending artery.

Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage.

Hepatitis B virus (HBV) causes chronic infection in more than 350 million people worldwide. It replicates in hepatocytes but is non-cytopathic; liver damage is thought to be immune mediated. Here, we investigated the role of innate immune responses in mediating liver damage in patients with chronic HBV infection. Longitudinal analysis revealed a temporal correlation between flares of liver inflammation and fluctuations in interleukin (IL)-8, interferon (IFN)-alpha, and natural killer (NK) cell expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) directly ex vivo. A cross-sectional study confirmed these findings in patients with HBV-related liver inflammation compared with healthy carriers. Activated, TRAIL-expressing NK cells were further enriched in the liver of patients with chronic HBV infection, while their hepatocytes expressed increased levels of a TRAIL death-inducing receptor. IFN-alpha concentrations found in patients were capable of activating NK cells to induce TRAIL-mediated hepatocyte apoptosis in vitro. The pathogenic potential of this pathway could be further enhanced by the ability of the IFN-alpha/IL-8 combination to dysregulate the balance of death-inducing and regulatory TRAIL receptors expressed on hepatocytes. We conclude that NK cells may contribute to liver inflammation by TRAIL-mediated death of hepatocytes and demonstrate that this non-antigen-specific mechanism can be switched on by cytokines produced during active HBV infection.