Crosstalk between high-density lipoproteins and endothelial cells in health and disease: Insights into sex-dependent modulation

Atherosclerotic cardiovascular disease is the leading cause of death worldwide. Intense research in vascular biology has advanced our knowledge of molecular mechanisms of its onset and progression until complications; however, several aspects of the patho-physiology of atherosclerosis remain to be further elucidated. Endothelial cell homeostasis is fundamental to prevent atherosclerosis as the appearance of endothelial cell dysfunction is considered the first pro-atherosclerotic vascular modification. Physiologically, high density lipoproteins (HDLs) exert protective actions for vessels and in particular for ECs. Indeed, HDLs promote endothelial-dependent vasorelaxation, contribute to the regulation of vascular lipid metabolism, and have immune-modulatory, anti-inflammatory and anti-oxidative properties. Sex- and gender-dependent differences are increasingly recognized as important, although not fully elucidated, factors in cardiovascular health and disease patho-physiology. In this review, we highlight the importance of sex hormones and sex-specific gene expression in the regulation of HDL and EC cross-talk and their contribution to cardiovascular disease

Kardiologischer Check-up bei Frauen in den Wechseljahren

Kardiovaskuläre Erkrankungen, insbesondere atherothrombotische Ereignisse, verursachen jährlich über 4 Mio. Todesfälle in Europa. Herz-Kreislauf-Erkrankungen enden insgesamt tödlicher für die Frauen (2,2 Mio.) als für die Männer (1,8 Mio.), wohingegen kardiovaskuläre Todesfälle vor dem 65. Lebensjahr vorwiegend Männer betreffen (490.000 vs. 193.000). Das Herz-Kreislauf-Risiko ist nach der Menopause erhöht, das Risiko steigt weiter bei vorzeitiger oder früher Menopause. Risikofaktoren wie arterielle Hypertonie sollen spätestens ab dem 18. Lebensjahr abgeklärt werden, bei Verdacht auf eine familiäre Hypercholesterinämie soll eine Abklärung bereits im Kindesalter erfolgen. Frauen mit erhöhtem Risiko sollten deshalb früher zur Vorsorgeuntersuchung gehen. Für alle anderen Frauen ist ein kardialer Check-up generell nach der Menopause bzw. ab dem 50. Lebensjahr empfohlen. Welche kardiologischen Vorsorgeuntersuchungen für eine Frau in den Wechseljahren sinnvoll sind, hängt von individuellen Faktoren wie Krankheiten in der Familie, Alter, Vorerkrankungen oder kardiovaskulären Risikofaktoren ab. Zudem zählen als wichtige Aspekte die Lebensstilfaktoren (Konsum von Tabak oder Nikotin, Ernährung, körperliche Aktivität, Stress, Konsum von illegalen Drogen) sowie die familiäre und berufliche Situation. Ein kardiologischer Check-up bietet die Gelegenheit, Lebensgewohnheiten zu besprechen und individuelle Ratschläge zu erteilen. Auf Basis der Untersuchungsresultate werden gezielte, nach Alter und individuellen Risikofaktoren angepasste Präventivmassnahmen mit bewiesener Wirksamkeit empfohlen

Sex and gender in cardiovascular medicine: presentation and outcomes of acute coronary syndrome.

Although health disparities in women presenting with acute coronary syndrome (ACS) have received growing attention in recent years, clinical outcomes from ACS are still worse for women than for men. Women continue to experience higher patient and system delays and receive less aggressive invasive treatment and pharmacotherapies. Gender- and sex-specific variables that contribute to ACS vulnerability remain largely unknown. Notwithstanding the sex differences in baseline coronary anatomy and function, women and men are treated the same based on guidelines that were established from experimental and clinical trial data over-representing the male population. Importantly, younger women have a particularly unfavourable prognosis and a plethora of unanswered questions remains in this younger population. The present review summarizes contemporary evidence for gender and sex differences in vascular biology, clinical presentation, and outcomes of ACS. We further discuss potential mechanisms and non-traditional risk conditions modulating the course of disease in women and men, such as unrecognized psychosocial factors, sex-specific vascular and neural stress responses, and the potential impact of epigenetic modifications

Long-term prognostic value of coronary flow reserve in psoriasis patients

BACKGROUND AND AIMS Psoriasis affects more than 3% of the general population and is associated with an increased risk of premature cardiovascular events and death. We assessed the prognostic role of coronary flow reserve (CFR) as a marker of coronary microvascular function in psoriasis patients asymptomatic for cardiovascular disease. METHODS We retrospectively analyzed 153 prospectively collected patients affected by psoriasis (123 male; age 36 ± 8 years) without cardiovascular disease. CFR in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperemic to resting diastolic flow velocity. CFR ≤2.5 was the cut off to define the presence of coronary microvascular dysfunction (CMD). RESULTS CMD was present in 23 patients (15%). Multivariable logistic regression analysis showed that CMD was associated with severe psoriasis (OR 3.1, p = 0.03), psoriatic arthritis (OR 2.9, p = 0.03), hypertension (OR 4.1, p = 0.009), and time elapsing since psoriasis diagnosis >6 years (OR 1.9, p = 0.03). Patients with CFR ≤2.5 had a lower survival free from events (p < 0.0001). CONCLUSIONS In psoriasis patients, CFR may be a reliable prognostic marker for cardiovascular event-free survival and may help identify patients at higher risk of developing cardiovascular complications. Whether novel biologic therapies able to reduce skin disease will improve CMD and prognosis in these patients needs to be further studied, prospectively

Coronary Collateral Circulation: A New Predictor of Mortality in Heart Transplant Recipients With Allograft Vasculopathy

Background: Coronary collateral arteries (CCAs) are anastomotic channels between vessels; although beneficial in atherosclerosis, their role in heart transplantation (HT) recipients is underinvestigated. CCAs initially develop as microcirculation and cardiac allograft vasculopathy (CAV), promoting immune-dependent proliferative angiogenic response, and play a role in their development. In our hypothesis, ischemia induced by coronary microvascular dysfunction (CMD) triggers the development of CCAs, which are, in turn, less functional as affected by CAV themselves. Methods: One hundred twenty-one patients receiving HT at our institution were retrospectively evaluated and were included if transthoracic echocardiography with coronary flow velocity reserve (CFVR) assessment and coronary angiography were performed. CMD was defined as CFVR of ≤2.5. Patients with CAV were enrolled, and their angiograms were reviewed to evaluate the presence of CCAs. Cardiovascular mortality was assessed as the main clinical outcome. Results: Forty patients were found to have CCAs. Patients with CCAs have lower CFVR than those without CCAs (2.22 ± 0.72 versus 2.69 ± 0.92;P = 0.003), reflecting in different rates of CMD in the 2 groups (72.5% versus 37%; P < 0.001). CMD is associated with higher CAV grades (P < 0.001), which are also associated with CCAs (P < 0.001). Patients with poorly developed CCAs have lower CFVR (P < 0.001). At multivariable analysis, CMD (P = 0.008) and higher CAV grades (P = 0.005) are independent predictors of CCAs. During the median follow-up time of 10.2 (6.6-13.3) y, patients with CCAs have been found to have higher mortality than those without CCAs (57.5% versus 32.1%; P = 0.007). CCAs are associated with a lower probability of survival also in patients with CMD (P < 0.001) and are independent predictors of mortality (P < 0.001). Conclusions: Our results demonstrate an interplay between CAV, CMD, and CCAs. We confirm that CAV is associated with CMD, and we show, for the first time, that CMD is associated with CCAs. CCAs are pathophysiologically associated with more severe graft vasculopathy and independently predict mortality after HT

Effects of acute administration of trimethylamine N-oxide on endothelial function: a translational study

Elevated circulating levels of nutrient-derived trimethylamine N-oxide (TMAO) have been associated with the onset and progression of cardiovascular disease by promoting athero-thrombosis. However, in conditions like bariatric surgery (Roux-en-Y gastric bypass, RYGB), stable increases of plasma TMAO are associated with improved endothelial function and reduced cardiovascular morbidity and mortality, thus questioning whether a mechanistic relationship between TMAO and endothelial dysfunction exists. Herein, we translationally assessed the effects of acute TMAO exposure on endothelial dysfunction, thrombosis and stroke. After RYGB, fasting circulating levels of TMAO increased in patients and obese rats, in parallel with an improved gluco-lipid profile and higher circulating bile acids. The latter enhanced FXR-dependent signalling in rat livers, which may lead to higher TMAO synthesis post RYGB. In lean rats, acute TMAO injection (7 mg kg$^{−1}$) 1.5-h before sacrifice and ex-vivo 30-min incubation of thoracic aortas with 10$^{−6}$ M TMAO did not impair vasodilation in response to acetylcholine (Ach), glucagon-like peptide 1, or insulin. Similarly, in lean WT mice (n = 5–6), TMAO injection prior to subjecting mice to ischemic stroke or arterial thrombosis did not increase its severity compared to vehicle treated mice. Endothelial nitric oxide synthase (eNOS) activity and intracellular stress-activated pathways remained unaltered in aorta of TMAO-injected rats, as assessed by Western Blot. Pre-incubation of human aortic endothelial cells with TMAO (10$^{−6}$ M) did not alter NO release in response to Ach. Our results indicate that increased plasmatic TMAO in the near-physiological range seems to be a neutral bystander to vascular function as translationally seen in patients after bariatric surgery or in healthy lean rodent models and in endothelial cells exposed acutely to TMAO

Epigenetics in the primary and secondary prevention of cardiovascular disease: influence of exercise and nutrition

Increasing evidence links changes in epigenetic systems, such as DNA methylation, histone modification, and non-coding RNA expression, to the occurrence of cardiovascular disease (CVD). These epigenetic modifications can change genetic function under influence of exogenous stimuli and can be transferred to next generations, providing a potential mechanism for inheritance of behavioural intervention effects. The benefits of exercise and nutritional interventions in the primary and secondary prevention of CVD are well established, but the mechanisms are not completely understood. In this review, we describe the acute and chronic epigenetic effects of physical activity and dietary changes. We propose exercise and nutrition as potential triggers of epigenetic signals, promoting the reshaping of transcriptional programmes with effects on CVD phenotypes. Finally, we highlight recent developments in epigenetic therapeutics with implications for primary and secondary CVD prevention

Translational opportunities of single-cell biology in atherosclerosis

The advent of single-cell biology opens a new chapter for understanding human biological processes and for diagnosing, monitoring, and treating disease. This revolution now reaches the field of cardiovascular disease (CVD). New technologies to interrogate CVD samples at single-cell resolution are allowing the identification of novel cell communities that are important in shaping disease development and direct towards new therapeutic strategies. These approaches have begun to revolutionize atherosclerosis pathology and redraw our understanding of disease development. This review discusses the state-of-the-art of single-cell analysis of atherosclerotic plaques, with a particular focus on human lesions, and presents the current resolution of cellular subpopulations and their heterogeneity and plasticity in relation to clinically relevant features. Opportunities and pitfalls of current technologies as well as the clinical impact of single-cell technologies in CVD patient care are highlighted, advocating for multidisciplinary and international collaborative efforts to join the cellular dots of CVD