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Background: Coronary microvascular dysfunction (CMD) is usually evaluated measuring coronary flow velocity reserve (CFVR). A more comprehensive analysis of CFVR including additional consideration of the associated logical companion‐CFVR, where hyperemic diastolic coronary flow velocity may act as surrogate, was applied in this study to elucidate the mechanism of CMD in psoriasis. Methods and results: Coronary flow velocity reserve was analysed using transthoracic echocardiographs of 127 psoriasis patients (age 36 ± 8 years; 104 males) and of 52 sex‐ and age‐matched healthy controls. CFVR determination was repeated in the patient subgroup (n = 78) receiving anti‐inflammatory therapy. Baseline and hyperemic microvascular resistance (MR) were calculated. CMD was defined as CFVR ≤ 2.5. Four endotypes of CMD were identified referring to concordant or discordant impairments of hyperemic flow or CFVR. We evaluated the companion‐CFVR, as derived from the quadratic mean of hyperemic and diastolic flow velocity at rest. Coronary flow parameters, including CFVR (p = 0.01), were different among the two endotypes having CFVR > 2.5. Specifically, all 11 (14%) patients with CFVR deterioration despite therapy, belonged to endotype 1, and had higher baseline and hyperemic MR (p < 0.0001, both). Interestingly, while CFVR was comparable in patients with worsened versus those with improved CFVR, the companion‐CFVR could discriminate by being lower in patients with worsened CFVR (p = 0.01). Conclusions: The reduced CFVR in psoriasis is driven by decreased companion‐CFVR, combined with increased hyperemic MR. Adoption of the mandatory companion‐CFVR enables a personalized characterization superior to that achieved by exclusive consideration of CFVR. [ABSTRACT FROM AUTHOR]

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. 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). 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). 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. Image 1 • This study analyzed the prognostic role of coronary flow reserve in psoriasis. • 153 psoriatic patients without cardiovascular disease were included. • Coronary microvascular dysfunction was present in 15% of patients. • Coronary flow reserve may be a prognostic marker for events-free survival. [ABSTRACT FROM AUTHOR]

HDL has long been considered as 'good cholesterol', beneficial to the whole body and in particular to cardio-vascular health. However, HDL is a complex particle that undergoes dynamic remodeling through interactions with various enzymes and tissue types throughout its life cycle. In this review, we explore the novel understanding of HDL as a multifaceted class of lipoprotein, with multiple subclasses of different size, molecular composition, receptor interactions, and functionality, in health and disease. Further, we report on emergent HDL based therapeutics tested in small and larger scale clinical trials and their mixed successes. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective, well-tolerated, and safe glucose-lowering compounds for patients with type 2 diabetes mellitus (T2DM). SGLT2i benefit encompasses protection from heart and kidney failure, independently of the presence of diabetes. In addition, SGLT2i consistently reduce the risk of hospitalization for heart failure and, although with some heterogeneity between specific members of the class, favourably affect the risk of cardiovascular outcomes. The molecular mechanisms underlying the cardiovascular favourable effect are not fully clarified. Studies testing the efficacy of SGLT2i in human cohorts and experimental models of atherosclerotic cardiovascular disease (ASCVD) have reported significant differences in circulating levels and composition of lipoprotein classes. In randomized clinical trials, small but significant increases in low-density lipoprotein cholesterol (LDL-C) levels have been observed, with a still undefined clinical significance; on the other hand, favourable (although modest) effects on high-density lipoprotein cholesterol (HDL-C) and triglycerides have been reported. At the molecular level, glycosuria may promote a starving-like state that ultimately leads to a metabolic improvement through the mobilization of fatty acids from the adipose tissue and their oxidation for the production of ketone bodies. This, however, may also fuel hepatic cholesterol synthesis, thus inhibiting atherogenic lipoprotein uptake from the liver. Long-term studies collecting detailed information on lipid-lowering therapies at baseline and during the trials with SGLT2i, as well as regularly monitoring lipid profiles are warranted to disentangle the potential implications of SGLT2i in modulating lipoprotein-mediated atherosclerotic cardiovascular risk. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and aims In patients with psoriasis, the chronic exposure to systemic inflammation can result in coronary microvascular dysfunction (CMD). In this self-controlled, prospective pilot study, we investigated whether a long-term treatment with TNF-α inhibitors effective against skin symptoms also improves coronary flow reserve in psoriasis patients (CFR). Methods We prospectively studied 37 consecutive psoriasis patients (31 male; age, 37.7 ± 8.5 years) without cardiovascular disease, before and after anti-TNF-α treatment. 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. A CFR ≤ 2.5 was considered a marker of CMD. Psoriasis was assessed by Psoriasis Area and Severity Index (PASI). High sensitive C-reactive protein (hs-CRP) and serum TNF-α were assessed. Results Overall, CFR increased from 2.2 ± 0.7 to 3.02 ± 0.8 ( p < 0.0001) after TNF-α inhibitors therapy. In patients with CMD, CFR increased from 1.88 ± 0.3 to 2.74 ± 0.5 ( p < 0.0001). In patients with normal CFR, CFR increased from 3.0 ± 0.5 to 3.7 ± 0.9 ( p = 0.08). CFR improvement after TNF-α inhibitors treatment was correlated with hs-CRP and TNF-α reduction ( p = 0.004 and p = 0.02, respectively), but not with change in PASI ( p = 0.5). Conclusions The present study demonstrates that TNF-α inhibitors treatment ameliorates CMD in patients with established psoriasis not responding to long-term conventional therapy. These findings suggest that a therapy specifically targeted against inflammation is able to positively affect coronary microvascular function. [ABSTRACT FROM AUTHOR]

BACKGROUND: Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss-independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1-dependent mechanism. METHODS AND RESULTS: Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin9-39 (10 [mu]g·kg(-1)·h(-1)). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB. CONCLUSIONS: RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1-mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity. [ABSTRACT FROM AUTHOR]

Background—Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss-independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1-dependent mechanism. Methods and Results—Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin9-39 (10 µg∙kg-1∙h-1). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDLmediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB. Conclusions-RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1-mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity. [ABSTRACT FROM AUTHOR]

The article presents a study on the inducement of oxidative stress and acceleration of endothelial dysfunction through the excision of the activated protein-1 transcription factor, JunD. It mentions the impairment of endothelium-dependent vasorelaxation in a JunD mice which showed an age-dependent decline in endothelial nitric oxide synthase activity and increase in mitochondrial superoxide formation. It also notes that the transcription factor offer protection from such dysfunction.

Background--Symptomatic primary hyperparathyroidism (PHPT) is associated with increased cardiovascular mortality. However, data on the association between asymptomatic PHPT and cardiovascular risk are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic PHPT of recent onset. Methods and Results--We studied 100 PHPT patients (80 women; age, 58± 12 years) without cardiovascular disease and 50 control subjects matched for age and sex. 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 was lower in PHPT patients than in control subjects (3.0±0.8 versus 3.8±0.7; PC0.0001) and was abnormal (=£2.5) in 27 patients (27%) compared with control subjects (4%; P=0.0008). CFR was inversely related to parathyroid hormone (PTH) levels (r= --0.3, P<0.004). In patients with CFR <2.5, PTH was higher (26.4 pmol/L [quartiles 1 and 3, 16 and 37 pmol/L] versus 18 [13-25] pmol/L; P<0.007), whereas calcium levels were similar (2.9±0.1 versus 2.8±0.3 mmol/L; P=0.2). In multivariable linear regression analysis, PTH, age, and heart rate were the only factors associated with CFR (P=0.04, P=0.01, and P=0.006, respectively). In multiple logistic regression analysis, only PTH increased the probability of CFR <2.5 (P=0.03). In all PHPT patients with CFR <2.5, parathyroidectomy normalized CFR (3.3±0.7 versus 2.1±0.5; P<0.0001). Conclusions--PHPT patients have coronary microvascular dysfunction that is completely restored after parathyroidec-tomy. PTH independently correlates with the coronary microvascular impairment, suggesting a crucial role of the hormone in explaining the increased cardiovascular risk in PHPT. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Our study aimed to evaluate the effects of psoriasis (Pso) on coronary microvascular function and whether there is a relationship between disease activity scores and coronary blood flow abnormalities. Methods: 56 young patients (pts) with Pso (42 M, aged 37±3 years) without clinical evidence of cardiovascular diseases, and 56 controls matched for age and gender were studied. Coronary flow velocity in the left anterior descending coronary artery was detected by transthoracic echocardiography at rest and during adenosine infusion. Coronary flow reserve (CFR) was the ratio of hyperaemic diastolic flow velocity (DFV) to resting DFV. A CFR≤2.5 was considered abnormal. Results: In pts with Pso, CFR was lower than in controls (3.2±0.9 vs. 3.7±0.7, p =0.02). CFR was abnormal (≤2.5) in 12 pts (22% vs. 0% controls, p <0.0001). Moreover, in pts with CFR≤2.5, Psoriasis Area Severity Index (PASI), a clinical score for Pso severity, was higher (11±6 vs. 7±3, p =0.006) compared to pts with CFR>2.5. At multivariable analysis PASI remained the only determinant of CFR≤2.5 (p =0.02). Conclusion: CFR in young pts with severe Pso without coronary disease is reduced suggesting a coronary microvascular dysfunction, independently related to the severity and extension of Pso. This early microvascular impairment might be hypothesized as the consequence of prolonged and sustained systemic inflammation and might explain the increased cardiovascular risk conferred by Pso. [Copyright &y& Elsevier]

Background: Circulating progenitor cells (PCs) may play a role in the pathogenesis of cardiac allograft vasculopathy, the leading cause of morbidity and mortality in heart transplantation (HTx). We assessed the relationship between circulating PCs and their incorporation into allografts and coronary microvascular function in HTx. Methods: PCs were quantified by flow cytometry on the basis of the surface expression of CD34, CD133, and kinase domain receptor (KDR) antigens. Biopsy specimens at 2 different times were examined. Immunohistochemistry for the stem cell marker c-Kit, endothelial PC (EPC) marker KDR, and CD34 was performed in serial sections in all specimens. Cells positive for each marker were counted in all specimen area sections, and the number obtained was corrected by area section. Coronary flow in the left anterior descending coronary artery was detected at rest and during intravenous adenosine by transthoracic echocardiography. Coronary flow reserve (CFR) was the ratio of hyperemic diastolic mean velocity (DMV)/resting DMV. Results: CFR was measured in 29 patients and was abnormal (CFR < 2) in 6 (Group A) and normal in 23 (Group B). CFR was lower in Group A (1.5 ± 0.1 vs 3.3 ± 0.8, p < 0.0001). CD34+KDR+, CD133+KDR+, and CD34+CD133+KDR+ cell counts were lower in Group A (p < 0.05). EPCs in biopsy sections tended to be lower in Group A (p = 0.06) and correlated to circulating CD133+KDR+ and CD34+CD133+KDR+ (p = 0.003 and p = 0.052, respectively). Conclusions: EPCs are decreased in the circulation and in the allograft in patients with microvasculopathy. Defective mobilization and engraftment of EPCs may be involved in the pathogenesis of cardiac allograft vasculopathy. [ABSTRACT FROM AUTHOR]

Background: Determination of coronary flow reserve (CFR) is increasingly being used in cardiac allograft vasculopathy (CAV). We aimed to identify determinants of CFR in heart transplantation (HT). Methods: CFR was measured by transthoracic echocardiography in 119 HT recipients (97 men, 22 women; 50 ± 12 years of age at HT and 8 ± 5 years post-HT). CFR was expressed as the ratio of hyperemic (adenosine infusion at a rate of 0.14 mg/kg) to basal diastolic flow velocity. Rejection scores (RS) on endomyocardial biopsy were calculated. Angiographic CAV was analyzed using a qualitative grading system. The coronary tree was divided into 17 traits and a CAV severity/diffusion index (SDI) was calculated for each patient, summing the scores assigned to all lesions. Results: Upon multivariate analysis, CFR was related to CAV (p = 0.001), interventricular septum thickness (p = 0.01), ischemic heart disease pre-HT (p = 0.02) and SDI and SDI/segment number (p < 0.0001 and p = 0.003, respectively). In patients without CAV, CFR was related only to RS for severe grades (p = 0.01). Conclusions: Left ventricular hypertrophy, CAV and its severity/diffusion independently contribute to reduced CFR. In patients without angiographic CAV, CFR was only independently related to RS. Because a high rejection burden is associated with increased risk of CAV, CFR reduction may be an early marker of CAV. Microvascular dysfunction may contribute to the late morbidity and mortality seen in HT. [Copyright &y& Elsevier]

Mechanical forces and the activation of the renin-angiotensin system (RAS) may alter the NO/O2•- balance, imparing endothelial nitric oxide (NO) availability. This study investigates the link between RAS and NO/O2•- balance in human aortic endothelial cells (HAEC) exposed to pulsatile stretch with and without ACE inhibitor quinaprilat or angiotensin II type 1 (AT1) receptor antagonist losartan. Pulsatile stretch increased Ang II levels and O2•- production, reducing NO release. RAS blockade with quinaprilat or losartan restored the balance between NO and O2•-. These results provide a molecular basis for understanding the vascular protective effects of ACE inhibition and AT1 receptor antagonism. [ABSTRACT FROM AUTHOR]

Aging is the major risk factor for the development of cardiovascular diseases, the leading cause of morbidity, mortality and disability in western countries. Mounting data suggest that cardiovascular structure and function change with time as result of an “aging process”, regarded as an independent process which accompanies aging, interwines and modulates superimposed traditional cardiovascular risk factors to determine the peculiar occurrence, presentations and prognosis of heart disease in the elderly. A whole body of data underlies the impairment of endothelial function due to oxidative stress as a crucial feature of the aging process acting on the cardiovascular system. Insights into molecular and cellular mechanisms of age-associated endothelial dysfunction may provide new strategies to treat age-related cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The vascular endothelium serves as a barrier between the intravascular and extravascular compartments. High-density lipoproteins (HDL) have two kinds of interactions with this barrier. First, bloodborne HDL must pass the endothelium to access extravascular tissues, for example the arterial wall or the brain, to mediate cholesterol efflux from macrophages and other cells or exert other functions. To complete reverse cholesterol transport, HDL must even pass the endothelium a second time to re-enter circulation via the lymphatics. Transendothelial HDL transport is a regulated process involving scavenger receptor SR-BI, endothelial lipase, and ATP binding cassette transporters A1 and G1. Second, HDL helps to maintain the integrity of the endothelial barrier by (i) promoting junction closure as well as (ii) repair by stimulating the proliferation and migration of endothelial cells and their progenitor cells, and by preventing (iii) loss of glycocalix, (iv) apoptosis, as well as (v) transmigration of inflammatory cells. Additional vasoprotective functions of HDL include (vi) the induction of nitric oxide (NO) production and (vii) the inhibition of reactive oxygen species (ROS) production. These vasoprotective functions are exerted by the interactions of HDL particles with SR-BI as well as specific agonists carried by HDL, notably sphingosine-1-phophate (S1P), with their specific cellular counterparts, e.g., S1P receptors. Various diseases modify the protein and lipid composition and thereby the endothelial functionality of HDL. Thorough understanding of the structure–function relationships underlying the multiple interactions of HDL with endothelial cells is expected to elucidate new targets and strategies for the treatment or prevention of various diseases. [ABSTRACT FROM AUTHOR]

Aims BACH1 is up-regulated in hypertrophic hearts, but its function in cardiac hypertrophy remains largely unknown. This research investigates the function and mechanisms of BACH1 in the regulation of cardiac hypertrophy. Methods and results Male cardiac-specific BACH1 knockout mice or cardiac-specific BACH1 transgenic (BACH1-Tg) mice and their respective wild-type littermates developed cardiac hypertrophy induced by angiotensin II (Ang II) or transverse aortic constriction (TAC). Cardiac-specific BACH1 knockout in mice protected the hearts against Ang II- and TAC-induced cardiac hypertrophy and fibrosis, and preserved cardiac function. Conversely, cardiac-specific BACH1 overexpression markedly exaggerated cardiac hypertrophy and fibrosis and reduced cardiac function in mice with Ang II- and TAC-induced hypertrophy. Mechanistically, BACH1 silencing attenuated Ang II- and norepinephrine-stimulated calcium/calmodulin-dependent protein kinase II (CaMKII) signalling, the expression of hypertrophic genes, and hypertrophic growth of cardiomyocytes. Ang II stimulation promoted the nuclear localization of BACH1, facilitated the recruitment of BACH1 to the Ang II type 1 receptor (AT1R) gene promoter, and then increased the expression of AT1R. Inhibition of BACH1 attenuated Ang II-stimulated AT1R expression, cytosolic Ca2+ levels, and CaMKII activation in cardiomyocytes, whereas overexpression of BACH1 led to the opposite effects. The increased expression of hypertrophic genes induced by BACH1 overexpression upon Ang II stimulation was suppressed by CaMKII inhibitor KN93. The AT1R antagonist, losartan, significantly attenuated BACH1-mediated CaMKII activation and cardiomyocyte hypertrophy under Ang II stimulation in vitro. Similarly, Ang II-induced myocardial pathological hypertrophy, cardiac fibrosis, and dysfunction in BACH1-Tg mice were blunted by treatment with losartan. Conclusion This study elucidates a novel important role of BACH1 in pathological cardiac hypertrophy by regulating the AT1R expression and the Ca2+/CaMKII pathway, and highlights potential therapeutic target in pathological cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Background and aims Acromegaly increases the risk of cardiovascular mortality. Data on the cardiovascular risk in asymptomatic acromegaly are limited. In particular, data on coronary microvascular abnormalities are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic acromegaly. Methods We studied 40 acromegalic patients (23 male, age 52 ± 11 years) without clinical evidence of cardiovascular disease, and 40 control subjects matched for age and sex. Coronary flow velocity in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperaemic to resting diastolic flow velocity. Results CFR was lower in patients than in controls (2.9 ± 0.8 vs . 3.7 ± 0.6, p  < 0.0001) and was abnormal (≤2.5) in 13 patients (32.5%) compared with any control subjects (0%) ( p  < 0.0001). CFR was inversely related to insulin-like growth factor 1 (IGF-1) levels (r = −0.5, p  < 0.004). In patients with CFR≤2.5, IGF-1 was higher (756 [381–898] μg/l versus 246 [186–484] μg/l, p  < 0.007) whereas growth hormone (GH) levels were similar (6.3 [2.8–13.7] μg/l versus 5 [2.8–8.9] μg/l, p  = 0.8). In multivariable linear regression analysis, IGF-1 was independently associated with CFR ( p  < 0.0001). In multiple logistic regression analysis, IGF-1 independently increased the probability of CFR≤2.5 ( p  = 0.009). In four patients with active disease (all with CFR<2.5), treatment with somatostatin analogues normalized CFR. However the other four patients with active disease were not responder. Conclusions Acromegalic patients have coronary microvascular dysfunction that may be restored by therapy with somatostatin analogues. IGF-1 independently correlates with the coronary microvascular impairment, suggesting the pivotal role of this hormone in explaining the increased cardiovascular risk in acromegaly. [ABSTRACT FROM AUTHOR]

Fibrotic changes in the myocardium and cardiac arrhythmias represent fatal complications in systemic sclerosis (SSc), however the underlying mechanisms remain elusive. Mice overexpressing transcription factor Fosl-2 (Fosl-2tg) represent animal model of SSc. Fosl-2tg mice showed interstitial cardiac fibrosis, disorganized connexin-43/40 in intercalated discs and deregulated expression of genes controlling conduction system, and developed higher heart rate (HR), prolonged QT intervals, arrhythmias with prevalence of premature ventricular contractions, ventricular tachycardias, II-degree atrio-ventricular blocks and reduced HR variability. Following stimulation with isoproterenol Fosl-2tg mice showed impaired HR response. In contrast to Fosl-2tg, immunodeficient Rag2−/−Fosl-2tg mice were protected from enhanced myocardial fibrosis and ECG abnormalities. Transcriptomics analysis demonstrated that Fosl-2-overexpression was responsible for profibrotic signature of cardiac fibroblasts, whereas inflammatory component in Fosl-2tg mice activated their fibrotic and arrhythmogenic phenotype. In human cardiac fibroblasts FOSL-2-overexpression enhanced myofibroblast signature under proinflammatory or profibrotic stimuli. These results demonstrate that under immunofibrotic conditions transcription factor Fosl-2 exaggerates myocardial fibrosis, arrhythmias and aberrant response to stress. The role of the transcription factor Fosl-2 in promoting myocardial fibrosis, arrhythmias and aberrant response to stress under immunofibrotic conditions is described using an in vivo mouse model and human cardiac fibroblasts. [ABSTRACT FROM AUTHOR]

Here, we review the highlights of cardiovascular basic science published in 2021 and early 2022 on behalf of the European Society of Cardiology Council for Basic Cardiovascular Science. We begin with non-coding RNAs which have emerged as central regulators cardiovascular biology, and then discuss how technological developments in single-cell 'omics are providing new insights into cardiovascular development, inflammation, and disease. We also review recent discoveries on the biology of extracellular vesicles in driving either protective or pathogenic responses. The Nobel Prize in Physiology or Medicine 2021 recognized the importance of the molecular basis of mechanosensing and here we review breakthroughs in cardiovascular sensing of mechanical force. We also summarize discoveries in the field of atherosclerosis including the role of clonal haematopoiesis of indeterminate potential, and new mechanisms of crosstalk between hyperglycaemia, lipid mediators, and inflammation. The past 12 months also witnessed major advances in the field of cardiac arrhythmia including new mechanisms of fibrillation. We also focus on inducible pluripotent stem cell technology which has demonstrated disease causality for several genetic polymorphisms in long-QT syndrome and aortic valve disease, paving the way for personalized medicine approaches. Finally, the cardiovascular community has continued to better understand COVID-19 with significant advancement in our knowledge of cardiovascular tropism, molecular markers, the mechanism of vaccine-induced thrombotic complications and new anti-viral therapies that protect the cardiovascular system. [ABSTRACT FROM AUTHOR]

Rationale: Perioperative myocardial ischemia is common in high-risk patients. The use of interventional revascularisation or even thrombolysis is limited in this patient subset due to exceedingly high bleeding risks. Blockade of voltage-gated sodium channels (VGSC) with lidocaine had been suggested to reduce infarct size and cardiomyocyte cell death in ischemia/reperfusion models. However, the impact of lidocaine on cardiac function during sustained ischemia still remains unclear. Methods: Sustained myocardial ischemia was induced by ligation of the left anterior descending artery in 12–16 weeks old male BALB/c mice. Subcutaneous lidocaine (30 mg/kg) was used to block VGSC. Cardiac function was quantified at baseline and at 72h by conventional and speckle-tracking based echocardiography to allow high-sensitivity in vivo phenotyping. Infarct size and cardiomyocyte cell death were assessed post mortem histologically and indirectly using troponin measurements. Results: Ischemia strongly impaired both, global systolic and diastolic function, which were partially rescued in lidocaine treated in mice. No differences regarding infarct size and cardiomyocyte cell death were observed. Mechanistically, and as shown with speckle-tracking analysis, lidocaine specifically improves residual contractility in the ischemic but not in the remote, non-ischemic myocardium. Conclusion: VGSC blockade with lidocaine rescues function of ischemic myocardium as a potential bridging to revascularisation in the setting of perioperative myocardial ischemia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Beyond its hemodynamic function, the heart also acts as a neuroendocrine and immunoregulatory organ. A dynamic communication between the heart and other organs takes place constantly to maintain cardiovascular homeostasis. The current understanding highlights the importance of the endocrine, immune, and nervous factors to fine-tune the crosstalk of the cardiovascular system with the entire body. Once disrupted, this complex interorgan communication may promote the onset and the progression of cardiovascular diseases. Thus, expanding our knowledge on how these factors influence the cardiovascular system can lead to novel therapeutic strategies to improve patient care. In the present paper, we review novel concepts on the role of endocrine, immune, and nervous factors in the modulation of microvascular coronary function. [ABSTRACT FROM AUTHOR]

Aims: Perivascular fat attenuation index (FAI) has emerged as a novel coronary computed tomography angiography (CCTA)–based biomarker predicting cardiovascular outcomes by capturing early coronary inflammation. It is currently unknown whether FAI adds prognostic value beyond that provided by single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) and CCTA findings including coronary artery calcium scoring (CACS). Methods and results: A total of 492 patients (mean age 62.5 ± 10.8 years) underwent clinically indicated multimodality CCTA and electrocardiography (ECG)-gated 99mTc-tetrofosmin SPECT-MPI between May 2005 and December 2008 at our institution, and follow-up data on major adverse cardiovascular events (MACE) was obtained for 314 patients. FAI was obtained from CCTA images and was measured around the right coronary artery (FAI[RCA]), the left anterior descending artery (FAI[LAD]), and the left main coronary artery (FAI[LMCA]). During a median follow-up of 2.7 years, FAI[RCA] > − 70.1 was associated with an increased rate of MACE (log rank p = 0.049), while no such association was seen for FAI[LAD] or FAI[LMCA] (p = NS). A multivariate Cox regression model accounting for cardiovascular risk factors, CCTA and SPECT-MPI findings identified FAI[RCA] as an independent predictor of MACE (HR 2.733, 95% CI: 1.220–6.123, p = 0.015). However, FAI[RCA] was no longer a significant predictor of MACE after adding CACS (p = 0.279). A first-order interaction term consisting of sex and FAI[RCA] was significant in both models (HR 2.119, 95% CI: 1.218–3.686, p = 0.008; and HR 2.071, 95% CI: 1.111–3.861, p = 0.022). Conclusion: FAI does not add incremental prognostic value beyond multimodality MPI/CCTA findings including CACS. The diagnostic value of FAI[RCA] is significantly biased by sex. [ABSTRACT FROM AUTHOR]

Early revascularization -the gold standard therapy for ischemic stroke- is often withheld in the elderly population due to high risk of complications. Thus, safe and effective preventive and therapeutic options are needed. The plant-derived omega-3-fatty-acid alpha-linolenic-acid (ALA) has emerged as a novel cardiovascular-protective agent. As of yet, little is known about its potential therapeutic effects on stroke. We hereby aimed to investigate the impact of a clinically relevant long-term dietary intervention with ALA on stroke outcome. Six month-old C57BL/6 wildtype males were either fed an ALA-rich (high ALA) or a control diet (low ALA) for 12 months. At 18 months, brain ischemia/reperfusion was induced by transient middle cerebral artery occlusion (tMCAO). Stroke size and neurological function were assessed. Functional blood-brain-barrier-(BBB) permeability and protein expression were assessed by immunohistochemistry. Baseline inflammatory markers were measured at 18 months. High ALA-fed animals displayed decreased circulating TNF-α levels and Neutrophil-to-Lymphocyte Ratios at 18 months. Stroke size and neurological dysfunction were significantly reduced in high ALA-fed animals. Coherently to the reduced stroke size, functional BBB integrity and occludin endothelial expression were maintained by high ALA supplementation. Additionally, ALA reduced endothelial activation and thus recruitment and activation of macrophages and resident microglia. Finally, high ALA diet reduced the expression of BBB-degrading and neurotoxic MMP-3 and MMP-9. We demonstrate the beneficial effects of a clinically relevant and feasible dietary intervention with a safe and readily available compound in the setting of stroke. The protective effects observed with ALA supplementation may relate to blunting of inflammation and might pave the way for novel stroke treatments. [Display omitted] • Long-term alpha-linolenic acid dietary supplementation improves stroke outcome. • Dietary alpha-linolenic acid reduces post-stroke blood-brain barrier impairment. • Alpha-linolenic acid reduces cerebral endothelial activation and inflammation. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic is an unprecedented healthcare emergency causing mortality and illness across the world. Although primarily affecting the lungs, the SARS-CoV-2 virus also affects the cardiovascular system. In addition to cardiac effects, e.g. myocarditis, arrhythmias, and myocardial damage, the vasculature is affected in COVID-19, both directly by the SARS-CoV-2 virus, and indirectly as a result of a systemic inflammatory cytokine storm. This includes the role of the vascular endothelium in the recruitment of inflammatory leucocytes where they contribute to tissue damage and cytokine release, which are key drivers of acute respiratory distress syndrome (ARDS), in disseminated intravascular coagulation, and cardiovascular complications in COVID-19. There is also evidence linking endothelial cells (ECs) to SARS-CoV-2 infection including: (i) the expression and function of its receptor angiotensin-converting enzyme 2 (ACE2) in the vasculature; (ii) the prevalence of a Kawasaki disease-like syndrome (vasculitis) in COVID-19; and (iii) evidence of EC infection with SARS-CoV-2 in patients with fatal COVID-19. Here, the Working Group on Atherosclerosis and Vascular Biology together with the Council of Basic Cardiovascular Science of the European Society of Cardiology provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address. We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients. A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications. [ABSTRACT FROM AUTHOR]

Amongst patients with coronary artery disease (CAD), women experience relatively worse outcomes as compared to men. Evidence to date has failed to explore unique female imaging targets as major determinants of cardiovascular risk. We sought to assess the prognostic value of epicardial (EFV) and intrathoracic fat volume (IFV) quantification in women and men with suspected and known CAD. Intrathoracic fat volume and EFV were calculated from non-contrast CT and analyzed in a propensity-matched cohort of 190 patients (95 women, mean age 62.5 ± 11.3 years) undergoing myocardial perfusion imaging (MPI) and coronary computed tomography angiography (CCTA) for evaluation of CAD. IFV and EFV were significantly lower in women as compared to men (198.2 ± 78.4 vs 293.2 ± 114.7 cm3 and 105.6 ± 48.9 vs 135.8 ± 60.9 cm3, p < 0.001) and showed a strong association with coronary artery calcium score (CACS) and obstructive CAD in women (p < 0.05), but not in men. Fat volumes were not related to abnormal MPI in either population (p = NS). During a median follow-up of 2.8 years, high IFV was associated with reduced event free survival (log rank = 0.019 vs low IFV) in women, but not in men. Accordingly, a multivariate Cox regression model adjusted for cardiovascular risk factors, CACS, CCTA, and MPI findings selected IFV as a significant predictor of major adverse cardiovascular events (MACE) in women (HR 1.32, 95%CI 1.18–1.55, p = 0.001). Quantification of IFV provides incremental prognostic value for MACE in women, beyond that provided by traditional risk factors and imaging findings. • IFV provides incremental prognostic value for MACE in women. • IFV values are significantly higher in women who experience adverse outcome. • EFV and IFV are associated with CACS and obstructive CAD in women and men. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is considered the gold standard in bariatric surgery, achieving durable long-term weight loss with improvement of obesity-related comorbidities. Lately, the laparoscopic mini gastric bypass (LMGB) has gained worldwide popularity with similar results to LRYGB in terms of weight loss and comorbidity resolution. However, there is a lack of randomized controlled trials (RCT) comparing LMGB and LRYGB. This article describes the design and protocol of a randomized controlled trial comparing the outcomes of these two bariatric procedures.Methods/design: The trial is designed as a single center, randomized, patient and observer blinded trial. The relevant ethics committee has approved the trial protocol. To demonstrate that LMGB is not inferior to LRYGB in terms of excess weight loss (EWL) the study is conducted as a non-inferiority trial with the sample-size calculations performed accordingly. EWL 12 months after surgery is the primary endpoint, whereas 3-year EWL, morbidity, mortality, remission of obesity related comorbidities, quality of life (QOL) and hormonal and lipid profile changes are secondary endpoints. Eighty patients, 18 years or older and with a body mass index (BMI) between 35 and 50 kg/m2 who meet the Swiss guidelines for the surgical treatment of morbid obesity will be randomized. The endpoints and baseline measurements will be assessed pre-surgery, peri-surgery and post-surgery (fixed follow up measurements are at discharge and at the time points 6 weeks and 12 and 36 months postoperatively).Discussion: With its 3-year follow up time, this RCT will provide important data on the impact of LMGB and LRYGB on EWL, remission of comorbidities, QOL and hormonal and lipid profile changes.Trial Registration: ClinicalTrials.gov, NCT02601092 . Registered on 28 September 2015. [ABSTRACT FROM AUTHOR]

Background and aims High-density lipoprotein cholesterol (HDL-C) is inversely related to cardiovascular risk. HDL-C raising ester transfer protein (CETP) inhibitors, are novel therapeutics. We studied the effects of CETP inhibitors anacetrapib and evacetrapib on triglycerides, cholesterol and lipoproteins, cholesterol efflux, paraoxonase activity (PON-1), reactive oxygen species (ROS), and endothelial function in E3L and E3L.CETP mice. Methods Triglycerides and cholesterol were measured at weeks 5, 14 and 21 in E3L.CETP mice on high cholesterol diet and treated with anacetrapib (3 mg/kg/day), evacetrapib (3 mg/kg/day) or placebo. Cholesterol efflux was assessed ex-vivo in mice treated with CETP inhibitors for 3 weeks on a normal chow diet. Endothelial function was analyzed at week 21 in isolated aortic rings, and serum lipoproteins assessed by fast-performance liquid chromatography. Results Anacetrapib and evacetrapib increased HDL-C levels (5- and 3.4-fold, resp.) and reduced triglycerides (−39% vs. placebo, p = 0.0174). Total cholesterol levels were reduced only in anacetrapib-treated mice (−32%, p = 0.0386). Cholesterol efflux and PON-1 activity (+45% and +35% vs. control, p < 0.005, resp.) were increased, while aortic ROS production was reduced with evacetrapib (−49% vs. control, p = 0.020). Anacetrapib, but not evacetrapib, impaired endothelium dependent vasorelaxation ( p < 0.05). In contrast, no such effects were observed in E3L mice for all parameters tested. Conclusions Notwithstanding a marked rise in HDL-C, evacetrapib did not improve endothelial function, while anacetrapib impaired it, suggesting that CETP inhibition does not provide vascular protection. Anacetrapib exerts unfavorable endothelial effects beyond CETP inhibition, which may explain the neutral results of large clinical trials in spite of increased HDL-C. [ABSTRACT FROM AUTHOR]