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Background/Objectives: The identification of coronary artery disease (CAD) high-risk individuals is a major clinical need for timely diagnosis and intervention. Many different polygenic scores (PGSs) for CAD risk are available today to estimate the genetic risk. It is necessary to carefully choose the score to use, in particular for studies on populations, which are not adequately represented in the large datasets of European biobanks, such as the Italian one. This work aimed to analyze which PGS had the best performance within the Italian population. Methods: We used two Italian independent cohorts: the EPICOR case–control study (576 individuals) and the Atherosclerosis, Thrombosis, and Vascular Biology (ATVB) Italian study (3359 individuals). We evaluated 266 PGS for cardiovascular disease risk from the PGS Catalog, selecting 51 for CAD. Results: Distributions between patients and controls were significantly different for 49 scores (p-value < 0.01). Only five PGS have been trained and tested for the European population specifically. PGS003727 demonstrated to be the most accurate when evaluated independently (EPICOR AUC = 0.68; ATVB AUC = 0.80). Taking into account the conventional CAD risk factors further enhanced the performance of the model, particularly in the ATVB study (p-value = 0.0003). Conclusions: European CAD PGS could have different risk estimates in peculiar populations, such as the Italian one, as well as in various geographical macro areas. Therefore, further evaluation is recommended for clinical applicability. [ABSTRACT FROM AUTHOR]

Aim: To compare the efficacy of polymer-free drug-eluting stents (PF-DES) versus other stents in diabetic patients with coronary artery disease undergoing percutaneous coronary interventions. Materials & methods: A systematic review and meta-analysis were performed to identify pertinent randomized controlled trials. The primary end point was the occurrence of target lesion failure. Results: Eight randomized controlled trials were included for a total of 4854 subjects. The PF-DES group experienced a trend in favor of a lower rate of target lesion failure (Incidence rate ratio = 0.91; p = 0.11) and a significantly lower rate of cardiac mortality, as compared with the control group (Incidence rate ratio = 0.82; p = 0.04). However, statistical significance was lost if bare-metal stent patients were excluded and a trend in favor of the PF-DES strategy was reported only for cardiac mortality. Conclusion: PF-DES could be a valuable strategy in diabetic patients with coronary artery disease undergoing percutaneous coronary interventions. Plain Language Summary What is this summary about? Polymer-free drug-eluting stents (PF-DES) are a novel type of coronary stent with potential benefits in terms of chronic coronary inflammation. This is a comprehensive, up-to-date, systematic review and meta-analysis of randomized controlled trials comparing the efficacy of PF-DES versus other stents in diabetic patients with coronary artery disease undergoing percutaneous coronary intervention. What were the results? Patients treated with PF-DES experienced similar prognosis, with a trend toward better outcomes, as compared with conventional stents. What do the results mean? PF-DES could represent a novel and effective strategy for treating coronary artery disease in diabetic patients. Tweetable Abstract Polymer-free drug-eluting stents could be a valuable strategy in diabetic patients with coronary artery disease undergoing percutaneous coronary intervention. Graphical Abstract Graphical summary of the study. IRR: Incidence rate ratio. Article highlights Background Polymer-free drug-eluting stents (PF-DES) allow for antiproliferative agent release without the presence of polymers, which leads to chronic coronary inflammation and delayed endothelialization of stent struts. Whether PF-DES could provide prognostic benefits as compared with other types of stents in diabetic populations undergoing percutaneous coronary intervention (PCI) is controversial to date. Methods This study was a comprehensive, up-to-date, systematic review and meta-analysis aimed to compare the efficacy of PF-DES versus other stents in diabetic patients undergoing PCI. Results A total of eight randomized controlled trials for a total of 4854 subjects were included in the analysis. There was a trend in favor of PF-DES in the primary end point of target lesion failure (IRR = 0.91, [95% CI: 0.81–1.02]; p = 0.11). PF-DES group experienced a significantly lower rate of cardiac mortality, as compared with the control group (IRR = 0.82, [95% CI: 0.68–0.99]; p = 0.04). Conclusion PF-DES could be a valuable strategy in diabetic patients with coronary artery disease (CAD) undergoing PCI. The pathophysiology underlying these results remains to be addressed. Future larger randomized controlled trials are warranted to address DM subpopulations that could gain more benefit from PF-DES revascularization. [ABSTRACT FROM AUTHOR]

Context Coronary collateral (CC) vessel development appears to be protective with regard to adverse cardiovascular events and survival in patients with coronary chronic total occlusion (CTO). The influence of type 2 diabetes mellitus (T2DM) on CC growth has been controversial. In particular, the role of diabetic microvascular complications (DMC) in determining coronary collateralization has not been elucidated. Objective To investigate whether patients with DMC presented differences in CC vessel presence and grading as compared with patients without DMC. Methods We conducted a single-center observational study, including consecutive T2DM patients, without previous cardiovascular history, undergoing a clinically indicated coronary angiography for chronic coronary syndrome (CCS) and angiographic evidence of at least one CTO. Patients were subdivided into 2 study groups according to the presence/absence of at least one DMC (neuropathy, nephropathy, or retinopathy). The presence and grading of angiographically visible CC development from the patent vessels to the occluded artery were assessed using the Rentrop classification. Results We enrolled 157 patients (mean age 68.6 ± 9.8 years; 120 [76.4%] men). Patients with DMC (75 [47.8%]) had a higher prevalence of CC (69 [92.0%] vs 62 [75.6%], P =.006) and high-grade CC (55 [73.3%] vs 39 [47.6%], P =.001) compared with those without, and we found a positive association between the number of DMC in each patient and the prevalence of high-grade CC. Conclusion Among T2DM patients with coronary CTO, the presence of DMC was associated with a high CC development. [ABSTRACT FROM AUTHOR]

Increasing evidence supports the direct healing effects of forests, partly attributed to the exposure to plant-emitted monoterpenes available in the forest atmosphere. The potential benefits on respiratory functions from inhaling monoterpenes have gained attention, especially due to the global rise in respiratory diseases. This study involved 42 asthmatic adolescents attending a summer rehabilitation camp at an Altitude Pediatric Asthma Center within a densely forested area in the Eastern Italian Alps. Volatile organic compound measurements indicated a pristine atmosphere, enabling the modeling of continuous hourly monoterpene concentration. The monoterpene concentration exposure and total inhaled dose were assessed over a 14-day stay, during which spirometry, lung oscillometry, and fractional exhaled nitric oxide were measured. Statistically significant correlations were observed between modifications in lung function parameters among asthmatic adolescents and monoterpene exposure. These findings suggest a potential localized airway effect that is specific to monoterpenes. This pilot cohort study might pave the way for further investigations into the therapeutic effects of forest monoterpenes on lung function tests, asthma, and the broader healing potential of forest environments. [ABSTRACT FROM AUTHOR]

Despite evidence-based therapies, patients presenting with atherosclerosis involving more than one vascular bed, such as those with peripheral artery disease (PAD) and concomitant coronary artery disease (CAD), constitute a particularly vulnerable group characterized by enhanced residual long-term risk for major adverse cardiac events (MACE), as well as major adverse limb events (MALE). The latter are progressively emerging as a difficult outcome to target, being correlated with increased mortality. Antithrombotic therapy is the mainstay of secondary prevention in both patients with PAD or CAD; however, the optimal intensity of such therapy is still a topic of debate, particularly in the post-acute and long-term setting. Recent well-powered randomized clinical trials (RCTs) have provided data in favor of a more intense antithrombotic therapy, such as prolonged dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor or a therapy with aspirin combined with an anticoagulant drug. Both approaches increase bleeding and selection of patients is a key issue. The aim of this review is, therefore, to discuss and summarize the most up-to-date available evidence for different strategies of anti-thrombotic therapies in patients with chronic PAD and CAD, particularly focusing on studies enrolling patients with both types of atherosclerotic disease and comparing a higher- versus a lower-intensity antithrombotic strategy. The final objective is to identify the optimal tailored approach in this setting, to achieve the greatest cardiovascular benefit and improve precision medicine. [ABSTRACT FROM AUTHOR]

Sudden cardiac death represents the leading cause of death worldwide; although the majority of sudden deaths occur in an elderly population with coronary artery disease, some occur in young and otherwise healthy individuals, as is the case of cardiomyopathies. The aim of the present review is to provide a stepwise hierarchical approach for the global sudden death risk estimation in primary cardiomyopathies. Each individual risk factor is analyzed for its contribution to the overall risk of sudden death for each specific cardiomyopathy as well as across all primary myocardial diseases. This stepwise hierarchical and personalized approach starts from the clinical evaluation, subsequently passes through the role of electrocardiographic monitoring and multimodality imaging, and finally concludes with genetic evaluation and electro-anatomical mapping. In fact, the sudden cardiac death risk assessment in cardiomyopathies depends on a multiparametric approach. Moreover, current indications for ventricular arrhythmia ablation and defibrillator implantation are discussed. [ABSTRACT FROM AUTHOR]

The crucial role of dyslipidaemia, especially hypercholesterolemia, in the development of atherosclerosis-related cardiovascular diseases has been extensively documented in genetic, pathologic, observational and intervention studies. The European guidelines for dyslipidaemia management include the possible use of lipid-lowering nutraceuticals to support a relatively large number of natural compounds. In this context, we have conducted a study to investigate whether dietary supplementation with a functional nutraceutical beverage, containing a standardized polyphenolic fraction from fruit, red yeast rice, phytosterols, and berberine complexed with β-cyclodextrin, could positively affect serum lipid concentration in 14 subjects with hypercholesterolemia. After 12 weeks of treatment, dietary supplementation with this nutraceutical combination was associated with significant improvements in total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B, compared to baseline. Compliance was excellent and no adverse effects were reported. In conclusion, this study demonstrates that 100 mL of a functional beverage containing lipid-lowering nutraceuticals safely leads to significant improvements in serum lipids in subjects with moderate hypercholesterolemia. Future research is needed to unravel the role that the polyphenols contained in fruit extracts play in the reduction of cholesterolemia and in cardiovascular disease prevention. [ABSTRACT FROM AUTHOR]

Background: Patients with type 2 diabetes mellitus (T2DM) are considered as a homogeneous cohort of patients. However, the specific role of diabetic microvascular complications (DMC), in determining the features of coronary plaques is poorly known. We investigated whether the presence of DMC may identify a different phenotype of patients associated to specific clinical, angiographic, optical coherence tomography (OCT) features and different prognosis. Methods: We prospectively enrolled consecutive T2DM patients with obstructive coronary artery disease (CAD) at their first coronary event. Patients were stratified according to the presence or absence of DMC, including diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. OCT assessment of the culprit vessel was performed in a subgroup of patients. The incidence of major adverse cardiac events (MACEs) was assessed at follow-up. Results: We enrolled 320 T2DM patients (mean age 70.3 ± 8.8 years; 234 [73.1%] men, 40% acute coronary syndrome, 60% chronic coronary syndrome). Patients with DMC (172 [53.75%]) presented a different clinical and biochemical profile and, of importance, a higher prevalence of multivessel CAD (109 [63.4%] vs. 68 [45.9%], p = 0.002). At OCT analysis, DMC was associated to a higher prevalence of large calcifications and healed plaques and to a lower prevalence of lipid plaques. Finally, MACEs rate was significantly higher (25 [14.5%] vs. 12 [8.1%], p = 0.007) in DMC patients, mainly driven by a higher rate of planned revascularizations, and DMC predicted the occurrence of MACEs (mean follow-up 33.4 ± 15.6 months). Conclusions: The presence of DMC identifies a distinct diabetic population with more severe CAD but with a more stable pattern of coronary atherosclerosis. [ABSTRACT FROM AUTHOR]

Introduction: Studies on effectiveness of cardiac rehabilitation (CR) in elderly cardiovascular disease patients are rare, and it is unknown, which patients benefit most. We aimed to identify predictors for 1-year outcomes of cardiorespiratory fitness and CV risk factor (CVRF) control in patients after completing CR programs offered across seven European countries. Methods: Cardiovascular disease patients with minimal age 65 years who participated in comprehensive CR were included in this observational study. Peak oxygen uptake (VO2), body mass index (BMI), resting systolic blood pressure (BPsys), and low-density lipoprotein-cholesterol (LDL-C) were assessed before CR (T0), at termination of CR (T1), and 12 months after start of CR (T2). Predictors for changes were identified by multivariate regression models. Results: Data was available from 1241 out of 1633 EU-CaRE patients. The strongest predictor for improvement in peak VO2 was open chest surgery, with a nearly four-fold increase in surgery compared to non-surgery patients. In patients after surgery, age, female sex, physical inactivity and time from index event to T0 were negative predictors for improvement in peak VO2. In patients without surgery, previous acute coronary syndrome and higher exercise capacity at T0 were the only negative predictors. Neither number of attended training sessions nor duration of CR were significantly associated with change in peak VO2. Non-surgery patients were more likely to achieve risk factor targets (BPsys, LDL-C, BMI) than surgery patients. Conclusions: In a previously understudied population of elderly CR patients, time between index event and start of CR in surgery and disease severity in non-surgery patients were the most important predictors for long-term improvement of peak VO2. Non-surgery patients had better CVRF control. [ABSTRACT FROM AUTHOR]

Objective: We aimed 1) to test the applicability of the previously suggested prognostic value of CPET to elderly cardiac rehabilitation patients and 2) to explore the underlying mechanism of the greater improvement in exercise capacity (peak oxygen consumption, VO2) after CR in surgical compared to non-surgical cardiac patients. Methods: Elderly patients (≥65 years) commencing CR after coronary artery bypass grafting, surgical valve replacement (surgery-group), percutaneous coronary intervention, percutaneous valve replacement or without revascularisation (non-surgery group) were included in the prospective multi-center EU-CaRE study. CPETs were performed at start of CR, end of CR and 1-year-follow-up. Logistic models and receiver operating characteristics were used to determine prognostic values of CPET parameters for major adverse cardiac events (MACE). Linear models were performed for change in peak VO2 (start to follow-up) and parameters accounting for the difference between surgery and non-surgery patients were sought. Results: 1421 out of 1633 EU-CaRE patients performed a valid CPET at start of CR (age 73±5.4, 81% male). No CPET parameter further improved the receiver operation characteristics significantly beyond the model with only clinical parameters. The higher improvement in peak VO2 (25% vs. 7%) in the surgical group disappeared when adjusted for changes in peak tidal volume and haemoglobin. Conclusion: CPET did not improve the prediction of MACE in elderly CR patients. The higher improvement of exercise capacity in surgery patients was mainly driven by restoration of haemoglobin levels and improvement in respiratory function after sternotomy. Trial registration: Netherlands Trial Register, Trial NL5166. [ABSTRACT FROM AUTHOR]

To reconstruct the phenotypical and clinical implications of the Italian genetic structure, we thoroughly analyzed a whole‐exome sequencing data set comprised of 1686 healthy Italian individuals. We found six previously unreported variants with remarkable frequency differences between Northern and Southern Italy in the HERC2, OR52R1, ADH1B, and THBS4 genes. We reported 36 clinically relevant variants (submitted as pathogenic, risk factors, or drug response in ClinVar) with significant frequency differences between Italy and Europe. We then explored putatively pathogenic variants in the Italian exome. On average, our Italian individuals carried 16.6 protein‐truncating variants (PTVs), with 2.5% of the population having a PTV in one of the 59 American College of Medical Genetics (ACMG) actionable genes. Lastly, we looked for PTVs that are likely to cause Mendelian diseases. We found four heterozygous PTVs in haploinsufficient genes (KAT6A, PTCH1, and STXBP1) and three homozygous PTVs in genes causing recessive diseases (DPYD, FLG, and PYGM). Comparing frequencies from our data set to other public databases, like gnomAD, we showed the importance of population‐specific databases for a more accurate assessment of variant pathogenicity. For this reason, we made aggregated frequencies from our data set publicly available as a tool for both clinicians and researchers (http://nigdb.cineca.it; NIG‐ExIT). [ABSTRACT FROM AUTHOR]

Objectives: Guidelines for exercise intensity prescription in Cardiac Rehabilitation (CR) are inconsistent and have recently been discussed controversially. We aimed (1) to compare training intensities between European CR centres and (2) to assess associations between training intensity and improvement in peak oxygen consumption (V˙ O2) in elderly CR patients. Methods: Peak V˙ O2, heart rate and work rate (WR) at the first and second ventilatory thresholds were measured at start of CR. Training heart rate was measured during three sessions spread over the CR. Multivariate models were used to compare training characteristics between centres and to assess the effect of training intensity on change in peak V˙ O2. Results: Training intensity was measured in 1011 out of 1633 EU-CaRE patients in 7 of 8 centers and the first and secondary ventilatory threshold were identified in 1166 and 817 patients, respectively. The first and second ventilatory threshold were found at 44% (SD 16%) and 78% (SD 9%) of peak WR and 78% (SD 9%) and 89% (SD 5%) of peak heart rate, respectively. Training intensity and session duration varied significantly between centres but change in peak V˙ O2 over CR did not. Training above the first individual threshold (β 0.62, 95% confidence interval [0.25–1.02]) and increase in training volume per hour (β 0.06, 95%CI [0.01–0.12]) were associated with a higher change in peak V˙ O2. Conclusion: While training intensity and volume varied greatly amongst current European CR programs, changes in peak V˙ O2 were similar and the effect of training characteristics on these changes were small. [ABSTRACT FROM AUTHOR]

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10−11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10−43), alkaline phosphatase (-0.025 SD, 1.2*10−37), total cholesterol (-0.030 SD, p = 1.9*10−36) and LDL cholesterol (-0.027 SD, p = 5.1*10−30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis. Author summary: Cirrhosis is a leading cause of death worldwide. However, the genetic underpinnings of cirrhosis remain poorly understood. In this study, we analyze twelve thousand individuals with cirrhosis and identify a common missense variant in a gene called MARC1 that protects against cirrhosis. Carriers of this missense variant also have lower blood cholesterol levels, lower liver enzyme levels and reduced liver fat. We identify an additional two low-frequency coding variants in MARC1 that are also associated with lower cholesterol levels, lower liver enzyme levels and protection from cirrhosis. Finally, we identify an individual homozygous for a predicted loss-of-function variant in MARC1 who exhibits very low blood LDL cholesterol levels. These genetic findings suggest that MARC1 deficiency may lower blood cholesterol levels and protect against cirrhosis, pointing to MARC1 as a potential therapeutic target for liver disease. [ABSTRACT FROM AUTHOR]

Background: The prevalence of patients with concomitant cardiovascular disease and diabetes mellitus (DM) is increasing rapidly. We aimed to compare the effectiveness of current cardiac rehabilitation (CR) programs across seven European countries between elderly cardiac patients with and without DM. Methods: 1633 acute and chronic coronary artery disease (CAD) patients and patients after valve intervention with an age 65 or above who participated in comprehensive CR (3 weeks to 3 months, depending on centre) were included. Peak oxygen uptake (VO2 peak), body mass index, resting systolic blood pressure, low-density lipoprotein-cholesterol (LDL-C), and glycated haemoglobin (HbA1c) were assessed before start of CR, at termination of CR (variable time point), and 12 months after start of CR, with no intervention after CR. Baseline values and changes from baseline to 12-month follow-up were compared between patients with and without DM using mixed models, and mortality and hospitalisation rates using logistic regression. Results: 430 (26.3%) patients had DM. Patients with DM had more body fat, lower educational level, more comorbidities, cardiovascular risk factors, and more advanced CAD. Both groups increased their VO2 peak over the study period but with a significantly lower improvement from baseline to follow-up in patients with DM. In the DM group, change in HbA1c was associated with weight change but not with change in absolute VO2 peak. 12-month cardiac mortality was higher in patients with DM. Conclusions: While immediate improvements in VO2 peak after CR in elderly patients with and without DM were similar, 12-month maintenance of this improvement was inferior in patients with DM, possibly related to disease progression. Glycemic control was less favourable in diabetic patients needing insulin in the short- and long-term. Since glycemic control was only related to weight loss but not to increase in exercise capacity, this highlights the importance of weight loss in obese DM patients during CR. Trial registration NTR5306 at trialregister.nl; trial registered 07/16/2015; https://www.trialregister.nl/trial/5166 [ABSTRACT FROM AUTHOR]

A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (-0.09 SD, P = 3.4 × 10-17), Ile195Thr (-0.15 SD, P = 1.0 × 10-9), Ile482Val (-0.019 SD, P = 1.6 × 10-5), and rs72927479 (-0.035 SD, P = 2.6 × 10-12). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 × 10-13). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; P = 0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes. [ABSTRACT FROM AUTHOR]

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease. [ABSTRACT FROM AUTHOR]

Aims To study the relation between visit-to-visit variability of blood pressure (BP) and cardiovascular risk in patients with stable coronary heart disease. Methods and results In 15 828 patients from the STABILITY trial (darapladib vs. placebo in patients with established coronary heart disease), BP variability was assessed by the standard deviation (SD) of systolic BP, the SD of diastolic BP, maximum BP and minimum BP, from 5 measurements (baseline and months 1, 3, 6, and 12) during the first year after randomisation. Mean (SD) average BP during the first year of study was 131.0 (13.7) mmHg over 78.3 (8.3) mmHg. Mean (SD) of the visit-to-visit SD was 9.8 (4.8) mmHg for systolic and 6.3 (3.0)mmHg for diastolic BP. During the subsequent median follow-up of 2.6 years, 1010 patients met the primary endpoint, a composite of time to cardiovascular death, myocardial infarction, or stroke. In Cox regression models adjusted for average BP during first year of study, baseline vascular disease, treatment, renal function and cardiovascular risk factors, the primary endpoint was associated with SD of systolic BP (hazard ratio for highest vs. lowest tertile, 1.30, 95% CI 1.10-1.53, P = 0.007), and with SD of diastolic BP (hazard ratio for highest vs. lowest tertile, 1.38, 95% CI 1.18-1.62, P < 0.001). Peaks and troughs in BP were also independently associated with adverse events. Conclusion In patients with stable coronary heart disease, higher visit-to-visit variabilities of both systolic and diastolic BP are strong predictors of increased risk of cardiovascular events, independently of mean BP. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) is frequently found at the time of diagnosis of pulmonary embolism (PE). An incomplete resolution of PE can lead to chronic thromboembolic pulmonary hypertension (CTPH). Transthoracic echocardiogram (TTE) is the first step to diagnose an abnormality of the pulmonary vasculature. Based on computed tomography (CT), the Qanadli vascular obstruction index has been extensively used to assess acute PE. Objectives: Our aim was to ascertain whether at the time of diagnosis of an acute PE episode TTE variables and a Qanadli CT index score may be associated with CTPH 2 years later. Method: Patients with PE were prospectively enrolled. TTE was performed and the Qanadli CT obstruction index was calculated on admission to the hospital, while only TTE was repeated at the 2-year follow-up. The NYHA (New York Heart Association) functional classification was evaluated. Correlation analyses were performed. Results: Twenty patients (11 males, median age 69.5 years) were considered for the study. There was no significant correlation between TTE parameters and the Qanadli CT obstruction index. A significant distribution (χ² = 5.69, p = 0.017) was found in the analysis among patients with CTPH at 24 months and the Qanadli CT index, categorized by a receiver operating characteristic curve cutoff value of 42.5%. Additionally, a significant distribution (χ² = 4.09, p = 0.043) was found in the analysis among patients with CTPH at 24 months and right ventricular systolic pressure on admission, categorized as PH (>31 mm Hg). Conclusion: Our study demonstrates that in patients with acute PE there is no relationship between the Qanadli CT obstruction index and TTE parameters on admission to the hospital. However, the occurrence of CTPH at the 24-month follow-up is associated with PH and with a high Qanadli CT obstruction index score. [ABSTRACT FROM AUTHOR]

Objective: The effects of ticagrelor in the subpopulation of patients with ST-elevation myocardial infarction (STEMI) were consistent with those observed in the overall Platelet Inhibition and Patient Outcomes (PLATO) study. However, this subgroup included patients initially or ultimately treated conservatively. The aim of this study is to compare treatment using ticagrelor with treatment using clopidogrel in patients with STEMI undergoing primary percutaneous coronary intervention (PCI).Methods: This post-hoc subgroup analysis compared ticagrelor with clopidogrel in 4949 PLATO patients with STEMI that were treated with primary PCI within 12 h of admission. The primary endpoint was cardiovascular death, myocardial infarction or stroke. The safety endpoint consisted of any major bleeding. Secondary endpoints included stent thrombosis. The analysis was not adequately powered to establish significance of any treatment effects.Results: During a median of 286 days, the primary endpoint occurred in 7.9% of ticagrelor-treated patients versus 8.6% of clopidogrel-treated patients (HR 0.91, 95% CI 0.75 to 1.12, p=0.38). Major bleeding occurred in 6.7% in ticagrelor-treated patients versus 6.8% of clopidogrel-treated patients (HR 0.97, 95% CI 0.77 to 1.22, p=0.79). No interactions were observed for the treatment effect of ticagrelor versus clopidogrel on the primary efficacy (p=0.40) and primary safety endpoints (p=0.15) as compared with the full PLATO population. Treatment with ticagrelor versus clopidogrel reduced the occurrence of definite stent thrombosis (HR 0.58, 95% CI 0.37 to 0.89, p=0.013).Conclusions: In the subset of patients with STEMI treated with primary PCI, ticagrelor compared with clopidogrel was safe, and efficacy outcomes were consistent with the overall PLATO trial.Trial Registration Number: NCT00391872; Results. [ABSTRACT FROM AUTHOR]

Aims Ticagrelor reduced major adverse cardiovascular event (MACE) by 15-16% in patients with prior myocardial infarction (MI) in PEGASUS-TIMI 54. We hypothesized that patients who recently discontinued P2Y12 inhibition, even years after MI, may be at particular risk of MACE and may derive particular benefit from continuation or reinitiation of therapy. Methods and results Patients in PEGASUS-TIMI 54 were categorized by time from last P2Y12 inhibitor (days: ≤30, >30-360, >360). The risk of MACE and the efficacy of ticagrelor were compared across categories. In the placebo arm, patients who more recently stopped P2Y12 inhibitor therapy had a greater number of risk factors but still had a higher risk of MACE after multivariable adjustment [≤30 days, hazard ratio (HR)adj 1.47, 95% confidence interval (CI) 1.12-1.93, P = 0.0051; 30 days-1 year, HRadj 1.28, 95% CI 0.98-1.67, P = 0.073] compared with those who stopped >1 year prior (P-trend = 0.0097). The benefit of ticagrelor depended on the time from last dose, with HRs (95% CI) for ticagrelor (pooled doses) vs. placebo of 0.73 (0.61-0.87), 0.86 (0.71-1.04), and 1.01 (0.80-1.27), respectively, by category (P-trend for interaction < 0.001). The benefit in those ≤30 days of stopping was similar regardless of time from MI (<2 years, HR 0.73, 95% CI 0.60-0.89 vs. ≥2 years, HR 0.71, 95% CI 0.50-1.00). Conclusion The benefit of ticagrelor for long-term secondary prevention in patients with prior MI and at least one additional risk factor appeared more marked in patients continuing on or re-starting after only a brief interruption of P2Y12 inhibition, when compared with patients who had proved themselves stable more than 2 years from their MI and off P2Y12 inhibitor therapy for more than a year. The increase in bleeding events with ticagrelor was similar regardless of this time interval. For clinicians considering a strategy of prolonged P2Y12 inhibitor therapy in high-risk patients, these data suggest greater benefit in the continuation of such therapy without interruption after MI, rather than re-initiating such therapy in patients who have remained stable for an extended period. Future analyses may help to clarify further the profile of post-MI patients most likely to benefit from uninterrupted dual antiplatelet therapy. [ABSTRACT FROM AUTHOR]

Aims We evaluated the relationship of renal function and ischaemic and bleeding risk as well as the efficacy and safety of ticagrelor in stable patients with prior myocardial infarction (MI). Methods and results Patients with a history of MI 1-3 years prior from PEGASUS-TIMI 54 were stratified based on estimated glomerular filtration rate (eGFR), with, 60 mL/min/1.73 m² pre-specified for analysis of the effect of ticagrelor on the primary efficacy composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events, MACE) and the primary safety endpoint of TIMI major bleeding. Of 20 898 patients, those with eGFR, 60 (N = 4849, 23.2%) had a greater risk of MACE at 3 years relative to those without, which remained significant after multivariable adjustment (hazard ratio, HRadj 1.54, 95% confidence interval, CI 1.27-1.85, P, 0.001). The relative risk reduction in MACE with ticagrelor was similar in those with eGFR, 60 (ticagrelor pooled vs. placebo: HR 0.81; 95% CI 0.68-0.96) vs. ≥60 (HR 0.88; 95% CI 0.77-1.00, Pinteraction = 0.44). However, due to the greater absolute risk in the former group, the absolute risk reduction with ticagrelor was higher: 2.7 vs. 0.63%. Bleeding tended to occur more frequently in patients with renal dysfunction. The absolute increase in TIMI major bleeding with ticagrelor was similar in those with and without eGFR, 60 (1.19 vs. 1.43%), whereas the excess of minor bleeding tended to be more pronounced (1.93 vs. 0.69%). Conclusion In patients with a history of MI, patients with renal dysfunction are at increased risk of MACE and consequently experience a particularly robust absolute risk reduction with long-term treatment with ticagrelor. [ABSTRACT FROM AUTHOR]

It has been suggested that Type D Personality is a risk factor for acute coronary syndrome ( ACS) and the DS14 has been developed for its assessment. However, some of the items on the DS14 seem to evaluate depressive symptoms rather than personality features. Therefore, the present study aims to verify whether an overlap exists between the constructs of Type D Personality and depression. Three-hundred-and-four consecutive patients who were both presenting their first ACS and had no history of major depression completed the Hospital Anxiety and Depression Scale ( HADS) and the DS14 to assess Type D personality at baseline and have been re-evaluated at 1, 2, 4, 6, 9 and 12-month follow-ups. Out of 304 subjects (80.6% males), 40 were diagnosed as depressed. An exploratory factor analysis of HADS and the DS14 in the second month revealed that four out of seven items on the depressive subscale of HADS ( HADS-D) and six out of seven items on the Negative Affectivity ( NA) subscale of the DS14 segregated on the same factor. Results were verified by a Partial Confirmatory Factor Analysis performed at the twelfth month when most of the patients achieved complete remission from the depressive episode. Temporal stability was poor for NA and Type D Personality and these construct co-vary with HADS-D over time. Our data suggests that NA and depression are overlapping constructs, supporting the idea that the DS14 measures depressed features, rather than a personality disposition. [ABSTRACT FROM AUTHOR]

A fundamental challenge to contemporary genetics is to distinguish rare missense alleles that disrupt protein functions from the majority of alleles neutral on protein activities. High-throughput experimental tools to securely discriminate between disruptive and non-disruptive missense alleles are currently missing. Here we establish a scalable cell-based strategy to profile the biological effects and likely disease relevance of rare missense variants in vitro. We apply this strategy to systematically characterize missense alleles in the low-density lipoprotein receptor (LDLR) gene identified through exome sequencing of 3,235 individuals and exome-chip profiling of 39,186 individuals. Our strategy reliably identifies disruptive missense alleles, and disruptive-allele carriers have higher plasma LDL-cholesterol (LDL-C). Importantly, considering experimental data refined the risk of rare LDLR allele carriers from 4.5- to 25.3-fold for high LDL-C, and from 2.1- to 20-fold for early-onset myocardial infarction. Our study generates proof-of-concept that systematic functional variant profiling may empower rare variant-association studies by orders of magnitude. [ABSTRACT FROM AUTHOR]

The number of patients diagnosed with atrial fibrillation who will be candidates for antithrombotic therapy with direct oral anticoagulants (i.e., dabigatran, rivaroxaban, apixaban and edoxaban) is exponentially arising worldwide, thus posing substantial economic and organizational challenges for their urgent monitoring. Due to long turnaround time and inherent technical complexity, liquid chromatography techniques are unsuitable for rapid assessment of their concentration. Even the use of surrogate tests such as thrombin clotting time or anti-factor Xa activity carries some economic and technical drawbacks. Based on literature data, we have hence developed an algorithm based on first-line tests for urgent screening of the anticoagulant effect of direct oral anticoagulants, which entails activated partial thromboplastin time (aPTT) for dabigatran and prothrombin time (PT) for rivaroxaban. Although these tests also display a concentration-dependent prolongation in patients taking apixaban and edoxaban, neither of them is sufficiently sensitive for providing accurate estimation of the pharmacodynamic effect, so that the measurement of anti-factor Xa activity remains the most suitable approach in patients taking these drugs. According to literature data, this strategy appears suitable to reliably define the thrombotic or bleeding risk in an urgent setting, contextually saving precious laboratory resources. [ABSTRACT FROM AUTHOR]

In recent years, it has become evident that the level of guideline adherence in patients presenting with acute coronary syndrome (ACS) is highly correlated with patient outcomes. Unfortunately, guideline adherence is low in some geographic areas and especially in those patients at high-risk. Regional networks including ambulance systems and hospitals with catheterization laboratories are able to increase guideline adherence and patient outcomes by streamlining the critical pre- and intra-hospital processes as well as improving timely access to invasive procedures and recommended medication. Successful organization of an ACS network requires engagement of multiple stakeholders to create effective solutions for the specific local setting. There is no 'one-size-fits all' strategy to set-up and successfully run an ACS network. We present a framework for how to set up and organize an effective ACS network, delivering guideline-based care to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH; MIM 600799) is frequently associated with concomitant diseases, including congenital heart disease. 6% of patients with PAH show a family history of the disease [hereditary PAH (HPAH)], with the major genetic determinants of HPAH being heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR2). We present the case of a 38-year-old woman of Indian descent; initially admitted with progressive dyspnea [New York Heart Association (NYHA) class III]. The results of the proband's clinical assessments are presented here. Cardiac catheterization confirmed idiopathic PAH with severe right ventricular hypertrophy associated with pulmonary arteriopathy. Initial treatment comprised the dual endothelin receptor antagonist, bosentan, furosemide, warfarin and intravenous infusion of prostaglandin I2 (PGI2) for 3 days. Despite this, the patient died of pulmonary hemorrhagic edema and cardiogenic shock after 6 days of intensive care. After relatives' consent, post mortem assessments confirmed a diagnosis of PAH; the heart displayed significant right ventricular hypertrophy and it was particularly noted that the right atrial appendage had undergone extreme dilation. Pulmonary arteriopathy was characterized by medial hypertrophy, arterialization of muscular arteries and muscularization of non-muscularized distal arteries. Molecular genetic analyses revealed the presence of cis-mutations in the BMPR2 gene (p.Cys123Arg and p.Arg332X). Cosegregation studies were not available. Our findings suggest that mutations of the BMPR2 gene gave rise to the onset of PAH in this patient and that the severity of the onset and progression could be attributed to the presence of multiple mutations in a genedosage manner. [ABSTRACT FROM AUTHOR]

(PDF) Reference 1 Emdin CA, Haas ME, Khera AV, Aragam K, Chaffin M, Klarin D, et al. (2020) A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease. In the Methods, the first sentence of the first paragraph: To examine whether known alcoholic and non-alcoholic cirrhosis variants associate with all-cause cirrhosis, we tested the association of six known cirrhosis variants ( I PNPLA3 i I48M, I TM6SF2 i E167K, I MBOAT7 i rs641738, I HSD17B13 i rs72613567, I HFE i C282Y and I SERPINA1 i E366K [11,16,18,19]) with all-cause cirrhosis in UK Biobank (hospitalization or death due to ICD codes K70.2, K70.3, K70.4, K74.0, K74.1, K74.2, K74.6, K76.6, or I85). should read: To examine whether known alcoholic and non-alcoholic cirrhosis variants associate with all-cause cirrhosis, we tested the association of six known cirrhosis variants ( I PNPLA3 i I148M, I TM6SF2 i E167K, I MBOAT7 i rs641738, I HSD17B13 i rs72613567, I HFE i C282Y and I SERPINA1 i E366K [11,16,18,19]) with all-cause cirrhosis in UK Biobank (hospitalization or death due to ICD codes K70.2, K70.3, K70.4, K74.0, K74.1, K74.2, K74.6, K76.6, or I85). In the Introduction, the third sentence of the second paragraph: For example, I PNPLA3 i p.I48M and I TM6SF2 i p.E40K, although initially identified as associated with hepatic steatosis [9,10], strongly predispose to the development of alcoholic cirrhosis [11], non-alcoholic cirrhosis [12,13] and hepatitis C-related cirrhosis [14,15]. should read: For example, I PNPLA3 i p.I1148M and I TM6SF2 i p.E167K, although initially identified as associated with hepatic steatosis [9,10], strongly predispose to the development of alcoholic cirrhosis [11], non-alcoholic cirrhosis [12,13] and hepatitis C-related cirrhosis [14,15]. [Extracted from the article]

Background: The optimal timing of coronary intervention in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) is a matter of debate. Conflicting results among published studies partly relate to different risk profiles of the studied populations.Purpose: To do the most comprehensive meta-analysis of current evidence on early versus delayed invasive treatment in NSTE-ACS.Data Sources: MEDLINE, PubMed Central, and Google Scholar databases; conference proceedings; ClinicalTrials.gov registry; and Current Controlled Trials registry through May 2012.Study Selection: Available randomized, controlled trials (RCTs) and observational studies comparing early versus delayed intervention in the NSTE-ACS population.Data Extraction: Data were extracted for populations, interventions, outcomes, and risk of bias. All-cause mortality was the prespecified primary end point. The longest follow-up available in each study was chosen. The odds ratio with 95% CI was the effect measure.Data Synthesis: Seven RCTs (5370 patients) and 4 observational studies (77 499 patients) were included. Early intervention was less than 20 hours after hospitalization or randomization for RCTs and 24 hours or less for observational studies. Meta-analysis of the RCTs was inconclusive for a survival benefit associated with the early invasive strategy (odds ratio, 0.83 [95% CI, 0.64 to 1.09]; P = 0.180); a similar result emerged from the observational studies. With early versus late intervention, the odds ratios in the RCTs were 1.15 (CI, 0.65 to 2.01; P = 0.63) and 0.76 (CI, 0.56 to 1.04; P = 0.090) for myocardial infarction and major bleeding during follow-up, respectively.Limitation: Current evidence from RCTs is limited by the small overall sample size, low numbers of events in some trials, and heterogeneity in the timing of intervention and in patient risk profiles.Conclusion: At present, there is insufficient evidence either in favor of or against an early invasive approach in the NSTE-ACS population. A more definitive RCT is warranted to guide clinical practice. [ABSTRACT FROM AUTHOR]

Background: The optimal timing of coronary intervention in pa-tients with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) is a matter of debate. Conflicting results among pub-lished studies partly relate to different risk profiles of the studied populations. Purpose: To do the most comprehensive meta-analysis of current evidence on early versus delayed invasive treatment in NSTE-ACS. Data Sources: MEDLINE, PubMed Central, and Google Scholar databases; conference proceedings; ClinicalTrials.gov registry; and Current Controlled Trials registry through May 2012. Study Selection: Available randomized, controlled trials (RCTs) and observational studies comparing early versus delayed intervention in the NSTE-ACS population. Data Extraction: Data were extracted for populations, interven-tions, outcomes, and risk of bias. All-cause mortality was the pre-specified primary end point. The longest follow-up available in each study was chosen. The odds ratio with 95% CI was the effect measure. Data Synthesis: Seven RCTs (5370 patients) and 4 observational studies (77 499 patients) were included. Early intervention was less than 20 hours after hospitalization or randomization for RCTs and 24 hours or less for observational studies. Meta-analysis of the RCTs was inconclusive for a survival benefit associated with the early invasive strategy (odds ratio, 0.83 [95% CI, 0.64 to 1.09]; P = 0.180); a similar result emerged from the observational studies. With early versus late intervention, the odds ratios in the RCTs were 1.15 (CI, 0.65 to 2.01; P = 0.63) and 0.76 (CI, 0.56 to 1.04; P = 0.090) for myocardial infarction and major bleeding during follow-up, respectively. Limitation: Current evidence from RCTs is limited by the small overall sample size, low numbers of events In some trials, and heterogeneity in the timing of Intervention and in patient risk profiles. Conclusion: At present, there is insufficient evidence either in favor of or against an early invasive approach in the NSTE-ACS popula-tion. A more definitive RCT is warranted to guide clinical practice. [ABSTRACT FROM AUTHOR]