Alirocumab and cardiovascular outcomes according to sex and lipoprotein(a) after acute coronary syndrome: a report from the ODYSSEY OUTCOMES study.

BACKGROUND: The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS). OBJECTIVE: We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level. METHODS: This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment. RESULTS: Women were older, had higher baseline LDL-C levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (pinteraction=0.08). Medication adherence and adverse event rates were similar in both sexes. CONCLUSIONS: Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a).

Intravascular lithotripsy for the treatment of peri-stent calcific lesions in saphenous vein grafts: A case series report.

BACKGROUND: Coronary artery bypass grafting (CABG) is a cornerstone treatment for coronary artery disease, with the use of saphenous vein grafts (SVGs) being prevalent. However, SVGs are susceptible to high failure rates due to graft inflammation, intimal hyperplasia, and atherosclerosis, leading to a substantial number of patients requiring revascularization. Percutaneous coronary intervention (PCI) of SVGs poses unique challenges, including increased risk of distal embolization and perforation due to the grafts' structure and atherosclerotic nature. The role of intravascular lithotripsy (IVL) in calcific SVG lesions has not been elucidated. METHODS: We retrospectively analyzed four cases of patients treated with IVL for SVG stenosis at Leiden University Medical Centre between May 2019 and December 2023. Quantitative coronary analysis and intravascular ultrasound were utilized to assess procedural success and mid- to long-term clinical outcomes were reported as well. RESULTS: In all 4 cases, IVL was performed in stent (2 due to calcific in-stent neoatherosclerosis; 2 bail-out due to extrinsic stent calcification). No major adverse cardiovascular events (MACE) were reported during mid- to long-term follow-up. The procedure demonstrated effective calcium cracking, leading to optimal stent expansion and minimal residual stenosis with a low risk of procedural complications. CONCLUSIONS: IVL represents a promising approach for managing calcified peri-stent SVG lesions, showing potential for safe and effective revascularization with minimal complications. These findings suggest that IVL could be incorporated into the treatment paradigm for calcified peri-stent SVG stenosis, warranting further investigation in larger, prospective studies to validate its efficacy and safety.

Estimating uncertainty when providing individual cardiovascular risk predictions: A Bayesian survival analysis.

BACKGROUND: Cardiovascular disease (CVD) risk scores provide point estimates of individual risk without uncertainty quantification. The objective of the current study was to demonstrate the feasibility and clinical utility of calculating uncertainty surrounding individual CVD-risk predictions using Bayesian methods. METHODS AND RESULTS: Individuals with established atherosclerotic CVD were included from the Utrecht Cardiovascular Cohort - Secondary Manifestations of ARTerial disease (UCC-SMART). In 8,355 individuals, followed for median of 8.2 years (IQR 4.2-12.5), a Bayesian Weibull model was derived to predict the 10-year risk of recurrent CVD events. Model coefficients and individual predictions were very similar to that of a traditional ('frequentist') model but the Bayesian model also predicted 95% credible intervals (CIs) surrounding individual risk estimates. The median width of the individual 95%CrI was 5.3% (IQR 3.6-6.5) and 17% of the population had a 95%CrI width of 10% or greater. The uncertainty decreased with increasing sample size used for derivation of the model. Combining the Bayesian Weibull model with sampled hazard ratios based on trial reports may be used to estimate individual absolute risk reduction with uncertainty measures and the probability that a treatment option will result in a clinically relevant risk reduction. INTERPRETATION: Estimating uncertainty surrounding individual CVD risk predictions using Bayesian methods is feasible. The uncertainty regarding individual risk predictions could have several applications in clinical practice, like the comparison of different treatment options or by calculating the probability of the individual risk being below a certain treatment threshold. However, as the individual uncertainty measures only reflect sampling error and no biases in risk prediction, physicians should be familiar with the interpretation before widespread clinical adaption.

Efficacy of the Cardiac Implantable Electronic Device Multisensory Triage-HF Algorithm in Heart Failure Care: A Real-World Clinical Experience.

Heart failure (HF) admissions are burdensome, and the mainstay of prevention is the timely detection of impending fluid retention, creating a window for medical treatment intensification. This study evaluated the accuracy and performance of a Triage-HF-guided carepath in real-world ambulatory HF patients in daily clinical practice. In this prospective, observational study, 92 adult HF patients (71 males (78%), with a median age of 69 [IQR 59-75] years) with the Triage-HF algorithm activated in their cardiac implantable electronic devices (CIEDs), were monitored. Following high-risk alerts, an HF nurse contacted patients to identify signs and symptoms of fluid retention. The sensitivity and specificity were 83% and 97%, respectively. The positive predictive value was 89%, and negative predictive value was 94%. The unexplained alert rate was 0.05 alerts/patient year, and the false negative rate was 0.11 alerts/patient year. Ambulatory diuretics were initiated or escalated in 77% of high-risk alert episodes. In 23% (n = 6), admission was ultimately required. The median alert handling time was 2 days. Fifty-eight percent (n = 18) of high-risk alerts were classified as true positives in the first week, followed by 29% in the second-third weeks (n = 9), and 13% (n = 4) in the fourth-sixth weeks. Common sensory triggers included an elevated night ventricular rate (84%), OptiVol (71%), and reduced patient activity (71%). The CIED-based Triage-HF algorithm-driven carepath enables the timely detection of impending fluid retention in a contemporary ambulatory setting, providing an opportunity for clinical action.

Current applications, procedural and 1-year outcomes of Rotatripsy for the treatment of calcified coronary lesions.

BACKGROUND: Intravascular lithotripsy (IVL) combined with rotational atherectomy (RA), known as Rotatripsy, is used to treat severe coronary artery calcification (CAC), though data on efficacy, midterm safety and use sequence is limited. We aimed to identify indicators for Rotatripsy use and to assess its safety and success rates, both acutely and at 1-year follow-up. METHODS: Patients undergoing Rotatripsy for severe CAC across six centers from May 2019 to December 2023 were included. Demographic, clinical, procedural and follow-up data were collected. Efficacy endpoints included device success (delivery of the RA-burr and IVL-balloon across the target lesion and administration of therapy without related complications), technical success (TIMI 3 flow and residual stenosis <30% by quantitative coronary analysis) and procedural success [composite of technical success with absence of in-hospital major adverse cardiovascular events (MACE: cardiac death, myocardial infarction or target vessel revascularization). Safety endpoints comprised Rotatripsy-related complications and MACE at 1-year follow-up. RESULTS: A total of 114 patients (75 ± 9 years, 78% male) underwent Rotatripsy for 120 lesions. In the majority of procedures RA was followed by IVL, mostly electively (n = 68, 57%) but also for balloon underexpansion (n = 37, 31%) and stent crossing failure (n = 1, 1%). Diverse and complex target lesions were addressed with an average SYNTAX score of 24.6 ± 13.0. Device, technical and procedural success were 97%, 94% and 93%, respectively. Therapy-related complications included two (2%) coronary perforations, one (1%) coronary dissection and one (1%) burr entrapment. At 1-year follow-up(present in 77(67%) patients), MACE occurred in 7(9%) cases. CONCLUSIONS: Over a 1-year follow-up period, Rotatripsy was safe and effective, predominantly using RA electively before IVL.

Coronary calcifications as assessed on routine non-gated chest CT; a gatekeeper to tailor downstream additional imaging in patients with stable chest pain.

Background and aims: Currently applied methods for risk-assessment in coronary artery disease (CAD) often overestimate patients' risk for obstructive CAD. To enhance risk estimation, assessment of coronary artery calcium (CAC) can be applied. In 10 % of patients presenting with stable chest pain a previous non-gated computed tomography (CT) has been performed, suitable for CAC-assessment. This study is the first to investigate the clinical utility of CAC-assessment on non-gated CT for risk-assessment of obstructive CAD in symptomatic patients. Methods: For this analysis, all patients referred for coronary computed tomography angiography (CCTA), in whom a previous non-gated chest CT was performed were included. The extent of CAC was assessed on chest CT and ordinally scored. CAD was assessed on CCTA and obstructive CAD defined as stenosis of ≥70 %. Patients were stratified according to CAC-severity and percentages of patients with obstructive CAD were compared between the CAC groups. Results: In total, 170 patients of 32-88 years were included and 35 % were male. The percentage of obstructive CAD between the CAC groups differed significantly (p < 0.01). A calcium score of 0 ruled out obstructive CAD irrespective of sex, pre-test probability, type of complaints and number of risk factors with a 100 % certainty. Furthermore, a mild CAC score ruled out obstructive CAD in patients with low - intermediate PTP or non-anginal complaints with 100 % certainty. Conclusion: When available, CAC on non-gated chest CT can accurately rule out obstructive CAD and can therefore function as a radiation-free and cost-free gatekeeper for additional imaging in patients presenting with stable chest pain.

CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization.

Introduction: The CC chemokine ligand 18 (CCL18) is a chemokine highly expressed in chronic inflammation in humans. Recent observations of elevated CCL18 plasma levels in patients with acute cardiovascular syndromes prompted an investigation into the role of CCL18 in the pathogenesis of human and mouse atherosclerosis. Methods and results: CCL18 was profoundly upregulated in ruptured human atherosclerotic plaque, particularly within macrophages. Repeated administration of CCL18 in Western-type diet-fed ApoE -/- mice or PCSK9mut-overexpressing wild type (WT) mice led to increased plaque burden, enriched in CD3+ T cells. In subsequent experimental and molecular modeling studies, we identified CCR6 as a functional receptor mediating CCL18 chemotaxis, intracellular Ca2+ flux, and downstream signaling in human Jurkat and mouse T cells. CCL18 failed to induce these effects in vitro in murine spleen T cells with CCR6 deficiency. The ability of CCR6 to act as CCL18 receptor was confirmed in vivo in an inflammation model, where subcutaneous CCL18 injection induced profound focal skin inflammation in WT but not in CCR6-/- mice. This inflammation featured edema and marked infiltration of various leukocyte subsets, including T cells with a Th17 signature, supporting CCR6's role as a Th17 chemotactic receptor. Notably, focal overexpression of CCL18 in plaques was associated with an increased presence of CCR6+ (T) cells. Discussion: Our studies are the first to identify the CCL18/CCR6 axis as a regulator of immune responses in advanced murine and human atherosclerosis.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Safety of the PCSK9 inhibitor alirocumab: insights from 47 296 patient-years of observation.

The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

Oleic acid triggers metabolic rewiring of T cells poising them for T helper 9 differentiation.

T cells are the most common immune cells in atherosclerotic plaques, and the function of T cells can be altered by fatty acids. Here, we show that pre-exposure of CD4+ T cells to oleic acid, an abundant fatty acid linked to cardiovascular events, upregulates core metabolic pathways and promotes differentiation into interleukin-9 (IL-9)-producing cells upon activation. RNA sequencing of non-activated T cells reveals that oleic acid upregulates genes encoding key enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis links these expression changes to the differentiation toward TH9 cells, a pro-atherogenic subset. Spectral flow cytometry shows that pre-exposure to oleic acid results in a skew toward IL-9+-producing T cells upon activation. Importantly, pharmacological inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, oleic acid may affect inflammatory diseases like atherosclerosis by rewiring T cell metabolism.

Effects of repeated weight cycling on non-alcoholic steatohepatitis in diet-induced obese mice.

Lifestyle interventions remain the treatment of choice for patients with obesity and metabolic complications, yet are difficult to maintain and often lead to cycles of weight loss and regain (weight cycling). Literature on weight cycling remains controversial and we therefore investigated the association between weight cycling and metabolic complications using preexistent obese mice. Ldlr-/-.Leiden mice received a high-fat diet (HFD) for 20 weeks to induce obesity. Subsequently, weight-cycled mice were switched between the healthy chow diet and HFD for four 2-week periods and compared to mice that received HFD for the total study period. Repeated weight cycling tended to decrease body weight and significantly reduced fat mass, whereas adipose tissue inflammation was similar relative to HFD controls. Weight cycling did not significantly affect blood glucose or plasma insulin levels yet significantly reduced plasma free fatty acid and alanine transaminase/aspartate transaminase levels. Hepatic macrovesicular steatosis was similar and microvesicular steatosis tended to be increased upon weight cycling. Weight cycling resulted in a robust decrease in hepatic inflammation compared to HFD controls while hepatic fibrosis and atherosclerosis development were not affected. These results argue against the postulate that repeated weight cycling leads to unfavorable metabolic effects, when compared to a continuous unhealthy lifestyle, and in fact revealed beneficial effects on hepatic inflammation, an important hallmark of non-alcoholic steatohepatitis.

Coronary artery calcium assessment on non-gated chest CT to optimize pre-operative cardiac screening in liver transplantation.

BACKGROUND: Guidelines recommend standard pre-operative cardiac screening in all liver transplantation (LT) recipients, despite the relatively low prevalence of obstructive coronary artery disease. Most LT recipients often have non-gated computed tomography (CT) performed of the chest and abdomen. This study evaluated the ability of coronary artery calcification (CAC) assessment on consecutively available scans, to identify a selection of low-risk patients, in whom further cardiac imaging can be safely withheld. METHODS: LT recipients with prior non-gated CT chest-abdomen were included. CAC was visually scored on a semi-quantitative ordinal scale. Stress myocardial perfusion, coronary CT angiography (CCTA) and invasive coronary angiography (ICA) were used as golden standard. The sensitivity and specificity of CAC to exclude and predict obstructive CAD were assessed. In addition, peri- and postoperative mortality and cardiac events were analyzed. RESULTS: 149 LT recipients (ranged 31-71 years) were included. In 75% of patients, no CAC and mild CAC could rule out obstructive CAD on CCTA and ICA with 100% certainty. The threshold of mild CAC had a sensitivity of 100% for both CCTA and ICA and a specificity of 91% and 68%, respectively. None of the patients with no or mild calcifications experienced peri- and post-operative cardiac events or died of cardiac causes. CONCLUSION: Visual evaluation of CAC on prior non-gated CT can accurately and safely exclude obstructive CAD in LT recipients. Incorporation of these already available data can optimize cardiac screening, by safely withholding or correctly allocating dedicated cardiac imaging in LT recipients. Thereby, reducing patients' test burden and save health care expenses.

Effect of Sodium-Glucose Cotransporter 2 Inhibitors in Adults With Congenital Heart Disease.

BACKGROUND: Heart failure (HF) is the principal cause of morbidity and mortality in adults with congenital heart disease (ACHD). Robust evidence-based treatment options are lacking. OBJECTIVES: This study aims to evaluate the safety, tolerability, and short-term HF-related effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in a real-world ACHD population. METHODS: All patients with ACHD treated with SGLT2i in 4 European ACHD centers were included in this retrospective study. Data were collected from 1 year before starting SGLT2i to the most recent follow-up. Data on side effects, discontinuation, mortality, and hospitalizations were collected. RESULTS: In total, 174 patients with ACHD were treated with SGLT2i from April 2016 to July 2023. The mean age was 48.7 ± 15.3 years, 72 (41.4%) were female, and 29 (16.7%) had type 2 diabetes mellitus. Ten (5.7%) patients had mild, 75 (43.1%) moderate, and 89 (51.1%) severe congenital heart disease. HF was the most frequent starting indication (n = 162, 93.1%), followed by type 2 diabetes (n = 11, 6.3%) and chronic kidney disease (n = 1, 0.6%). At median follow-up of 7.7 months (Q1-Q3: 3.9-13.2 months), 18 patients (10.3%) reported side effects, 12 (6.9%) permanently discontinued SGLT2i, and 4 (2.3%) died of SGLT2i-unrelated causes. A significant reduction in the HF hospitalization rate was observed from 6 months before to 6 months after starting SGLT2i (relative rate = 0.30; 95% CI: 0.14-0.62; P = 0.001). CONCLUSIONS: SGLT2i generally seem safe, well-tolerated, and potentially beneficial in patients with ACHD. SGLT2i was associated with a 3-fold reduction in the 6-month HF hospitalization rate. These results warrant prospective randomized investigation of the potential benefits of SGLT2i for patients with ACHD.

Atypical Progeria Primarily Manifesting as Premature Cardiac Valvular Disease Segregates with LMNA-Gene Variants.

Mutations in the LMNA-gene can cause a variety of 'laminopathies'. These laminopathies are associated with a range of phenotypes, including disorders affecting the adipose tissue, peripheral nerves, the heart, such as dilated cardiomyopathy and conduction system abnormalities, and less commonly, progeroid disorders. This case series describes two families in which two novel LMNA-gene variants were identified, and who presented with an atypical progeroid phenotype with primarily premature aortic and mitral valve stenosis. Interestingly, these families exhibited no clear evidence of multisystem involvement, illustrating the complex role of lamins A/C.

The Potential of the HeartLogicTM Algorithm in Patients with a Left Ventricular Assist Device, an Initial Report.

BACKGROUND: Survival and quality-of-life of left ventricular assist device (LVAD) recipients improved significantly because of growing experience and technological advances. However, LVAD-related complication rates, including recurrent episodes of congestion, remain high. Early detection of fluid retention to provide a time-window for medical intervention is the pillar in preventing hospitalizations. The multisensory HeartLogicTM algorithm accurately detected impending congestion in ambulant heart failure patients. The aim of the current study is to investigate the feasibility of HeartLogicTM-driven care in LVAD patients. METHODS: Consecutive LVAD destination therapy patients were followed-up according the structured HeartLogicTM-based heart failure carepath. An alert triggered a device check-up, and the heart failure team contacted the patient to evaluate for signs and symptoms of impending congestion. An alert was adjudicated as true positive or unexplained. An episode of congestion not preceded by an alert was deemed as a false negative. RESULTS: Data from 7 patients were included: the median age was 67 years [IQR 61-71], 71% were male and 71% had a non-ischemic aetiology. Total follow-up entailed 12 patient-years. All patients experienced at least one alert. In total, 33 alerts were observed. Majority of alerts (70%, n = 23) were driven by congestion and one alerts (15%) were clinically meaningful but not primarily fluid-retention-related (e.g., altered hemodynamic triggered by a pump thrombosis). Of all the alerts, five (15%) were classified as an unexplained alert, and during follow-up, four false negative episodes were documented. CONCLUSIONS: HeartLogicTM-driven care with continuous monitoring to detect impending fluid retention in LVAD patients was feasible and deserves further prospective validation.

The Clear Value of Coronary Artery Calcification Evaluation on Non-Gated Chest Computed Tomography for Cardiac Risk Stratification.

To enhance risk stratification in patients suspected of coronary artery disease, the assessment of coronary artery calcium (CAC) could be incorporated, especially when CAC can be readily assessed on previously performed non-gated chest computed tomography (CT). Guidelines recommend reporting on patients' extent of CAC on these non-cardiac directed exams and various studies have shown the diagnostic and prognostic value. However, this method is still little applied, and no current consensus exists in clinical practice. This review aims to point out the clinical utility of different kinds of CAC assessment on non-gated CTs. It demonstrates that these scans indeed represent a merely untapped and underestimated resource for risk stratification in patients with stable chest pain or an increased risk of cardiovascular events. To our knowledge, this is the first review to describe the clinical utility of different kinds of visual CAC evaluation on non-gated unenhanced chest CT. Various methods of CAC assessment on non-gated CT are discussed and compared in terms of diagnostic and prognostic value. Furthermore, the application of these non-gated CT scans in the general practice of cardiology is discussed. The clinical utility of coronary calcium assessed on non-gated chest CT, according to the current literature, is evident. This resource of information for cardiac risk stratification needs no specific requirements for scan protocol, and is radiation-free and cost-free. However, some gaps in research remain. In conclusion, the integration of CAC on non-gated chest CT in general cardiology should be promoted and research on this method should be encouraged.

Leisure time physical activity is associated with improved diastolic heart function and is partly mediated by unsupervised quantified metabolic health.

Objectives: To investigate the association between leisure time physical activity (LTPA) and MRI-based diastolic function and the mediating role of metabolic health. Methods: This cross-sectional analysis comprised 901 participants (46% women, mean age (SD): 56 (6) years (The Netherlands, 2008-2012)). LTPA was assessed via questionnaire, quantified in metabolic equivalent of tasks (METs)-minutes per week and participants underwent abdominal and cardiovascular MRI. Confirmatory factor analysis was used to construct the metabolic load factor. Piecewise structural equation model with adjustments for confounders was used to determine associations between LTPA and diastolic function and the mediating effect of metabolic load. Results: Significant differences in mitral early/late peak filling rate (E/A) ratio per SD of LTPA (men=1999, women=1870 MET-min/week) of 0.18, (95% CI= 0.03 to 0.33, p=0.021) were observed in men, but not in women: -0.01 (-0.01 to 0.34, p=0.058). Difference in deceleration time of mitral early filling (E-DT) was 0.13 (0.01 to 0.24, p=0.030) in men and 0.17 (0.05 to 0.28, p=0.005) in women. Metabolic load, including MRI-based visceral and subcutaneous adipose tissue, fasting glucose, high-density lipoprotein cholesterol and triglycerides, mediated these associations as follows: E/A-ratio of 0.030 (0.000 to 0.067, 19% mediated, p=0.047) in men but not in women: 0.058 (0.027 to 0.089, p<0.001) and E-DT not in men 0.004 (-0.012 to 0.021, p=0.602) but did in women 0.044 (0.013 to 0.057, 27% mediated, p=0.006). Conclusions: A larger amount of LTPA was associated with improved diastolic function where confirmatory factor analysis-based metabolic load partly mediated this effect. Future studies should assess whether improving indicators of metabolic load alongside LTPA will benefit healthy diastolic function even more.

Identification of a gene network driving the attenuated response to lipopolysaccharide of monocytes from hypertensive coronary artery disease patients.

Introduction: The impact of cardiovascular disease (CVD) risk factors, encompassing various biological determinants and unhealthy lifestyles, on the functional dynamics of circulating monocytes-a pivotal cell type in CVD pathophysiology remains elusive. In this study, we aimed to elucidate the influence of CVD risk factors on monocyte transcriptional responses to an infectious stimulus. Methods: We conducted a comparative analysis of monocyte gene expression profiles from the CTMM - CIRCULATING CELLS Cohort of coronary artery disease (CAD) patients, at baseline and after lipopolysaccharide (LPS) stimulation. Gene co-expression analysis was used to identify gene modules and their correlations with CVD risk factors, while pivotal transcription factors controlling the hub genes in these modules were identified by regulatory network analyses. The identified gene module was subjected to a drug repurposing screen, utilizing the LINCS L1000 database. Results: Monocyte responsiveness to LPS showed a highly significant, negative correlation with blood pressure levels (ρ< -0.4; P<10-80). We identified a ZNF12/ZBTB43-driven gene module closely linked to diastolic blood pressure, suggesting that monocyte responses to infectious stimuli, such as LPS, are attenuated in CAD patients with elevated diastolic blood pressure. This attenuation appears associated with a dampening of the LPS-induced suppression of oxidative phosphorylation. Finally, we identified the serine-threonine inhibitor MW-STK33-97 as a drug candidate capable of reversing this aberrant LPS response. Conclusions: Monocyte responses to infectious stimuli may be hampered in CAD patients with high diastolic blood pressure and this attenuated inflammatory response may be reversed by the serine-threonine inhibitor MW-STK33-97. Whether the identified gene module is a mere indicator of, or causal factor in diastolic blood pressure and the associated dampened LPS responses remains to be determined.

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.