Cardiovascular Risk Phenotypes Research Articles

Association between high versus low cardiovascular risk in individuals with corresponding unexpected absent versus severe subclinical coronary atherosclerosis, a nationwide, multicenter study

Abstract Background It remains unclear as to why some individuals at low risk of cardiovascular disease (CVD) develop severe coronary atherosclerosis, while those at high CVD risk may remain free from coronary atherosclerosis. Purpose Using Coronary Computed Tomography Angiography (CCTA), we aimed to identify factors associated with absence and severe coronary atherosclerosis in subjects from the general population with very high and low-moderate CVD risk, respectively. Methods We assessed cross-sectionally a nationwide, multicenter population-based cohort, consisting of 30,154 individuals randomly recruited from the general population (age range 50-64 years, 51.4% women). Coronary calcified plaque burden was estimated by coronary artery calcium score (CACS) assessed by CCTA. Absent coronary atherosclerosis was defined as CACS 0 and severe coronary atherosclerosis was defined as CACS ≥301. We investigated only individuals with low-moderate (<5%) and very high CVD risk (≥10%) according to SCORE2 were included. Individuals with CACS 0 and prevalent CVD were excluded, as well as those with moderate CACS (1-300) or SCORE2 risk 5-9%. Out of 26 722 subjects with complete data on CACS and SCORE2, 13 075 were included. Logistic regression was performed adjusted for age and sex. Results The overall distribution of CACS in relation to SCORE2 CVD risk is illustrated in the Figure. Study characteristics are displayed in Table 1. Severe-extensive CACS in combination with low-moderate CVD risk was present in 2.3% (n=296). A further 2.3% (n=311) had very high CVD risk but CACS 0. Factors associated with CACS 0 despite a very-high estimated CVD risk included: lower age, being female, being born in Sweden, not having hypertension or hyperlipidemia, fewer pack-years of smoking, and lower waist circumference in men. On the contrary, severe-extensive CACS despite a low-moderate estimated CVD risk was associated with higher age, being male, being an ex-smoker, reporting more pack-years of smoking, having higher HbA1c, higher BMI, higher waist circumference, and prevalent hyperlipidemia and hypertension (Table 2). Conclusions We identified extreme cardiovascular risk phenotypes (subgroups) in the general population that either lacked coronary calcifications despite being at very high estimated CVD risk or had severe subclinical coronary atherosclerosis despite being at estimated low-moderate CVD risk. Further studies are warranted to elucidate putative enhancing or protective mechanisms explaining this unexpected phenomenon.

Severe heart failure and intracardiac thrombosis: going beyond the appearance for diagnosis and treatments.

We describe the case of a 45-year-old female affected by asthma and nasal polyposis who presented to the emergency department because of worsening dyspnea and paresthesia of the left lower limb. Comprehensive instrumental examinations revealed the presence of severe left ventricle dysfunction, intra-cardiac thrombus, deep vein thrombosis, pulmonary embolism, lung infiltrates, polyserositis, and neurological involvements. Finally, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA), formerly Churg-Strauss syndrome, a rare vasculitis of small-medium blood vessels with several organ involvements. Treatment with anticoagulants, corticosteroids, and cyclophosphamide led to a significant clinical improvement. However, a subcutaneous cardiac defibrillator was implanted because of the persistence of severe left ventricular dysfunction and the high cardiovascular risk phenotype. Indeed, several cardiac manifestations may occur in EGPA, particularly in patients with anti-neutrophil cytoplasmic antibody-negative disease. Therefore, clinicians should have high clinical suspicion because cardiac involvement in EGPA results in a poor prognosis if not diagnosed and adequately treated.

Body mass index and depressive rumination are positively associated with each other only in case of GG genotype of catenin alpha 2 gene rs13412541 variant

IntroductionCatenin alpha 2 gene (CTNNA2) is important in the stability of hippocampal synapses and also in brain development. Our recent paper (Eszlari et al, Pharmaceuticals 2021, 14, 850) has demonstrated that rumination on sad mood mediates the association of CTNNA2 only towards psychiatric symptoms, but not towards cardiovascular risk phenotypes.ObjectivesOur present aim was to test the moderating role of rumination and its two subtypes, brooding and reflection, in genetic associations between CTNNA2 and the same cardiovascular risk phenotypes.Methods633 unrelated subjects from the Budakalasz Health Examination Survey with non-missing phenotypic data, and 160 single-nucleotide CTNNA2 variants remaining after quality control, were included. Linear regression models were run in Plink 1.9 for separate outcomes of body mass index (BMI), and Framingham risk scores for cardiovascular disease, coronary heart disease, myocardial infarction, and stroke. With each variant, predictors were the variant, rumination or its subtype, the variant x rumination interaction, sex, age, and the top ten principal components of the genome. 100,000 label-swapping max(T) permutation was applied for the interaction term within each analysis.ResultsWhile no significant interaction term survived the familywise permutation, two trends emerged. Namely, BMI seems to have positive association with rumination and its maladaptive brooding subtype only in case of GG genotype of rs13412541, otherwise no association can be detected.ConclusionsAlthough replication is needed in larger samples, the relationship between rumination and BMI, conditional on CTNNA2 genotype, can be important in atypical depression, thus may contribute to stratification of depressed patients.DisclosureThe study was supported by the New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund (ÚNKP-21-4-II-SE-1); and by 2019-2.1.7-ERA-NET-2020-00005.

Gut microbiota regulates cardiac ischemic tolerance and aortic stiffness in obesity.

The gut microbiota has emerged as an important regulator of host physiology, with recent data suggesting a role in modulating cardiovascular health. The present study determined if gut microbial signatures could transfer cardiovascular risk phenotypes between lean and obese mice using cecal microbiota transplantation (CMT). Pooled cecal contents collected from obese leptin-deficient (Ob) mice or C57Bl/6j control (Con) mice were transplanted by oral gavage into cohorts of recipient Ob and Con mice maintained on identical low-fat diets for 8 wk (n = 9-11/group). Cardiovascular pathology was assessed as the degree of arterial stiffness (aortic pulse wave velocity) and myocardial infarct size following a 45/120 min ex vivo global cardiac ischemia-reperfusion protocol. Gut microbiota was characterized by 16S rDNA sequencing, along with measures of intestinal barrier function and cecal short-chain fatty acid (SCFA) composition. Following CMT, the gut microbiota of recipient mice was altered to resemble that of the donors. Ob CMT to Con mice increased arterial stiffness, left ventricular (LV) mass, and myocardial infarct size, which were associated with greater gut permeability and reduced cecal SCFA concentrations. Conversely, Con CMT to Ob mice increased cecal SCFA, reduced LV mass, and attenuated myocardial infarct size, with no effects on gut permeability or arterial stiffness. Collectively, these data demonstrate that obesity-related changes in the gut microbiota, independent of dietary manipulation, regulate hallmark measures of cardiovascular pathology in mice and highlight the potential of microbiota-targeted therapeutics for reducing cardiovascular pathology and risk in obesity.NEW & NOTEWORTHY These data are the first to demonstrate that cecal microbiota transplantation (CMT) can alter cardiovascular pathology in lean and obese mice independent from alterations in dietary intake. Myocardial infarct size was reduced in obese mice receiving lean CMT and worsened in lean mice receiving obese CMT. Lean mice receiving obese CMT also displayed increased aortic stiffness. These changes were accompanied by alterations in short-chain fatty acids and gut permeability.

4348Cluster analysis of cardiovascular risk phenotypes in patients with type 2 diabetes and established atherosclerotic cardiovascular disease: a potential approach to precision medicine

4348Cluster analysis of cardiovascular risk phenotypes in patients with type 2 diabetes and established atherosclerotic cardiovascular disease: a potential approach to precision medicine

Associations of mental health with cardiovascular risk phenotypes and adiposity in adolescence: A cross-sectional community-based study.

Cardiovascular disease and mental illness commonly co-occur in later life, but it is unknown how early these associations arise. We aimed to determine the extent to which: (i) childhood mental health is associated with functional and structural cardiovascular risk phenotypes and adiposity in late childhood/adolescence, and (ii) associations between mental health and cardiovascular phenotypes may be explained by differential body mass index. This cross-sectional study drew on three longitudinal community-based cohort studies (two enriched for overweight/obesity) in metropolitan Melbourne, Australia, with harmonized follow-up in 2014. Mental health exposures included emotional and behavioural problems (Strength and Difficulties Questionnaire) and psychosocial health and general well-being (Pediatric Quality of Life Inventory (PedsQL)), which were assessed by self- and parent-proxy report. Cardiovascular risk phenotypes and adiposity measures included mean arterial pressure, pulse wave velocity, carotid artery intima-media thickness, retinal arterioleto-venule ratio, waist circumference, % body fat, and BMI z-score. We used multivariable linear regression models, adjusting for age, sex and neighbourhood disadvantage, to examine associations. Of the 364 participants (mean age 14.7, standard deviation 2.0, years), 30% were overweight and 16% obese. All adiposity indicators were positively associated with higher behavioural/emotional problems and poorer psychosocial health and negatively associated with better ratings of positive general well-being, as reported by parents and children (all P ≤ 0.03). However, there was little evidence that cardiovascular functional or structural phenotypes varied by mental health. By late childhood/adolescence, mental health is strongly associated with adiposity but not with cardiovascular structure or function. This suggests that the known relationship between these constructs may not develop until early or mid-adulthood.

Translational evidence of prothrombotic and inflammatory endothelial damage in Cushing syndrome after remission.

Sustained evidence from observational studies indicates that after remission of Cushing syndrome (CS) a cardiovascular risk phenotype persists. Here, we performed a translational study in active CS and CS in remission (RCS) to evaluate the subclinical cardiometabolic burden and to explore the direct pro-inflammatory and prothrombotic potential of their sera on the endothelium in an in vitro translational atherothrombotic cell model. Cross sectional study. The groups were (n=9/group): I. RCS; II. Active CS (ACS) and III. Controls (CTR), all matched for age, body mass index, sex, without other hormonal deficits. We evaluated in vivo: cardiometabolic profile; endothelial markers (sVCAM-1, NO); endothelial dysfunction (FMD); intima-media thickness and body composition (DEXA). In vitro endothelial cells (EC) were exposed to sera taken from the different subjects to evaluate inflammatory EC response (tisVCAM) and thrombogenicity of the generated extracellular matrix (ECM): von Willebrand factor (VWF) and platelet reactivity. Three of the 9 RCS subjects were on glucocorticoid replacement therapy (GC-RT). Patients on GC-RT had a shorter period of time in stable remission. In vivo analysis ACS showed typically metabolic features, while cardiometabolic markers reached statistical significance for RCS only for Hs-CRP (P<.01). In vitro:EC exposed to ACS and RCS sera displayed increased tisVCAM-1 (P<.01 for ACS and P<.05 for RCS vs CTR), VWF (P<.01 for ACS and P<.05 for RCS vs CTR) and platelet adhesion on ECM (P<.01 for ACC and P<.05 for RCS vs CTR). No statistically significant differences were observed between GC-RT RSC and RCS without GC-RT. The sera of premenopausal women with CS in remission, without atherothrombotic disease, contain circulatory endothelial deleterious factors with a direct thrombogenic and pro-inflammatory endothelial effect that could increase cardiovascular risk.

Association of Optimal Combination Drug Treatment with Obesity Status among Recent Ischemic Stroke Patients: Results of the Vitamin Intervention for Stroke Prevention (VISP) Trial.

Background and PurposeOne explanation for the ‘obesity paradox’, where obese patients seem to have better cardiovascular outcomes than lean patients, is that obese patients display an identifiable high cardiovascular risk phenotype that may lead to receiving or seeking earlier/more aggressive treatment. MethodsWe analyzed a clinical trial dataset comprising 3643 recent (<120 days) ischemic stroke patients followed up for 2 years. Subjects were categorized as lean (body mass index [BMI], <25 kg/m2, n=1,006), overweight (25-29.9 kg/m2, n=1,493), or obese (≥30 kg/m2, n=1,144). Subjects were classified as level 0 to III depending on the number of secondary prevention prescriptions divided by the number of potentially indicated drugs (0=none of the indicated medications and III=all indicated medications as optimal combination drug treatment [OCT]). Independent associations between each BMI category and stroke/myocardial infarction/vascular death (major vascular events [MVEs]) and all-cause death were assessed. ResultsMVEs occurred in 17.4% of lean, 16.1% of overweight, and 17.1% of obese patients; death occurred in 7.3%, 5.5%, and 5.1%, respectively. Individuals with a higher BMI status received more OCT (45.8%, 51.7%, and 55.3%, respectively; P<0.001). In the lean patient group, multivariable adjusted Cox analyses, showed that compared with levels 0-I, level II and level III were linked to lower risk of MVEs (hazard ratio [HR] 0.55; 95% confidence interval [CI]: 0.32–0.95 and HR 0.48; 95% CI: 0.28−0.83, respectively) and death (0.44; 0.21–0.96 and 0.23; 0.10−0.54, respectively). ConclusionsOCT for secondary prevention after an ischemic stroke is less frequent in lean (vs. obese) subjects, but when implemented is related to significantly better clinical outcomes.

Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity.

Dopamine β-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine in the central nervous system and peripherally. DBH variants are associated with large changes in circulating DBH and implicated in multiple disorders; yet causal relationships and tissue-specific effects remain unresolved. To characterize regulatory variants in DBH, effect on mRNA expression, and role in modulating sympathetic tone and disease risk. Analysis of DBH mRNA in human tissues confirmed high expression in the locus coeruleus and adrenal gland, but also in sympathetically innervated organs (liver>lung>heart). Allele-specific mRNA assays revealed pronounced allelic expression differences in the liver (2- to 11-fold) attributable to promoter rs1611115 and exon 2 rs1108580, but only small differences in locus coeruleus and adrenals. These alleles were also associated with significantly reduced mRNA expression in liver and lung. Although DBH protein is expressed in other sympathetically innervated organs, mRNA levels were too low for analysis. In mice, hepatic Dbh mRNA levels correlated with cardiovascular risk phenotypes. The minor alleles of rs1611115 and rs1108580 were associated with sympathetic phenotypes, including angina pectoris. Testing combined effects of these variants suggested protection against myocardial infarction in 3 separate clinical cohorts. We demonstrate profound effects of DBH variants on expression in 2 sympathetically innervated organs, liver and lung, but not in adrenals and brain. Preliminary results demonstrate an association of these variants with clinical phenotypes responsive to peripheral sympathetic tone. We hypothesize that in addition to endocrine effects via circulating DBH and norepinephrine, the variants act in sympathetically innervated target organs.

Quercetin supplementation and its effect on human monocyte gene expression profiles in vivo

Quercetin has been described as having a wide range of beneficial effects in humans, ranging from anti-carcinogenic properties to reducing the risk of CVD. Nevertheless, underlying molecular mechanisms have been mostly investigated in vitro. Here, we tested whether a daily supplementation of quercetin leads to reproducible changes in human monocyte gene expression profiles. In study I, quercetin in varying dosages was given to healthy subjects for 2 weeks. RNA from monocytes isolated at the beginning and end of the study from subjects receiving 150 mg quercetin per d was subjected to transcriptome-wide microarray analysis. In study II, a double-blind cross-over study, twenty subjects exhibiting a 'cardiovascular risk phenotype' received 150 mg quercetin or placebo daily for 6 weeks each and served as the verification group. Microarray analysis revealed a number of differentially expressed genes. The most significantly represented functional groups were those of the immune system, nucleic acid metabolism, apoptosis and O-glycan biosynthesis. Twenty-four genes were chosen for technical replication and independent verification by quantitative real-time PCR. When comparing placebo and quercetin treatment, four genes showed significantly different expression changes (C1GALT1, O-glycan biosynthesis; GM2A, glycolipid catabolism; HDGF, cell proliferation; SERPINB9, apoptosis). However, these were minimal in respect to magnitude of fold change. In conclusion, although microarray analysis revealed extensive effects of quercetin on gene expression, the employment of a placebo-controlled study design showed no comparable results for twenty-four verification targets. This emphasises the need for stringent designs in nutritional intervention studies with the aim to identify relevant changes in gene expression.

Effect of Quercetin on Paraoxonase 2 Levels in RAW264.7 Macrophages and in Human Monocytes—Role of Quercetin Metabolism

There is increasing evidence that the intracellular antioxidant enzyme paraoxonase 2 (PON2) may have a protective function in the prevention of atherogenesis. An enhancement of PON2 activity by dietary factors including flavonoids is therefore of interest. In the present study we determined the effect of quercetin on paraoxonase 2 levels in cultured murine macrophages in vitro and in overweight subjects with a high cardiovascular risk phenotype supplemented with 150 mg quercetin/day for 42 days in vivo. Supplementation of murine RAW264.7 macrophages in culture with increasing concentrations of quercetin (1, 10, 20 μmol/L) resulted in a significant increase in PON2 mRNA and protein levels, as compared to untreated controls. Unlike quercetin, its glucuronidated metabolite quercetin-3-glucuronide did not affect PON2 gene expression in cultured macrophages. However the methylated quercetin derivative isorhamnetin enhanced PON2 gene expression in RAW264.7 cells to similar extent like quercetin. Although supplementing human volunteers with quercetin was accompanied by a significant increase in plasma quercetin concentration, dietary quercetin supplementation did not change PON2 mRNA levels in human monocytes in vivo. Current data indicate that quercetin supplementation increases PON2 levels in cultured monocytes in vitro but not in human volunteers in vivo.

Common Coding Variants of the HNF1A Gene Are Associated With Multiple Cardiovascular Risk Phenotypes in Community-Based Samples of Younger and Older European-American Adults

Background— The transcription factor hepatocyte nuclear factor (HNF)-1α regulates the activity of a number of genes involved in innate immunity, blood coagulation, lipid and glucose transport and metabolism, and cellular detoxification. Common polymorphisms of the HNF-1α gene ( HNF1A ) were recently associated with plasma C-reactive protein and γ-glutamyl transferase concentration in middle-aged to older European Americans (EA). Methods and Results— We assessed whether common variants of HNF1A are associated with C-reactive protein, γ-glutamyl transferase, and other atherosclerotic and metabolic risk factors, in the large, population-based Coronary Artery Risk Development in Young Adults Study of healthy young EA (n=2154) and African American (AA; n=2083) adults. The minor alleles of Ile27Leu ( rs 1169288) and Ser486Asn ( rs 2464196) were associated with 0.10 to 0.15 standard deviation units lower C-reactive protein and γ-glutamyl transferase levels in EA. The same HNF1A coding variants were associated with higher low-density lipoprotein cholesterol, apolipoprotein B, creatinine, and fibrinogen in EA. We replicated the associations between HNF1A coding variants and C-reactive protein, fibrinogen, low-density lipoprotein cholesterol, and renal function in a second population-based sample of EA adults 65 years and older from the Cardiovascular Health Study. The HNF1A Ser486Asn and/or Ile27Leu variants were also associated with increased risk of subclinical coronary atherosclerosis in Coronary Artery Risk Development in Young Adults and with incident coronary heart disease in Cardiovascular Health Study. The Ile27Leu and Ser486Asn variants were 3-fold less common in AA than in EA. There was little evidence of association between HNF1A genotype and atherosclerosis-related phenotypes in AA. Conclusions— Common polymorphisms of HNF1A seem to influence multiple phenotypes related to cardiovascular risk in the general population of younger and older EA adults.

Myocardial mechano-energetic efficiency in hypertensive adults

Myocardial mechanical efficiency can be measured as the ratio between systolic work and energy consumption. We evaluated the relation between myocardial mechanical efficiency and left ventricular (LV) mass in untreated hypertensive patients. Myocardial work was estimated in 256 normotensive (35 +/- 12 years) and 306 hypertensive patients (47 +/- 10 years) with normal ejection fraction, as stroke work in gram-meters (stroke work = BPs x SV x 0.0144, where BPs is systolic blood pressure, SV is echocardiographic stroke volume). Myocardial O2 consumption was estimated as the product of heart rate (HR) x BPs (eMVO2). Myocardial mechanical efficiency was estimated as the ratio of stroke work/eMVO2, which can be simplified and expressed as ml/s. LV mass was greater in hypertensive than in normotensive patients (46 +/- 13 vs. 38 +/- 11 g/m2.7, P < 0.0001), but myocardial mechanical efficiency was identical (85 +/- 23 vs. 86 +/- 26 ml/s). Relations between myocardial mechanical efficiency and LV mass were close (both P < 0.0001), but more scattered among hypertensive patients because of 56 patients exhibiting low myocardial mechanical efficiency relative to the magnitude of LV mass. At comparable age and body size, these patients had higher HR, BPs, and pulse pressure than those with normal myocardial mechanical efficiency (all P < 0.001). After adjusting for age and sex, hypertensive patients with low myocardial mechanical efficiency showed greater relative wall thickness and lower ejection fraction and midwall shortening than those with normal myocardial mechanical efficiency (all P < 0.001). Low myocardial mechanical efficiency was also associated with inappropriately high LV mass (P < 0.0001). In some hypertensive patients the left ventricle works inefficiently with a high energy wasting, at the same level of LV mass as hypertensive patients with normal myocardial mechanical efficiency. Those patients feature a high cardiovascular risk phenotype, with concentric LV geometry, systolic dysfunction, and indirect signs of more severe vascular impairment.

Common Coding Variants of the HNF1A Gene Are Associated With Multiple Cardiovascular Risk Phenotypes in Community-Based Samples of Younger and Older European-American Adults: The Coronary Artery Risk Development in Young Adults Study and The Cardiovascular Health Study

Common Coding Variants of the HNF1A Gene Are Associated With Multiple Cardiovascular Risk Phenotypes in Community-Based Samples of Younger and Older European-American Adults: The Coronary Artery Risk Development in Young Adults Study and The Cardiovascular Health Study

Link of nonhemodynamic factors to hemodynamic determinants of left ventricular hypertrophy.

Despite current evidence suggesting that hemodynamic load is the fundamental stimulus to begin the sequence of biological events leading to the development of left ventricular hypertrophy, genotype, gender, body size, and less easily recognizable environmental factors may contribute to generate the cascade of molecular changes that eventually yield the increase in protein synthesis needed to increase left ventricular mass. However, even nonhemodynamic factors such as gender and body size eventually regulate the growth of left ventricular mass by at least in part influencing loading conditions. Consideration of measurable factors, such as gender, body size, and hemodynamic load, allows evaluation of individual echocardiographic left ventricular mass as the deviation from the level that would be required to face a gender-specific hemodynamic load at a given body size. Values of left ventricular mass that are inappropriately high for individual gender, body size, and hemodynamic load are associated with a high cardiovascular risk phenotype, even independent of the presence of arterial hypertension. Thus, the condition of inappropriately high left ventricular mass may be recognized as a more advanced stage of pathological structural changes initially induced by overload, going beyond the compensatory needs. The biological process that yields inappropriate left ventricular mass is probably linked to the protracted activity over time of biological mediators of left ventricular hypertrophy, such as proto-oncogenes and other growth factors, neurohormones, and cytokines, inducing structural modifications that initially compensate imposed overload but eventually change the structure of myocardial tissue and the composition of motor units.