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Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P

Background We asked whether, after excluding familial hypercholesterolemia, individuals with high low-density lipoprotein cholesterol ( LDL -C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population-based hyperlipidemias. Methods and Results We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (≥2 first-degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias ( LDL -C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta-analysis of the hyperlipidemic families and the population cohort (high LDL -C: hazard ratio, 1.74 [95% CI, 1.48-2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI, 1.09-1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid-lowering medication. In lipidomic profiling, high LDL -C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P-value range 0.038-2.3×10-56). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population ( LDL -C: r=0.80; triacylglycerides: r=0.96; no lipid species deviated between the cohorts). Conclusions Hyperlipidemias with family history conferred similar coronary artery disease risk as population-based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL -C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.

Simple Summary: Small intestinal neuroendocrine tumors (SI-NETs) can lead to carcinoid syndrome and carcinoid heart disease (CHD). In this prospective study we aimed to identify early risk markers for CHD and mortality in patients with SI-NETs. We measured basal serum 5-HIAA and cumulative 5-HIAA (Cum-5-HIAA) based on repeated measurements, proBNP, vascular function, transesophageal echocardiography (TTE), and hepatic tumor load in 65 patients with SI-NETs during the median follow-up of 5 years in 54 of the patients who underwent prospective follow-up. Survival was evaluated during the median follow-up of 6 years. Three patients had CHD at baseline and two (4%) developed CHD. Cum-5-HIAA and proBNP correlated with CHD. Of note, Cum-5-HIAA was the best biomarker for CHD, outperforming pro-BNP, chromogranin A (CgA), and individual 5-HIAA. The strongest predictors of mortality were the diagnosis of CHD and high liver tumor burden, while high blood vessel stiffness was also associated with lower survival rates. The incidence of CHD was low during follow-up, probably reflecting efficient treatment regimens. These findings may help identify patients at high risk for CHD and mortality and guide early interventions to improve patient outcomes. Background: Small intestinal neuroendocrine tumors (SI-NETs) are characterized by carcinoid syndrome and carcinoid heart disease (CHD). The aim of the present study was to identify early risk markers for carcinoid heart disease and survival in a prospective median-term follow-up setting. Methods: We measured 5-HIAA and cumulative 5-HIAA exposure (Cum-5-HIAA) based on repeated measurements, proBNP, vascular function, hepatic tumor load, and transthoracic echocardiography (TTE) at baseline and during the median 5-year follow-up. Of 65 patients with SI-NETs, 54 patients underwent a prospective follow-up. In addition, survival was evaluated during the median follow-up of 6 years. Results: At baseline, three patients had CHD. During the median follow-up of 5 years, two patients (4%) developed CHD. Cum-5-HIAA and proBNP correlated with CHD (Westberg score, Spearman's ρ = 0.32 and 0.31, respectively). Cum-5-HIAA had a superior diagnostic capability, predicting CHD in receiver operator characteristic analysis with an AUC of 0.98 (95% CI: 0.94–1.00) and outperformed proBNP, chromogranin A (CgA), and individual serum 5-HIAA measurements (AUC = 0.75, 0.85, and 0.91, respectively). Minor changes in valve regurgitation were frequently detected but did not correlate with vascular function. Regurgitation increased or decreased in 29% of tricuspid and 30% of pulmonic valves. CHD, hepatic tumor load, serum 5-HIAA, and elevated aortic pulse wave velocity (PWV) were associated with increased mortality in SI-NET patients. Conclusions: Cum-5-HIAA is a promising biomarker for CHD risk and outperformed other biomarkers. CHD and hepatic tumor load are the strongest predictors of mortality. PWV is a novel predictor of survival. The incidence of CHD was low among the SI-NET patients, probably reflecting successful treatment regimens. [ABSTRACT FROM AUTHOR]

BACKGROUND The incidence of cardiovascular complications may be higher in unilateral than bilateral primary aldosteronism (PA). We compared noninvasive hemodynamics after targeted therapy of bilateral vs. unilateral PA. METHODS Adrenal vein sampling was performed, and hemodynamics recorded using radial artery pulse wave analysis and whole-body impedance cardiography (n  = 114). In 40 patients (adrenalectomy n  = 20, spironolactone-based treatment n  = 20), hemodynamic recordings were performed after 33 months of PA treatment. RESULTS In initial cross-sectional analysis, 51 patients had bilateral and 63 unilateral PA. The mean ages were 50.6 and 54.3 years (P  = 0.081), and body mass indexes 30.3 and 30.6 kg/m2 (P  = 0.724), respectively. Aortic blood pressure (BP) and cardiac output did not differ between the groups, but left cardiac work was ~10% higher in unilateral PA (P  = 0.022). In the follow-up study, initial and final BPs in the aorta were not significantly different, while initial cardiac output (+13%, P  = 0.015) and left cardiac work (+17%, P  = 0.009) were higher in unilateral than bilateral PA. After median treatment of 33 months, the differences in cardiac load were abolished, and extracellular water volume was reduced by 1.3 and 1.4 l in bilateral vs. unilateral PA, respectively (P  = 0.814). CONCLUSIONS These results suggest that unilateral PA burdens the heart more than bilateral PA, providing a possible explanation for the higher incidence of cardiac complications in unilateral disease. A similar reduction in aldosterone-induced volume excess was obtained with targeted surgical and medical treatment of PA. [ABSTRACT FROM AUTHOR]

Background and aimsHypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41-0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH).MethodsWe utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a)).ResultsWe did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.

Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.

Background: Screening for primary aldosteronism is based on measuring aldosterone-to-renin ratio. Non-suppressed renin may cause false negative screening results, and such patients may miss focused, potentially curable treatment. We investigated the association between renal cysts and non-suppressed plasma renin. Methods: Altogether, 114 consecutive patients with confirmed primary aldosteronism undergoing adrenal vein sampling were prospectively recruited between October 7, 2020 and December 30, 2021. During the procedure, plasma samples for renin analyses were collected from the right and left renal veins and the inferior vena cava. Renal cysts were identified using contrast-enhanced computed tomography. Results: Renal cysts were found in 58.2% of the 114 patients. Neither screening nor renal vein renin concentrations were significantly different in patients with and without cysts, or when the kidneys with and without cysts were evaluated. However, cysts were significantly more prevalent in the "high-normal renin" group (cut point 23.0 mU/L) than in the "low to low-normal renin" group (90.9%, n = 11 vs. 56.0%, n = 102, P = .027, respectively). All patients ≤50 years of age in the "high-normal renin" group had renal cysts. Strong correlations were found between renin concentrations in the right and left renal veins (r = .984), and between renin concentration and renin activity in the inferior vena cava (r = .817). Conclusion: Renal cysts are found in the majority of patients with primary aldosteronism, and they may interfere with diagnostics, especially in patients aged 50 years or less. In patients with non-suppressed renin due to renal cysts, aldosterone-to-renin ratio below the diagnostic threshold does not always exclude the diagnosis of primary aldosteronism. [ABSTRACT FROM AUTHOR]

Introduction: Subtype classification method is essential when considering adrenalectomy as a possible treatment for primary aldosteronism. We aimed to retrospectively evaluate surgical outcomes of primary aldosteronism in patients who had undergone 11C‐metomidate positron emission tomography (11C‐MTO‐PET) for subtype classification. Methods: Postoperative clinical and biochemical cure and histopathological diagnosis from biobank samples were retrospectively evaluated in 44 patients who had all undergone preoperative 11C‐MTO‐PET with or without adrenal venous sampling (AVS). We compared those operated based on 11C‐MTO‐PET alone and those with concordant or discordant lateralization in 11C‐MTO‐PET and AVS studies according to postoperative immunohistochemical findings and biochemical and clinical cure. Results: Adrenalectomy side was based on 11C‐MTO‐PET alone in 14 cases and on AVS in 30 cases of whom 42 achieved complete and two partial biochemical cures. Among those who underwent AVS and were operated according to it, the two lateralization methods were concordant in 22 cases and discordant in 8 cases. Similar immunohistochemical profiles and cure rates were seen after 11C‐MTO‐PET alone or AVS‐based operations. Respectively, those with concordant or discordant 11C‐MTO‐PET and AVS lateralization did not differ in surgical outcome. Together, we found errors of lateralization diagnostics with 11C‐MTO‐PET in 18% and with AVS in 3% among those eligible for adrenal surgery. Conclusions: Outcomes of adrenalectomy based on clinically significant lateralization in 11C‐MTO‐PET alone correspond to those based on 11C‐MTO‐PET with concordant AVS lateralization. However, our results suggest that diagnosis of unilateral PA should be performed with caution with 11C‐MTO‐PET in case of discordant lateralization studies. [ABSTRACT FROM AUTHOR]