Sex-specific genetic risks for adverse outcomes after coronary revascularization procedures.

Men and women have differing risks of adverse events after revascularization procedures and these differences could be partially driven by genetics. We studied the sex-specific differences in associations of polygenic risk scores (PRSs) with atrial fibrillation (AF), ischaemic stroke (STR), intracranial haemorrhage (ICH), myocardial infarction (MI) and gastrointestinal haemorrhage (GIH) in coronary revascularization patients. The study cohort comprised 5561 and 17 578 revascularized women and men. All participants underwent genotyping and register-based follow-up from 1961 to 2021. We calculated PRSs for all individuals and used Cox models with interaction term to examine the sex-specific associations between the PRSs and adverse outcomes after revascularization. The AF-PRS was more strongly associated with AF in men [hazard ratio (HR) per 1 standard deviation increase, 1.16; 95% confidence interval (CI), 1.12-1.19; P = 7.6 × 10-22) than in women (P for interaction 0.006). Conversely, ICH-PRS was more strongly associated with ICH after revascularization in women (HR, 1.32; 95% CI, 1.08-1.62; P = 0.008) than in men (P for interaction 0.008). We observed no sex-specific differences for the associations of PRSs with STR, MI or GIH. The genetic risk of AF after revascularization is greater in men than in women, and vice versa for ICH. Sex-specific PRSs could be used to identify individuals in high genetic risk for these complications.

Prolonged Systemic Inflammatory Response Syndrome After Cardiac Surgery.

OBJECTIVES: Cardiac surgery induces systemic inflammatory response syndrome (SIRS), leading to higher morbidity and mortality. There are no individualized predictors for worse outcomes or biomarkers for the multifactorial, excessive inflammatory response. The interest of this study was to evaluate whether a systematic use of the SIRS criteria could be used to predict postoperative outcomes beyond infection and sepsis, and if the development of an exaggerated inflammation response could be observed preoperatively. DESIGN: The study was observational, with prospectively enrolled patients. SETTING: This was a single institution study in a hospital setting combined with laboratory findings. PARTICIPANTS: The study included a cohort of 261 volunteer patients. INTERVENTIONS: Patients underwent cardiac surgery with cardiopulmonary bypass, and were followed up to 90 days. Biomarker profiling was run preoperatively. MEASUREMENTS AND MAIN RESULTS: Altogether, 17 of 261 (6.4%) patients had prolonged SIRS, defined as fulfilling at least 2 criteria on 4 consecutive postoperative days. During hospitalization, postoperative atrial fibrillation (POAF) was found in 42.2% of patients, and stroke and transient ischemic attack in 3.8% of patients. Prolonged SIRS was a significant predictor of POAF (odds ratio [OR] 4.5, 95% CI 1.2-17.3), 90-day stroke (OR 4.5, 95% CI 1.1-18.0), and mortality (OR 10.7, 95% CI 1.7-68.8). Biomarker assays showed that preoperative nerve growth factor and interleukin 5 levels were associated with prolonged SIRS (OR 5.6, 95%, CI 1.4-23.2 and OR 0.7, 95%, CI 0.4-1.0, respectively). CONCLUSIONS: Nerve growth factor and interleukin 5 can be used to predict prolonged systemic inflammatory response, which is associated with POAF, stroke, and mortality.

Associations of polygenic risk scores for preeclampsia and blood pressure with hypertensive disorders of pregnancy.

BACKGROUND: Preexisting hypertension increases risk for preeclampsia. We examined whether a generic blood pressure polygenic risk score (BP-PRS), compared with a preeclampsia-specific polygenic risk score (PE-PRS), could better predict hypertensive disorders of pregnancy. METHODS: Our study sample included 141 298 genotyped FinnGen study participants with at least one childbirth and followed from 1969 to 2021. We calculated PRSs for SBP and preeclampsia using summary statistics for greater than 1.1 million single nucleotide polymorphisms. RESULTS: We observed 8488 cases of gestational hypertension (GHT) and 6643 cases of preeclampsia. BP-PRS was associated with GHT [multivariable-adjusted hazard ratio for 1SD increase in PRS (hazard ratio 1.38; 95% CI 1.35-1.41)] and preeclampsia (1.26, 1.23-1.29), respectively. The PE-PRS was also associated with GHT (1.16; 1.14-1.19) and preeclampsia (1.21, 1.18-1.24), but with statistically more modest magnitudes of effect (P = 0.01). The model c-statistic for preeclampsia improved when PE-PRS was added to clinical risk factors (P = 4.6 × 10-15). Additional increment in the c-statistic was observed when BP-PRS was added to a model already including both clinical risk factors and PE-PRS (P = 1.1 × 10-14). CONCLUSION: BP-PRS is strongly associated with hypertensive disorders of pregnancy. Our current observations suggest that the BP-PRS could capture the genetic architecture of preeclampsia better than the current PE-PRSs. These findings also emphasize the common pathways in the development of all BP disorders. The clinical utility of a BP-PRS for preeclampsia prediction warrants further investigation.

Effect of menopause and age on vascular impairment.

AIMS: The prevalence of cardiovascular diseases increases in women after menopause. The aim of the study was to determine the impact of conventional cardiovascular risk factors such as age, blood pressure, smoking, cholesterol, obesity, and glucose balance, but also menopausal state and sleep-disordered breathing on vascular impairment during menopausal transition. METHODS: 89 women initiated the study and 74 of them participated in the 10-year follow-up. Cardiovascular disease risk factor assessments, ultrasound measurements of brachial artery function, including nitroglycerin-mediated vasodilatation and flow-mediated endothelium-dependent vasodilation, and sleep studies were repeated at baseline and at 5-year and 10-year follow-ups. RESULTS: Over the study period, all the cardiovascular disease risk estimates increased. Both flow-mediated endothelium-dependent vasodilatation (decline 55 %) and nitroglycerin-mediated vasodilatation (decline 18 %) worsened over the 10 years (p < 0.001). Vascular function was not associated with menopausal state (determined with follicle stimulating hormone). Systolic blood pressure (p = 0.009) and smoking (p = 0.006) at baseline were negatively associated with nitroglycerin-mediated vasodilatation at 5-year follow-up and the use of hormonal therapy at 5-year follow-up was positively associated with concurrent nitroglycerin-mediated vasodilatation (p = 0.041). Intermittent nocturnal hypoxemia at baseline was associated with flow-mediated endothelium-dependent vasodilatation at 10-year follow-up (p = 0.043). High body mass index and impaired glucose balance at 5-year follow-up were associated with nitroglycerin-mediated vasodilatation decline at 10-year follow-up (p = 0.022 and p = 0.037, respectively). CONCLUSIONS: We demonstrate how cardiovascular risk factors and vascular function evolve during menopausal transition. Although menopause was not associated with vascular impairment, short-term improvement in vascular function was observed in those using menopausal hormonal therapy. Intermittent nocturnal hypoxemia, obesity and impaired glucose control are early predictors of vascular decline during postmenopause.

Risk of fluid accumulation after cardiac surgery.

Objective: Patients undergoing heart surgery are at high risk of postoperative fluid accumulation due to long procedures and cardiopulmonary bypass. In the present study, we sought to investigate the prevalence of postoperative fluid accumulation and its relation to adverse events in patients undergoing cardiac surgery. Methods: CAREBANK is prospective, single-center cohort study focusing on the adverse events after cardiac surgery. The study population was divided into 2 groups based on 5% postoperative weight gain. All the in-hospital adverse events are registered on the database. The end points of the present study were length of hospital stay, length of intensive care unit stay, occurrence of new-onset atrial fibrillation after hospital major bleeding episodes major cardiac events, cerebrovascular events, and death. Three-month and 1-year follow-up data also include all major adverse events. Results: Altogether 1001 adult cardiac surgery patients were enrolled. The most frequent operations were coronary artery bypass grafting (56.3%). Five hundred fifty-four out of 939 (59.0%) patients had ≥5% weight gain during index hospitalization. Patients with a weight gain ≥5% were more likely to be women, have lower body mass index, had heart failure, and more often had preoperative atrial fibrillation. In-hospital period fluid accumulation was associated with reoperation due bleeding and longer total hospital stay. At 3 months' follow-up, weight gain 5% or more was associated with increased occurrence of new-onset atrial fibrillation, this was not reflected in the occurrence of strokes, transient ischemic attacks, or myocardial infarctions. Conclusions: Postoperative fluid excess is associated with adverse outcomes in cardiac surgery. Women, low-weight patients, and patients with cardiac failure or atrial fibrillation are prone to perioperative fluid accumulation.

Sex differences in coronary artery bypass grafting-related morbidity and mortality.

Background: Coronary artery bypass grafting (CABG) is associated with both cardiovascular disease (CVD) and non-CVD traits. In addition, women's prognosis after coronary events and revascularizations is worse than in men. As the course of CVD in women differs from that of men, we performed a phenome-wide analysis on the sex differences in CABG -related morbidity and mortality. Materials and methods: We performed an untargeted analysis on the sex differences in predictors and outcomes of CABG. We studied a sample of 176,680 FinnGen participants, including 5,950 individuals who underwent CABG (4,988 men and 962 women) and were followed between 1998 and 2019. Over 1,100 different traits were analyzed for both sexes and the results were adjusted with age, smoking status and BMI. Cox proportional hazards models with sex-trait interactions were used to estimate the associations between (1) traits and incident CABG; and (2) CABG and incident traits. Results: In women, CABG was more strongly related to greater increases in risk of diseases such as hypertension, Alzheimer's, aortic aneurysms, gout, and chronic kidney disease compared to risk increases observed in men (all interaction p-values < 0.03). After CABG, men had 2.5-fold (p = 3.1E-15) and women 6.3-fold (p = 9.4E-08) greater risk of cardiac death compared to same-sex individuals who did not undergo CABG (p for interaction 8.2E-4). Moreover, the risk of death in women remained higher even 12 years after CABG, whereas the long-term risk of death in men was not increased, compared to same-sex individuals who did not undergo CABG. Conclusion: The adverse outcomes after CABG, both quantity and quality, also appear to differ between men and women. In women, CABG is related to greater long-term increases in risk of cardiac death and several other disease states than in men. Consideration should therefore be given to whether women receive adequate long-term post-operative therapy and follow-up as CABG is not associated with equally improved cardiovascular disease prognosis in women than in men.

Retrospective observational analysis of a coronary artery bypass grafting surgery patient cohort: Off-pump versus on-pump.

Objectives: To determine whether surgical technique has an effect on prognosis in coronary artery bypass grafting (CABG). Design: Retrospective observational. Setting: Single center. Participants: All the off-pump (OPCABG) and on-pump (ONCABG) patients at Turku University Central Hospital in 2018. Interventions: None. Measurements and main results: After propensity score matching, perioperative, 1-year and 3-year mortality did not differ between the groups. The ONCABG patients received more allogenic red blood cells (1.3 vs. 0.6 units, p = 0.020), autologous red blood cells (564 vs. 285 ml, p < 0.001) and crystalloids (3388 vs. 2808 ml, p < 0.001), and had higher postoperative values of troponin T (581 vs. 222, p = 0.001) and lactate (1.69 vs. 1.23, p < 0.001) than the OPCABG patients. Conclusions: The both techniques seem equally safe. However, there may be some benefits to avoiding using a heart-lung machine, such as lower infused fluid volumes. Myocardial damage may also be milder and postoperative hemodynamics more balanced in OPCABG patients, based on lower levels of troponin T and lactate.

Early signs of sleep-disordered breathing in healthy women predict carotid intima-media thickening after 10 years.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in women. The risk of CVD increases in women after menopause. The aim was to study how sleep parameters and cardiovascular risk factors in 46-year-old women predict future carotid intima-media thickness (IMT) 10 years after. METHODS: Prospective study of 92 healthy women, aged 46 years, were studied at baseline and at 10-year follow-up. Polysomnography for sleep and breathing; blood samples for cholesterol, glucose and follicle stimulating hormone; blood pressure (BP), weight and height measurements; questionnaires for background variables and vasomotor symptoms were carried out at both time points. Carotid ultrasound was scanned for IMT at 10-year follow-up. RESULTS: After adjusting for conventional risk factors, apnea-hypopnea index (AHI) during rapid-eye-movement (REM) sleep was the only parameter at baseline that predicted IMT 10 years after (IMT mean: ß 81.4 [95% CI, 14.0-148.8]; IMT max: ß 104.7 [95% CI, 15.4-194.1]). At 10-year follow-up, higher arousal index (IMT mean: ß 55.6 [95% CI, 19.5-91.8]; IMT max ß 59.9 [95% CI, 11.4-108.4]) and lower vasomotor symptoms (IMT max: ß -60.5 [95% CI, -119.0 to -2.0]) were associated with concurrent higher IMT. The conventional risk factors at baseline did not associate with future IMT but 10 years after higher concurrent HbA1c (IMT mean: ß 11.0 [95% CI, 3.4-18.5]; IMT max ß 14.0 [95% CI, 4.1-23.8]) and systolic BP (IMT mean: ß 2.4 [95% CI, 1.1-3.7]; IMT max: ß 2.7 [95% CI, 1.03 to 4.53]) were associated with higher IMT. CONCLUSIONS: In healthy 46-year-old women, AHI during REM sleep predicted IMT 10 years after. The conventional risk factors (HbA1c and BP) only associated with the concurrent IMT at 10-year follow-up.

Genetic, Molecular, and Cellular Determinants of Sex-Specific Cardiovascular Traits.

Despite the well-known sex dimorphism in cardiovascular disease traits, the exact genetic, molecular, and cellular underpinnings of these differences are not well understood. A growing body of evidence currently points at the links between cardiovascular disease traits and the genome, epigenome, transcriptome, and metabolome. However, the sex-specific differences in these links remain largely unstudied due to challenges in bioinformatic methods, inadequate statistical power, analytic costs, and paucity of valid experimental models. This review article provides an overview of the literature on sex differences in genetic architecture, heritability, epigenetic changes, transcriptomic signatures, and metabolomic profiles in relation to cardiovascular disease traits. We also review the literature on the associations between sex hormones and cardiovascular disease traits and discuss the potential mechanisms underlying these associations, focusing on human studies.

Polygenic Risk Scores for Predicting Adverse Outcomes After Coronary Revascularization.

Coronary procedures predispose patients to adverse events. To improve our understanding of the genetic factors underlying postoperative prognosis, we studied the association of polygenic risk scores (PRSs) with postprocedural complications in coronary patients who underwent revascularization. The study sample comprised 8,296, 6,132, and 13,082 patients who underwent percutaneous coronary intervention, coronary artery bypass grafting, or any revascularization, respectively. We genotyped all subjects and identified adverse events during follow-up of up to 30 years by record linkage with nationwide healthcare registers. We computed PRSs for each postoperative adverse outcome (atrial fibrillation [AF], myocardial infarction, stroke, and bleeding complications) for all participants. Cox proportional hazards models were used to examine the association between PRSs and outcomes. A 1-SD increase in AF-PRS was associated with greater risk of postoperative AF with hazard ratios of 1.22 (95% confidence interval [CI] 1.16 to 1.28), 1.15 (95% CI 1.10 to 1.20) and 1.18 (95% CI 1.14 to 1.22) after percutaneous coronary intervention, coronary artery bypass grafting, and any revascularization, respectively. In contrast, the association of each PRSs with other postoperative complications was nonexistent to marginal. Inclusion of the AF-PRS in a model with a clinical risk score resulted in significant model improvement (increase in model c-statistic 0.0059 to 0.0098 depending on procedure; p <0.0002 for all). In conclusion, our results demonstrate that PRS can be used for AF risk-prediction in patients who underwent revascularization. The AF-PRS could potentially be used to improve AF prevention and outcomes in patients who underwent revascularization.

Anticoagulation Therapy After Biologic Aortic Valve Replacement.

Objectives: Thromboembolism prophylaxis after biologic aortic valve replacement (BAVR) is recommended for 3 months postoperatively. We examined the continuation of oral anticoagulation (OAC) treatment and its effect on the long-term prognosis after BAVR. Methods: We used nation-wide register data from 4,079 individuals who underwent BAVR. We examined the association between warfarin and the non-vitamin K antagonist oral anticoagulant use with death, stroke and major bleeding in 2010 - 2016. Results: The risk of stroke was higher (HR 2.39, 95% CI 1.62 - 3.53, p < 0.001) and the risk of death was lower (HR 0.79, 95% CI 0.65 - 0.96, p = 0.016) in OAC-users compared to individuals without OAC. We observed no significant associations between OAC use and bleeding risk. Conclusion: OAC use after BAVR was associated with increased risk of stroke and decreased risk of death. These observational findings warrant validation in randomized controlled trials before any clinical conclusions can be drawn.

Predictors and Outcomes of Coronary Artery Bypass Grafting: A Systematic and Untargeted Analysis of More Than 120,000 Individuals and 1,300 Disease Traits.

OBJECTIVE: To perform an untargeted data-driven analysis on the correlates and outcomes of coronary artery bypass grafting (CABG). DESIGN: FinnGen cohort study. SETTING: The authors collected information on up to 1,327 disease traits before and after CABG from nationwide healthcare registers. PARTICIPANTS: A mixed population and patient sample of 127,911 individuals including 3,784 CABG patients. INTERVENTIONS: The authors assessed the association between (1) traits and incident CABG and (2) CABG and incident traits using multivariate-adjusted Cox models. MAIN RESULTS: Patients who underwent CABG and were in the fourth quartile of a risk score based on the top predictors of mortality had 12.2-fold increased risk of dying (95% confidence interval [CI], 10.3-14.5) compared with those in the first quartile. Cardiovascular disease (CVD) and CVD risk factors were most strongly associated with incident CABG. However, CABG was associated with death due to cardiac causes (hazard ratio [HR], 3.7; 95% CI, 3.5-4.0) or other causes (HR, 2.5; 95% CI, 2.4-2.7). CABG also was related to increased risk of several non-CVD traits, including anemia (HR, 3.4; 95% CI, 2.8-4.1), gastrointestinal disorders (HR, 2.2; 95% CI, 1.8-2.6), acute renal failure (HR, 4.2; 95% CI, 3.5-5.1), septicemia (HR, 3.6; 95% CI, 3.1-4.1), lung cancer (HR, 2.3; 95% CI, 1.9-2.8), Alzheimer's disease (HR, 2.5; 95% CI, 2.2-2.7), and chronic obstuctive pulmonary disease (HR, 2.5; 95% CI, 2.2-2.9). CONCLUSIONS: Known CVD risk factors associate most strongly with incident CABG. However, CABG is associated with increased risk of several, somewhat unexpected, non-CVD traits. More detailed study of these links is warranted to establish potential causality and pathogenesis.

Effects of implementing rotational thromboelastometry in cardiac surgery: A retrospective cohort study.

Since 2013, rotational thromboelastometry has been available in our hospital to assess coagulopathy. The aim of the study was to retrospectively evaluate the effect of thromboelastometry testing in cardiac surgery patients. Altogether 177 patients from 2012 and 177 patients from 2014 were included. In 2014, the thromboelastometry testing was performed on 56 patients. The mean blood drainage volume decreased and the number of patients receiving platelets decreased between 2012 and 2014. In addition, the use of fresh frozen plasma units decreased, and the use of prothrombin complex concentrate increased in 2014. When studied separately, the patients with a thromboelastometry testing received platelets, fresh frozen plasma, fibrinogen and prothrombin complex concentrate more often, but smaller amounts of red blood cells. In conclusion, after implementing the thromboelastometry testing to the practice, the blood products were given more cautiously overall. The use of thromboelastometry testing was associated with increased possibility to receive coagulation product transfusions. However, it appears that thromboelastometry testing was mostly used to assist in management of major bleeding.

Sleep during menopausal transition: a 10-year follow-up.

STUDY OBJECTIVES: A 10-year observational follow-up study to evaluate the changes in sleep architecture during the menopausal transition. METHODS: Fifty-seven premenopausal women (mean age 46 years, SD 0.9) were studied at baseline and after a 10-year follow-up. At both time points, polysomnography (PSG) was performed, and the serum follicle-stimulating hormone (S-FSH) concentration was measured. Linear regression models were used to study the effects of aging and menopause (assessed as change in S-FSH) on sleep. RESULTS: After controlling for body mass index, vasomotor, and depressive symptoms, higher S-FSH level was associated with longer sleep latency (B 0.45, 95% confidence interval [CI]: 0.07 to 0.83). Aging of 10 years was associated with shorter sleep latency (B -46.8, 95% CI: -77.2 to -16.4), shorter latency to stage 2 sleep (B -50.6, 95% CI: -85.3 to -15.9), decreased stage 2 sleep (B -12.4, 95% CI: -21.4 to -3.4), and increased slow-wave sleep (B 12.8, 95% CI: 2.32 to 23.3) after controlling for confounding factors. CONCLUSIONS: This study suggests that PSG measured sleep of middle-aged women does not worsen over a 10-year time span due to the menopausal transition. The observed changes seem to be rather age- than menopause-dependent.

Markers of Poor Prognosis in Patients Requiring Continuous Renal Replacement Therapy After Cardiac Surgery.

OBJECTIVE: Acute kidney injury requiring renal replacement therapy after cardiac surgery has an incidence of 2% to 15%, and mortality in affected patients approximates 50%. The authors aimed to study the determinants of poor prognosis in patients receiving continuous renal replacement therapy (CRRT) after cardiac surgery. DESIGN: Retrospective, observational single-center study. SETTING: Tertiary care, university hospital. PARTICIPANTS: Cardiac surgery patients admitted to the intensive care unit (ICU) needing postoperative CRRT between January 1, 2010, and September 31, 2019. INTERVENTIONS: Predictors of mortality were examined using groupwide comparisons between ICU survivors versus nonsurvivors and univariate and multivariate Cox proportional hazards models. RESULTS: During the study period, 67 cardiac surgery patients without prior maintenance dialysis required CRRT postoperatively. ICU mortality was 47.7% and 90-day mortality was 58.2%. Only 37.3% of patients were alive at 1 year after surgery. Blood lactate at the start of dialysis was the most significant predictor of ICU and overall mortality. Eighty-seven percent of patients with lactate >3 mmol/L died in the ICU compared with 27.3% of patients with lactate ≤3 mmol/L (p < 0.0001). In patients with lactate exceeding 5.3 mmol/L, ICU mortality was 100%. In a stepwise multivariate Cox proportional hazards model, the association with mortality remained significant for lactate at the start of CRRT (per 1 mmol/L, hazard ratio [HR] 1.19 [95% confidence interval {CI} 1.11-1.28], p < 0.0001), troponin T on the first postoperative morning (per 0.1 µg/L, HR 1.004 [95% CI 1.001-1.008], p = 0.01), and 72-hour fluid balance (per 1000 mL, HR 1.12 [95% CI 1.04-1.21], p = 0.005). CONCLUSION: Blood lactate at the start of dialysis was the most significant predictor of ICU and overall mortality in patients with CRRT after cardiac surgery.

Self-reported Age of Hypertension Onset and Hypertension-Mediated Organ Damage in Middle-Aged Individuals.

BACKGROUND: Objectively defined early onset hypertension, based on repeated blood pressure measurements, is a strong risk factor for cardiovascular disease (CVD). We aimed to assess if also self-reported hypertension onset age is associated with hypertension-mediated organ damage (HMOD). Additionally, we evaluated the agreement between self-reported and objectively defined hypertension onset age. METHODS: We studied 2,649 participants (50 ± 4 years at the time of outcome assessment, 57% women) of the Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent measurements for echocardiographic left ventricular hypertrophy (LVH), left ventricular diastolic dysfunction (LVDD), coronary calcification, and albuminuria. We divided the participants into groups according to self-reported hypertension onset age (<35 years, 35-44 years, ≥45 years, and no hypertension). We used multivariable-adjusted logistic regression models to assess the relation between self-reported hypertension onset age with the presence of HMOD, with those who did not report hypertension as the referent group. RESULTS: Compared with individuals without self-reported hypertension, self-reported hypertension onset at <35 years was associated with LVH (odds ratio (OR), 2.38; 95% confidence interval (CI), 1.51-3.76), LVDD (OR, 2.32; 95% CI, 1.28-4.18, coronary calcification (OR, 2.87; 95% CI, 1.50-5.47), and albuminuria (OR, 1.62; 95% CI, 0.81-3.26). Self-reported hypertension onset at ≥45 years was only associated with LVDD (OR, 1.81; 95% CI, 1.06-3.08). The agreement between self-reported and objectively defined hypertension onset age groups was 78-79%. CONCLUSIONS: Our findings suggest that self-reported hypertension onset age, a pragmatically feasible assessment in clinical practice, is a reasonable method for assessing risk of HMOD and CVD.