95th Percentile Research Articles

Lipoprotein(a) levels and LPA genotypes are not associated with echocardiographic measures of left ventricular structure and function in the general population

Abstract Background Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for myocardial infarction and aortic valve stenosis, and elevated Lp(a) levels are associated with increased risk of heart failure. While part of this heart failure risk is mediated through atherosclerotic and valvular disease, other pathological pathways may also contribute to the association between Lp(a) and heart failure. Purpose To assess if Lp(a) levels and corresponding LPA genotypes are associated with echocardiographic measures of left ventricular structure and function in the general population. Methods We included 3,427 participants from an observational general population study who underwent protocol echocardiography between 2011-15 and had an available measurement of Lp(a) and LPA genotypes. Lp(a) was measured in 1991-94 and 2001-03 using well-validated assays with the most recent measurement used for the present analysis. Participants were divided into groups based on quartiles of Lp(a) with the top quartile further stratified to capture those above the 90th percentile. For genetic analysis, participants were grouped based on kringle IV type 2 [KIV-2] repeat corresponding to plasma Lp(a) percentile groups. Linear regression models were used to estimate β-coefficients for echocardiographic measures associated with Lp(a) levels and genotypes, while logistic regression models were used to estimate odds ratios for cardiac dysfunction or remodeling. All models were adjusted for age and sex. Results Mean age was 63±14 years and 44% were male. Median plasma Lp(a) was 18 mg/dL [IQR 10-40], median number of KIV-2 repeats were 36 [30-40], 102 (3%) were rs3798220 minor allele carriers and 467 (14%) were rs10455872 carriers. Mean left ventricular ejection fraction [LVEF] was 56.0±6.6% and we had 99% power to detect an absolute LVEF difference of 2% between those with Lp(a) levels above the 90th percentile (corresponding to >75 mg/dL) compared with those below the 25th percentile (<10 mg/dL). Mean absolute global longitudinal strain (GLS) was 19.2±2.7% and we had 99% power to detect an absolute difference of 1%. However, we found no statistically significant differences in echocardiographic measures according to Lp(a) levels or LPA genotypes (Table 1). The prevalence of impaired LVEF was 16%, and we had <20% power to detect an odds ratio of 1.2 for those with Lp(a) above the 90th percentile compared with those below the 25th percentile. We found no significant associations between odds for cardiac dysfunction or left ventricular hypertrophy and Lp(a) levels or LPA genotypes (Table 2). Conclusion Elevated Lp(a) levels and corresponding LPA genotypes were not associated with echocardiographic measures of left ventricular structure and function in this general population cohort. While we did not have sufficient power to detect associations between Lp(a) and cardiac dysfunction, our findings do not support a substantial effect of Lp(a).

Cardiac myosin-binding protein-C: assessing fragmentation patterns to differentiate between forms of myocardial injury

Abstract Background Cardiac myosin-binding protein-C (cMyC) is a novel biomarker of myocardial injury. We hypothesize that fragmentation of cMyC differs according to aetiology of myocardial injury. Assessing the fragmentation pattern of the protein may aid diagnosis of these conditions. Purpose This work represents an examination of cMyC fragmentation in human serum, and studies its utility in differentiating between forms of myocardial injury. Methods Patients who were admitted to a hospital during October-November 2023 with acute myocardial injury were recruited. Acute myocardial injury was defined as a dynamic troponin rise above the 99th centile (Abbott Alinity: cTnI>34ng/L male, cTnI >16ng/L female). Following collection, samples were left at room temperature for 30 minutes and then centrifuged. Serum was separated for cMyC measurement, frozen in liquid nitrogen and stored at -80 °C. Recruited patients were followed up during their inpatient journey. Their final diagnosis was defined using the 4th universal definition of MI by two cardiologists, with a third cardiologist acting as adjudicator, if required. The serum samples were analysed using two separate electrochemiluminescence sandwich ELISA assays detecting different portions of cMyC. One assay formulated for total concentration of cMyC using high affinity mouse N-terminal monoclonal antibodies (mAb) targeting epitopes in close proximity (Limit of Detection (LoD) = 9.0ng/L). The other assay uses a N-terminal and a C-terminal mouse mAb which straddle the major proteolytic cleavage site of cMyC. This assay detects the intact (fuller-length) cMyC (LoD= 14.2ng/L). Both assays perform with good sensitivity, low variability and are capable of detecting cMyC at concentrations well below the 99th centile. Results 11 patient samples were collected with final diagnoses of; type 1 MI (STEMI n=3, NSTEMI n=4), type 4 MI (alcohol septal ablation n=1), acute myocardial injury (myocarditis n=2) and type 2 MI (chest sepsis with known coronary disease n=2). Figure one details the percentage of intact cMyC relative to total cMyC measured in serum for each patient, and is split into their adjudicated diagnosis. The bars display the median and interquartile range (IQR). Our findings suggest that the fragmentation pattern of cMyC could help differentiate between forms of myocardial injury. The ratio of intact: total cMyC was higher in the type 2 MI than any other condition. The results did not reach statistical significance (p = 0.06) due to the small sample size. Conclusions The fragmentation pattern of cMyC is dependent on the type of myocardial injury and could aid in the differentiation between type 2 MI and other forms of myocardial injury.Figure One

Electrocardiographic findings in newborns with inadequate intrauterine growth during pregnancy

Abstract Background Infants born small for gestational age (SGA) or following fetal growth restriction (FGR) have an increased risk of neonatal mortality as well as cardiovascular disease later in life. Prenatal electrocardiograms (ECGs) in fetuses with FGR exhibit QT prolongation. However, neonatal alterations in the conduction system in infants born SGA or with FGR has not previously been assessed in a large cohort of infants. Purpose To investigate potential variations in electrocardiographic parameters between infants born SGA or diagnosed with FGR, in comparison to infants born appropriate for gestational age (AGA). Methods This study was based on data from a population-based cohort study of infants (n>25,000) with prenatal inclusion and postnatal cardiac examination including eight-lead ECG between 2016-2018. We conducted a multiple linear regression analysis to compare ECG parameters among infants with FGR (birthweight <3rd percentile, n=544) and SGA (birthweight ≥3rd and <10th percentile, n=1,384) to infants born AGA (birthweight ≥10th percentile and <90th percentile, n=14,076). Parameters of interest included: heart rate (HR), uncorrected and corrected (Bazzet and Fridericia) QT intervals, QRS duration, PR interval, QRS axis, maximum amplitudes of the R- and S-waves in V1 and V6. All analyses were adjusted for infant sex, gestational age at birth, and weight, length, and age at ECG examination. Results Infants born SGA or with FGR had higher HR and consequently shorter uncorrected QT intervals compared with infants born AGA (Table 1). Infants with FGR had significantly shorter corrected (Fridericias) QT intervals. Infants born SGA had smaller amplitudes of both the R- and S-wave in V6, and significantly larger amplitude of the S-wave in V1, compared with infants born AGA (Table 1). Conclusion ECGs from infants born SGA and infants with FGR differed from infants born AGA, including higher HRs and shorter uncorrected QT-intervals even after adjustments for infant size and age at the examination. Furthermore, we saw infants born SGA had reduced amplitudes of the S and R wave in the lateral lead (V6), and an increased amplitude of the S-wave in V1, compared with infants born AGA. Follow-up examinations of these infants could determine whether these alterations persist beyond the neonatal period, and to fully understand their implications of the cardiac function later in life.

Prevalence of elevated cardiac troponin in five non-cardiac diseases

Abstract Background Cardiac troponins (cTns) are regulatory proteins located in the cardiac muscle cells (cardiomyocytes). Since the 1990s, cTns have been the biochemical gold standard for detecting myocardial infarction. CTns are well studied among patients with cardiac illnesses and elevated concentrations are known to reflect myocardial injury. Still, high cTn concentrations are found in several non – cardiac conditions where signs of cardiac dysfunction are absent(1). This is especially found to be true for cardiac troponin T (cTnT) which is, more frequently than cardiac troponin I (cTnI), found to be elevated in patients with non – cardiac conditions(2,3). A study from 2016 of 1012 patients admitted to the emergency room, found troponin T elevations in 40.8% of patients without acute coronary syndrome vs. 7.4% with cTnI elevations(3). To our knowledge, no previous study has investigated cTn elevations across disease -groups where elevations of cTns are frequently detected. Purpose We aimed to investigate the prevalence of cTnT in five clinical non-cardiac disease-groups where frequent elevation of cTnT is previous described; Sepsis, rhabdomyolysis, end-stage renal disease (ESRD), stroke, and major non-cardiac surgery (MNCS). Methods Our study was a single-center prospective cross-sectional cohort study. Over a 6-month period, we included patients in the five above mentioned disease-groups. We excluded patients with any symptoms of cardiac disease or a prior history of cardiac diseases. All patients were included within 48 hours of admission and underwent clinical examination, vital signs, 12-lead electrocardiogram, echocardiography, and collections of blood samples. Cardiac troponin T was measured at patient’s bedside upon inclusion with the Cobas h232, cTnT point-of-care test. Results 89 patients were eligible for inclusion, 15 with sepsis, 18 with rhabdomyolysis, 11 with end-stage renal disease, 22 with stroke and 23 with major non-cardiac surgery. 53% were men. 17 patients (19%) had signs of cardiac disease confirmed on echocardiographic and/or electrocardiographic examinations and were excluded. Out of the 72 patients without signs of cardiac disease, elevated cTnT above the 99th percentile was found in 21 (29%) patients; 4 (36%) with sepsis, 6 (60%) with rhabdomyolysis, 4 (44%) with ESRD, 2 (9.5%) with stroke and 5 (24%) with MNCS. The median of cTnT in patients with elevated cTnT across all patient groups was 79.5 ng/L (IQR 52.5ng/L – 187.8 ng/L). Conclusions Cardiac troponin T elevations are frequent in the five non-cardiac diseases investigated. Elevations are most frequent in patients with rhabdomyolysis and end-stage renal disease. Further investigation is warranted to elucidate the underlying etiology contributing to the elevation of cardiac troponin in non-cardiac diseases.

Effect of unprocessed and minimally processed foods on blood pressure in children

Abstract Background The poor eating habits of children, including a decrease in the consumption of unprocessed foods and an increase in the consumption of processed foods, have been associated with excess body weight, which is a well-established risk factor for cardiovascular diseases (CVDs), especially high blood pressure (BP). We aimed to investigate whether the consumption of unprocessed and minimally processed foods is associated with high BP in children at nine years of age. Methods Cross-sectional study of 142 Brazilian children participating in a cohort study conducted at the participant’s home. The child’s food consumption markers were evaluated using the Brazilian Food and Nutrition Surveillance System (SISVAN) and were classified by NOVA. Using a standardized procedure for approaching the child, BP was measured by the auscultatory method. Biological, socioeconomical, demographic, and anthropometric data of the mother and child were also collected. Logistic regression analysis adjusting for important predictors was used to evaluate the association between food consumption and BP. Results The prevalence of high BP in children was 20.4%, and the mean systolic and diastolic BP were significantly (p < 0.05) higher in children classified as high BP (110.1 and 71.3 mmHg, respectively). An important proportion (44.8%) of children had excess body weight (>85th percentile) and high BP when compared to eutrophic children. Not consuming healthy foods was associated with high systolic BP, even after adjustment for other important covariates (OR = 3.97; p = 0.028). Conclusions Not consuming healthy foods was associated with increased odds of children having high BP at nine years of age. Interventions promoting a healthy diet and the consumption of fruits and vegetables in childhood may contribute to preventing diseases associated with CVD, a global public health problem. Key messages • Educating parents to avoid processed foods and monitoring children’s BP are essential actions to prevent associated chronic diseases throughout life. • Public policies aimed at educating parents to encourage the consumption of healthy foods may significantly contribute to reducing adverse cardiovascular outcomes.

Echocardiographic findings in newborns with inadequate intrauterine growth during pregnancy

Abstract Background Infants born small for gestational age (SGA) or diagnosed with fetal growth restriction (FGR) are at increased risk of neonatal mortality as well as cardiovascular disease later in life. Previous studies based on smaller cohorts (n<200) of newborns with SGA and FGR (n<200) have demonstrated structural and morphological alterations in the heart compared to infants born appropriate for gestational age (AGA). However, to our knowledge no previous study has systematically investigated the effect of SGA and FGR on echocardiographic parameters in the infant heart. Purpose To investigate whether echocardiographic parameters differ among infants born SGA or with FGR, in comparison to infants born AGA. Methods This study is a population-based cohort study of infants (n>25,000) offering postnatal cardiac examination including transthoracic echocardiography (TTE) between 2016-2018. We compared left ventricular (LV) TTE parameters in infants born SGA (birthweight ≥3rd and <10th percentile, n=2,106) and with FGR (birthweight <3rd percentile, n=972) with infants born AGA (birthweight ≥10th and <90th percentile, n=20,468) using a multiple linear regression analysis. We have investigated LV volumes, systolic function, diastolic function, and LV structure. All analyses were adjusted for sex, gestational age at birth, weight, length, and age at cardiac examination. Results Infants born SGA had higher heart rates compared with infants born AGA. Both infants born SGA and infants with FGR had significantly smaller LV dimensions including septal and posterior wall thicknesses (IVSd and LVPWd), and LV internal diameters (LVIDd and LVIDs). Infants born SGA had smaller end-diastolic and end-systolic volumes compared with infants born AGA (Table 1). Infants born SGA or with FGR had significantly higher mitral valve early peak velocities, compared with infants born AGA, and infants born SGA showed increased mitral valve atrial peak velocities indicating altered diastolic function (Table 1). Conclusion Infants born with inadequate intrauterine growth had smaller LV dimensions compared with infants born AGA, even when adjusting for infant size and age. Infants born SGA and with FGR both exhibited altered diastolic function. Longitudinal studies of children with inadequate intrauterine growth are needed to determine the impact on adult cardiac health.

Renal hyperfiltration as risk factor of major adverse cardiovascular events in patients with acute myocardial infarction

Abstract Objectives While the interaction between heart and kidney potentially contributes the development of renal hyperfiltration (RHF), its clinical consequence of is not clear in patients with acute myocardial infarction (AMI). Methods A total of 9,561 AMI patients with estimated GFR (eGFR) ≥60 mL/min/1.73 m² were enrolled from a large nationwide, multi-center, prospective, observational cohort between November 2011 and December 2015. RHF was defined as eGFR >90th percentile after multiple adjustments. The primary endpoint was a combination of 3-year major adverse cardiovascular events (MACEs) after AMI treatment. Results The cumulative event rate of MACEs was significantly higher in patients with RHF. In multivariable Cox-regression analysis, RHF increased the 1.34-fold risk of MACE (95% confidence interval [CI] 1.12-1.62) compared to those without RHF. Patients with RHF had a significantly higher risk of all-cause mortality (hazard ratio [HR] 1.64; 95% CI 1.25-2.14) and cardiac death (HR 1.78; 95% CI 1.26-2.51). There was a linear correlation between the adjusted risk of MACEs and eGFR, with the risk increasing as eGFR exceeded approximately 100 mL/min/1.73 m². In the 1:1 propensity-score matched population, the cumulative event rate of MACEs, all-cause mortality, and cardiac death were consistently higher in patients with RHF (all p <0.05). Conclusion RHF was significantly associated with an increased risk of MACEs, all-cause mortality, and cardiac death following AMI compared to patients without RHF. Our study offers new insights into the risk stratification of AMI patients presenting with RHF.

Association between arterial oxygen tension with clinical outcomes in patients undergoing VA-ECMO support: a systematic review and dose-response meta-analysis

Abstract Background Arterial hyperoxia has been associated with a worse prognosis in critically ill patients. However, studies conducted in patients undergoing Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO) used inconsistent and arbitrary thresholds for defining hyperoxia, which impeded the determination of the optimal target for arterial oxygen tension (PaO2) in this population. Purpose To investigate and visualise the dose-response relationship between post-ECMO level of PaO2 with early mortality (in-hospital and 1-month) and poor neurological outcomes in adult patients undergoing VA-ECMO support, including Extracorporeal Cardiopulmonary Resuscitation (ECPR). Methods A systematic search was conducted through Pubmed and Embase to include studies that stratified patients based on PaO2 levels and evaluated relevant outcomes. We utilised either adjusted Odds Ratio (OR) with 95% Confidence Interval (CI) when available, or unadjusted OR against the lowest exposure category. The median, mean, or midpoint value of PaO2 was assigned as the corresponding dose. A random-effects one-stage dose-response meta-analysis was performed to assess linear association for every 10 mmHg increase in PaO2, while potential non-linear relationship was explored with restricted cubic splines at 3 knots (10th, 50th, and 90th percentile). Non-linearity was assessed by using Wald test with p value <0.05 considered significant. Statistical analyses were performed using STATA 17.0. Results Fourteen eligible records were identified (cardiogenic shock/CS = 5 records; ECPR = 8 records; both = 1 record). Only four studies classified a separate category for hypoxemic patients (<60 mmHg). PaO2 levels were measured within 24-72 hours of VA-ECMO initiation, except in one study. PaO2 level was not associated with early mortality (9 studies; OR 1.021 [95% CI 0.988–1.055]; p for non-linearity = 0.893), but found to have a linear association with composite poor neurological outcomes (6 studies; OR 1.016 [1.009–1.024]; p for non-linearity = 0.346). Subgroup analysis of CS patients revealed a linear association between PaO2 >100 mmHg and early mortality (4 studies; OR 1.025 [95%CI 1.018–1.032]; p for non-linearity = 0.255). For ECPR patients, a J-shaped relationship was observed between PaO2 and early mortality (5 studies; p for non-linearity = 0.004), with the lowest odds being at PaO2 level of 110-210 mmHg, while PaO2 level >110 mmHg showed a linear trend towards higher odds of poor neurological function (4 studies; OR 1.091 [95%CI 0.938–1.269]; p for non-linearity = 0.257). Conclusion Pooled data from observational studies suggest that PaO2 >100 mmHg should be avoided in CS patients on VA-ECMO support, given its linear association with mortality, but it cannot be extrapolated to hypoxemic patients. In ECPR patients, PaO2 level around 110-210 mmHg conferred the best clinical outcomes. However, these findings should be confirmed through randomised controlled trials.

Relationship between lipoprotein(a) and endogenous fibrinolytic status in patients with STEMI

Abstract Background The risk of myocardial infarction is at least doubled in individuals with lipoprotein(a) (Lp[a]) levels >90th percentile.[1] Lp(a) may exert pro-thrombotic effects by impairing fibrinolysis. Lp(a) has a high degree of homology to plasminogen and can competitively inhibit tissue plasminogen activator (tPA)-mediated plasminogen activation and tPA-mediated clot lysis.[2] Furthermore, Lp(a) stimulates the activity of plasminogen activator inhibitor-1, the major inhibitor of the fibrinolytic system. In patients with ST-segment elevation myocardial infarction (STEMI), impaired endogenous fibrinolysis is a strong, independent risk factor for recurrent cardiovascular events,[3] but the drivers of this are not fully understood. Whether impaired endogenous fibrinolysis is related to increased Lp(a) levels in patients with STEMI, is not known. Purpose We aimed to assess the relationship between Lp(a) and endogenous fibrinolysis in patients with STEMI. Methods In a prospective, observational study, venous blood samples were drawn from patients presenting with STEMI immediately before revascularisation, after dual antiplatelet therapy but before heparin administration. Endogenous fibrinolysis was measured immediately in non-anticoagulated whole blood using the point-of-care Global Thrombosis Test, which measures the time for occlusive thrombus formation under high shear (occlusion time) and the time for spontaneous lysis of the thrombus (lysis time).[3] Assessment of Lp(a) levels, measured by particle enhanced immunoturbidimetric assay, was performed with paired plasma samples, standardized against the International Federation of Clinical Chemistry reference material SRM2B for nmol/L. Lp(a) >32 nmol/L is associated with increased risk of ischaemic heart disease. Results A total of 80 patients were included (age 64±14y, 25% females and 86% Caucasian). There was a positive correlation between Lp(a) level and lysis time (r = 0.330, P = 0.003) (Figure 1). Lysis time was significantly longer in patients with Lp(a) >32 nmol/L (2782 [1626-3683] vs. 1725 [1259-2955] s, P = 0.044). Using a cut-point of lysis time ≥2500 s previously associated with a significantly increased cardiovascular risk in patients with STEMI, we showed that Lp(a) was significantly higher in patients with lysis time ≥2500 s (40 (22-111) vs. 18 (7-73) nmol/L, P = 0.045). Table 1 shows the relationship between clinical characteristics and Lp(a) and lysis time. Lp(a) level was higher in non-Caucasian patients. There was no correlation between Lp(a) and occlusion time (r = 0.156, P = 0.168). Conclusion In patients with STEMI, longer endogenous fibrinolysis time is related to higher Lp(a) level. Raised Lp(a) levels may, in part, contribute to impaired endogenous fibrinolysis. Future studies are required to assess whether reduction in Lp(a) with novel therapies currently in phase 3 trials can favourably modulate fibrinolysis and improve clinical outcomes.Figure 1

Social vulnerability and disparities in incidence of diagnosed diabetes in the united states, 2004 to 2019

Abstract Introduction Vulnerable populations experience a higher burden of cardiovascular disease.(1) However, the incidence of cardiovascular risk factors, such as diabetes, within these populations, is incompletely characterized. Recently, the United States Centers for Disease Control and Prevention (US CDC) developed the Social Vulnerability Index (SVI) to categorize counties that may be vulnerable to worse health outcomes. The SVI is composed of 4 themes: socioeconomic status (Theme 1), household composition & disability (Theme 2), minority status & language (Theme 3), and housing type & transportation (Theme 4).(2) We sought to evaluate the association of the 4 SVI themes with county incidence of diagnosed diabetes. Method We used CDC data (2004-2019; reported for 94% of US counties), on county incidence of diagnosed diabetes. The SVI themes were scored from 0 to 1 (low to high vulnerability) based on national percentile ranking. We used weighted least squares regression with restricted cubic splines to model the relationship between SVI themes and incidence of diagnosed diabetes (median data 2004−2019), adjusting for median age, sex ratio, state, percent uninsured, food environment index, healthcare providers, and rurality.(3) The partial effects of SVI themes and diabetes incidence were reported as F-statistics (P-values) and diabetes incidence rate ratios (IRR [95% confidence interval]), which were plotted for all values compared with the 50th percentile (SVI 0.5). For each theme, we also present the IRR for a 0.5-point increase when moving over the lower (SVI score 0.5 vs. 0.0) and the upper (1.0 vs. 0.5) half of the SVI score distribution. Results The 4 SVI theme rank scores were significantly associated with diabetes incidence (all, P<.001). However, Theme 1 and 2 scores showed stronger associations with IRR than Theme 3 and 4 (Figure). For Theme 1, SVI score 0.5 vs. 0.0 was associated with a 15% higher incidence (IRR 1.15 [1.13–1.18]) and score 1.0 vs. 0.5 was associated with a 13% higher incidence (IRR 1.13 [1.11–1.16]). For Theme 2, SVI score 0.5 vs. 0.0 was associated with a 16% higher incidence (IRR 1.16 [1.14–1.18]), but there was no difference between rates for SVI score 1.0 vs. 0.5 (IRR 1.01 [0.99–1.03]). For Theme 3, there was no difference between SVI score 0.5 vs. 0.0 (IRR 0.98 [0.96–1.00]), but rates were 8% lower for SVI score 1.0 vs. 0.5 (IRR 0.92 [0.90–0.94]). For Theme 4, SVI score 0.5 vs. 0.0 was associated with a 3% lower incidence (IRR 0.97 [0.96–0.99]) and score 1.0 vs. 0.5 was associated with a 2% higher incidence (IRR 1.02 [1.01–1.04]). Conclusion In US counties, the strength and directionality of the association between SVI themes and diabetes incidence differed by theme and level of SVI scores. These themes, particularly socioeconomic status and household composition & disability may be leveraged to identify high-risk counties for primary prevention of diabetes, with implications for reduction in cardiovascular risk.

Improving the functional detection of sarcopenic obesity: prevalence and handgrip scoring in the OBESAR cohort.

The study objectives were: 1) to detect early signs of low muscle function and assess sarcopenic obesity (SO) prevalence in patients with obesity; and 2) to introduce a new online diagnostic tool for scoring handgrip strength (HGS), adjusted for age and sex. Patients from the OBESAR cohort (184 men and 499 women) were tested for body composition and functional testing (chair stand test or HGS based on the cutoffs from the European Society for Clinical Nutrition and Metabolism [ESPEN]/European Association for the Study of Obesity [EASO] or adjusted HGS [adHGS] based on reference values), and SO prevalence was calculated accordingly. Among the 683 patients (mean [SD], age 42.6 [12.8]years; BMI 44.4 [6.3] kg/m2), HGS averaged 25.6 (6.8) kg for women and 43.2 (10.4) kg for men. A total of 25.2% of patients had adHGS lower than the 10th percentile, but this was true for only 5.6% using ESPEN/EASO cutoffs of HGS. SO prevalence rates were different according to functional tests: 5.4%, 24.5%, and 3.2% for HGS, adHGS, and the chair stand test, respectively. Using adHGS through a scoring process considering age and sex may help to detect early signs of SO in a primary care setting in order to better prevent SO through a personalized approach in adults with obesity. A free online application, "GRip And Sarcopenia Prediction" (GRASP), is proposed to diagnose probable SO.

Lipoprotein (a), coronary artery disease risk, and MACE in individuals without standard modifiable risk factors in the UK Biobank

Abstract Background A significant proportion of patients with coronary artery disease (CAD) lack standard modifiable risk factors (SMuRFs; smoking, hypercholesterolaemia, diabetes and hypertension), for example with recent analyses demonstrating that around 25% of patients with ST-elevation myocardial infarction are SMuRF-less(1). With continued focus on primary prevention in cardiovascular disease, the SMuRF-less subset is likely to increase over time. A body of evidence has implicated lipoprotein (a) in CAD, but no such studies have investigated this association in a purely SMuRF-less population. Purpose To investigate the role of lipoprotein (a) in predicting CAD risk and major adverse cardiovascular events (MACE) in a large, SMuRF-less cohort. Methods The UK Biobank is a large prospective multicentre study which recruited over 500,000 participants in the UK aged 37-73 years at entry between 2006-2010. SMuRFs were defined as 1) smoking (current or historical), 2) hypercholesterolaemia – lipid lowering medication on enrolment or total cholesterol >5.5mmol/L or LDL-C >3.5mmol/L, 3) previous diagnosis of diabetes mellitus, or HbA1c >48mmol/mol, 4) previous diagnosis of hypertension. MACE was defined as a composite of coronary artery disease – previous myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft surgery –, stroke, or all-cause mortality. Results Of the total UK Biobank cohort, 46,139 participants were identified as SMuRF-less together with a valid lipoprotein (a) level. Median follow-up duration was 12yrs. In univariate analyses (Table 1), there was no significant difference in lipoprotein (a) concentrations between individuals with and without MACE (16.9 vs. 17.1nmol/L respectively, p = 0.913). The overall event rate was low, with just 3% MACE (1381 events) overall. Older age, male gender, apolipoprotein A, apolipoprotein B, HbA1c level, HDL cholesterol level and body mass index were all associated with MACE. In regard to all-cause mortality alone, there was no association with lipoprotein (a) level, although the other aforementioned parameters were all significantly associated with this outcome. Similarly, lipoprotein (a) was not a significant predictor of stroke. However, there was a large difference in lipoprotein (a) levels between patients with and without CAD (27.2 vs. 17.1nmol/L respectively, p = 0.004). In Kaplan-Meier analysis, lipoprotein (a) level above the 77th percentile (60.3nmol/L) was significantly associated with CAD (p=0.032). In Cox regression models, despite the low event rate, lipoprotein (a) was a significant predictor of CAD (HR 1.00-1.01, p=0.01), and importantly the only potentially modifiable parameter (N = 39,433, 111 events, Table 2). Conclusion Lipoprotein (a) independently predicts CAD in those without SMuRFs, highlighting the importance of checking this parameter in such patients, particularly given the novel antisense technologies in development which may lower lipoprotein (a)(2).Univariate analysesCox regression for CAD

High eosinophil counts aid in diagnosing Kawasaki disease in febrile children

Abstract Background Several recent studies have validated the newfound significance of elevated eosinophils in Kawasaki disease (KD). However, this finding was not incorporated into the suggested laboratory criteria outlined by the Kawasaki Disease Committee of the American Heart Association for assessing children with incomplete KD. Purpose We aimed to determine the potential benefits of including eosinophil levels in the laboratory evaluation of KD. Methods A retrospective cohort study involved 77,934 febrile children (FC, not KD) and 1,970 subjects diagnosed with KD. Participants were recruited from four hospitals, comprising two medical centers and two regional hospitals. The AHA recommends specific laboratory tests—white blood cell count, hemoglobin, platelet count, ALT levels, albumin, and urinalysis—for evaluating incomplete KD in children with a higher CRP than 30mg/dL. The first four items are standard blood assays. Additionally, we introduced high eosinophil counts as a new diagnostic criterion for identifying children with KD. Results All these five laboratory findings (anemia for age defined as below the 5th percentile), platelet count >450,000/mm3, white blood cell>15,000/mm3, ALT>40 U/L, and eosinophil count >190/mm3) are significantly different between KD children and FC. The proportion of having these features is higher in KD children than in FC (19.3% vs. 8.0% in anemia for age, 20.5% vs. 10.3% in thrombocytosis, 37.0% vs. 18.1% in leukocytosis, 45.7% vs. 5.8% in elevated ALT, and 62.6% vs. 29.3% in high eosinophils). Elevated eosinophil counts are most commonly associated with KD among these five parameters. Furthermore, when incorporating the parameter of elevated eosinophil counts, the proportion of KD children with at least two abnormalities rose from 35.4% to 60.7%. In a subgroup analysis of children with KD presenting at least two abnormalities, the proportion rose from 38.7% to 63.5% in the high CRP group (≧ 3.0 mg/L) and 21.6% to 49.0% in the low CRP group (< 3.0 mg/L), respectively. Conclusions Higher eosinophil counts are vital markers in KD children. This aids in the identification of additional potential KD cases, especially in those exhibiting low CRP levels.

Comparison of the predicting value for incident cardiovascular events by vascular age based on brachial-ankle pulse wave velocity or carotid-femoral pulse wave velocity

Abstract Background There is a good correlation between brachial-ankle pulse wave velocity（baPWV）and carotid-femoral pulse wave velocity (cfPWV). Whether baPWV has the same predictability for cardiovascular risk as cfPWV in calculating vascular age remains to be clarified. Purpose This study examines which vascular age calculated by baPWV or cfPWV has a stronger association with the risk of cardiovascular events. Methods This prospective cohort study included 5725 participants from a community atherosclerosis cohort in Beijing, China. Vascular age was the predicted age in a multivariable regression model, including classical cardiovascular risk factors (sex, systolic and diastolic blood pressure, glycemia, triglyceride, low density lipoprotein cholesterol, waist, body mass index, heart rate, smoking) and treatment (anti-hypertensive agents, hypoglycemic agents, lipid-lowering agents) and pulse wave velocity. Residuals between chronological age and vascular age were defined as ∆-age, and the 10th and 90th percentiles of ∆-age were used as cutoffs to define supernormal vascular aging, normal vascular aging, and early vascular aging, respectively. The major adverse cardiovascular event was a composite of myocardial infarction, stroke, and cardiovascular death. The study used Cox proportional hazards regression to examine the association between vascular age and major adverse cardiovascular events. Results During the median 3-year follow-up period, 172 endpoint events were observed. After adjusting for age and sex, ∆-age as a continuous variable calculated by baPWV was significantly and increasingly associated with cardiovascular events (every 1-year increase led to a rise of 1.04% [95% confidence interval [CI]: 1.00%-1.08%; p=0.03] in cardiovascular events risk). After adjusting for age, sex, smoking, body mass index, hypertension, diabetes, dyslipidemia, anti-hypertensive agents, lipid-lowering agents, hypoglycemic agents, family history of atherosclerotic cardiovascular disease, and estimated glomerular filtration rate, early vascular aging group calculated by baPWV had an increased risk of cardiovascular events (hazard ratio: 1.76; 95% CI: 1.19-2.62 p=0.005), compared with the normal vascular aging group. In contrast, no significant results were observed in vascular age calculated by cfPWV. Conclusion(s) Vascular age calculated by baPWV has a stronger predictive ability for cardiovascular events than that calculated by cfPWV in the Chinese population. Considering baPWV is a simple and convenient method, it is recommended for vascular age calculation.

Relationship of body height to thoracic aortic length: implications for sex differences and normative values

Abstract Introduction The scaling of organ to body size is highly variable and can affect organ function in individuals of different sizes. Despite the relationship between aortic length and body size, to our knowledge, its scaling relationship has not been assessed. We assessed the allometric relationship between thoracic aortic length and body height and generated normative data for this important structural parameter. Methods Using a convolutional neural network (U-Net) we segmented the thoracic aorta among 49,282 UKBB participants who underwent magnetic resonance imaging. To define normal allometric relationships, we included a highly selected subgroup (n=3,856) without cardiovascular risk factors or prevalent cardiovascular disease. Allometric relations were estimated using sex-adjusted log-log models. Results The mean thoracic aorta centerline length was 31.68 (SD=2.50) cm. Males exhibited longer thoracic aortas than females (32.93 vs. 31.15 cm; P<0.0001). In log-log models, body height accounted for 13.4% of the population variability in thoracic aortic length (R2=0.134; P<0.0001). The allometric power relating thoracic aortic length to body height was highly sublinear (power point estimate=0.44; 95% CI:0.37, 0.50). Sex was a predictor of thoracic aortic length (β=0.02; 95%CI=0.014, 0.029; P<0.0001), indicating that for any given body height, females had slightly shorter thoracic aortas compared to males. Among males, the 5th, 25th, 50th, 75th and 95th percentiles of allometrically scaled aortic length were 2.69, 3.20, 3.36, 3.53, and 3.96, respectively. Among females, the corresponding percentiles were 2.69, 3.11, 3.29, 3.46, 4.01. Conclusions The thoracic aorta exhibits a highly sublinear length relationship with body height, suggesting that disproportionate length relationships at the extremes of body height may have an important impact on pulsatile hemodynamics. Females exhibit slightly shorter thoracic aortas than males even after accounting for body height in an allometric fashion.aorta length vs height

Prognostic importance of persistent elevations in high-sensitivity troponin T in the early convalescent phase (two weeks) following high-risk myocardial infarction: insights from the PARADISE-MI trial

Abstract Introduction Myocardial infarction (MI) is defined by a rise and fall in cardiac troponin (cTn) with clinical evidence of acute myocardial ischemia. How often cTn remains elevated in high-risk patients stabilized following MI and the relation between convalescent cTn levels and subsequent clinical outcomes in these patients is unknown. Aims To evaluate the prognostic importance of high-sensitivity cTn T (hs-cTnT) in the early convalescent phase of a MI for a range of cardiovascular (CV) outcomes in patients enrolled in the Prospective ARNI vs ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI). Methods Patients ≥18 years without prior heart failure (HF) (n=5661) were randomized to sacubitril/valsartan or ramipril within 0.5 to 7 days of MI complicated by transient pulmonary congestion, LVEF ≤40%, or both. Hs-cTnT was measured using the Roche Elecsys Troponin T-high-sensitive assay in 1093 patients two weeks after randomization (median 2.6 weeks after the index MI). Associations between log (2)-transformed hs-cTnT and clinical outcomes were investigated in landmark analyses using Cox regression models adjusted for clinical covariates of known prognostic importance and NT-proBNP (Figure). Results Median week 2 hs-cTnT concentration was 34 ng/L [IQR 17-94 ng/L] and exceeded the 99th percentile upper reference limit in 69% of patients. Patients with persistently elevated hs-cTnT concentrations (n=753) were older, more likely men, more commonly had atrial fibrillation and lower estimated glomerular filtration rate and less likely had a prior MI. They more commonly had presented with ST-segment elevation MI and pulmonary congestion and had higher concentrations of NT-proBNP. Rates of primary reperfusion were similar. Log(2)-transformed hs-cTnT was only weakly correlated with LVEF (rho = -0.15, p<0.001), irrespective of the type of MI. hs-cTnT was independently and linearly associated with the primary composite outcome of CV death or incident HF (adj HR 1.17 per doubling; 95% CI, 1.03 – 1.34), all-cause death (adj HR 1.20; 95% CI, 1.01 – 1.44) and CV death (adj HR 1.25; 95% CI, 1.02 – 1.52) but not with non-CV death (adj HR 1.04; 95% CI, 0.70-1.54). hs-cTnT was not significantly associated with recurrent fatal or non-fatal MI (adj HR 1.00; 95% CI, 0.85-1.18) (Figure). Concentrations of week 2 hs-cTnT were not altered by sacubitril/valsartan relative to ramipril (+4%; 95% CI, -8% to 18%). Conclusions Persistent elevations in hs-cTnT during the early convalescent phase following high-risk MI are common and are associated with heightened risk of all-cause death, CV death and incident HF but not of recurrent MI or non-CV death. hs-cTnT measured ~2.5 weeks after high-risk MI provides incremental prognostic information beyond traditional risk factors and NT-proBNP.

Association between genetic predisposition of AF and the risk of ischemic stroke and thromboembolism

Abstract Background Ischemic stroke and thromboembolism are the major complications of atrial fibrillation (AF), however, its association with genetic background of AF remains unclear. To investigate the association between genetic predisposition of AF underlying common variants and the risk of ischemic stroke and thromboembolism. Methods We included unrelated individuals with non-valvular AF from UK biobank. The polygenic risk scores of AF (PRSAF) was calculated for each individual using the effect weight from a previous study which has been validated in both European and mixed-ancestry population[1, 2]. The SNPs from the original score were lifted over to GRCh38 and 6514708 of 6730541 were available in the UK biobank genotype data. The clinical data was defined by ICD-10 code. The primary endpoint is ischemic stroke or thromboembolism resulting in hospitalization after first AF diagnosis. Results A total of 28810 unrelated patients were included in the study. Among them, 4064 had PRSAF over 90th percentile of the general population, and were considered having high genetic risk. The rest 18746 with per SD increase in PRSAF lower than 90th percentile of the general population were considered having lower genetic risk. Generally, age and sex adjusted model demonstrated that per standard deviation change in PRSAF is associated with 9% increase in the risk of stroke or thromboembolism (HR=1.09, 95%CI: 1.03-1.14), and patients with high genetic risk was associated with 15% increase in the risk of stroke or thromboembolism (HR=1.15, 95%CI: 1.02-1.31).The result remained stable when further adjusted for clinical risk factors (1.09, 95%CI: 1.04-1.15 per SD increase in PRSAF) and competing risk of death (1.10, 95%CI: 1.05-1.16 per SD increase in PRSAF). There was no interaction between CHA2DS2-VASc score risk stratification and the per SD increase in PRSAF (P interaction = 0.751, Figure 1A). However, the association between per SD increase in PRSAF and the event tended to be affected by age at AF onset (HR = 1.02 95%CI: 0.94, 1.11 for early onset AF; HR = 1.12 95%CI: 1.05, 1.19 for non-early onset AF, P for interaction = 0.062, Figure 1B). Multi-variate COX regression including PRSAF, components of CHA2DS2-VASc score, and other AF risk factors revealed that history of stroke/thromboembolism, age over 65 years, hypertension, diabetes and high AF genetic risk were significantly associated with the outcome (Figure 1C). To evaluate the importance of these risk factors, average population attributable fraction for 10-year risk of stroke/thromboembolism in the study population was calculated, indicating that genetic risk of AF is responsible for 3.26% (0.89%-5.63%) of the events (Figure 1D). Conclusion Genetic predisposition of AF underlying common variants is associated with ischemic stroke and thromboembolism independent of clinical risk factors. But its role in different AF populations, like early onset AF, remains further investigation.Figure 1

Menopausal status and clinical outcomes in women with heart failure with reduced ejection fraction: the GALACTIC-HF trial

Abstract Introduction Mechanisms driving disease progression and potential responsiveness to investigational therapies may theoretically differ among women with heart failure (HF) based on menopausal status. However, few data are available describing the clinical course of premenopausal and postmenopausal women with HF. We investigated differences in baseline characteristics, clinical outcomes, and response to omecamtiv mecarbil in premenopausal and postmenopausal women participants of the GALACTIC-HF trial. Methods The GALACTIC-HF trial randomized patients with symptomatic HFrEF with LVEF of 35% or less to omecamtiv mecarbil or placebo. Menopausal status at randomization was collected. When menopausal status was unknown/unreported, menopausal status was inferred based on the expected distribution of age at menopause in the general population. The risk of the primary endpoint, worsening HF event or cardiovascular death, was compared among women by menopausal status using Cox regression models adjusted for clinical covariates, including age and baseline EF. Treatment effect heterogeneity was evaluated by menopausal status. Results Of the 8,232 patients enrolled, 1,749 (21.2%) were women. Menopausal status was available at baseline in 1,483 (84.8%). One hundred women reported being potentially childbearing (pre-menopausal) and 1,383 women reported being post-menopausal. Among the 266 patients that had unknown menopausal status, those younger than 47 years were additionally classified as pre-menopausal and those older than 56 years as post-menopausal based on estimated 10th /90th percentiles extrapolated from the general population. Compared to post-menopausal women, pre-menopausal women were younger, had higher eGFR, and had fewer comorbidities. Premenopausal women also had slightly higher BMI and lower LVEF, but lower NTproBNP and troponin at baseline compared to postmenopausal women. Premenopausal and postmenopausal women had similarly high burden of symptoms as assessed by the KCCQ-total symptoms score (median 63.5 vs. 64.6; P=0.79). During a median follow-up of 22 months, premenopausal and postmenopausal women experienced similar rates of primary and secondary outcomes (Table 1). Omecamtiv mecarbil was beneficial across the entire female cohort with no effect modification by menopausal status (Pinteraction=0.39). Sensitivity analysis excluding all women with unknown menopausal status yielded similar results. Conclusions In this high-risk HFrEF cohort, premenopausal women experienced similar rates of adverse cardiovascular outcomes as post-menopausal women despite younger age, fewer comorbidities, and lower cardiac biomarkers. Additional research is necessary to understand how risk factors unique to females might influence outcomes in those with heart failure. The benefit of omecamtiv mecarbil on reducing cardiovascular risk was consistent regardless of menopausal status.Primary/secondary outcomes by menopausal

Imprecision and real-time clinical performance of a whole blood high sensitivity point of care troponin i: ready for prime time?

Abstract Introduction High sensitivity troponin (hs-cTn) measurement is central to rapid diagnostic algorithms in acute coronary syndrome (ACS). Point of care (POC) testing reduces turnaround time when compared to central lab (CL) testing. Currently there is very little data on the performance of POC hs-cTn assays in a clinical environment with non-expert operators. Method In a nested sub-study of a randomised controlled trial (RCT), patients with suspected ACS were randomised to either the ESC 0/1 or 0/3 hour algorithm. They underwent whole blood (WB) sampling for Siemens Atellica VTLi hs-cTnI POC (VTLi POC), CL hs-cTnI and CL hs-cTnT assays. This was for both initial and repeat samples. Assay imprecision of the VTLi POC assay was assessed by 2 runs of 10 tests with whole blood at 9 different troponin levels. 4 devices were used with samples stored at room temperature.Final diagnosis was adjudicated based on all relevant clinical and imaging data together with CL hs-cTnT as the diagnostic biomarker in clinical use (10% coefficient of variation (CV) 3-5 ng/L, 99th percentile 14 ng/L) and using the 4th universal definition of myocardial infarction (MI). Clinical performance was assessed using Receiver Operator Characteristics (ROC) curves. Results 2144 patients consented and had WB VTLi POC, CL hs-cTnI and CL hs-cTnT available. The index adjudicated type 1 MI rate was 6.1%. Assay imprecision of the VTLi POC assay demonstrated a 10% Coefficient of Variation (CV) at 9.8ng/l. This was >50% lower than the 99th centile of 23ng/l (average for males and females) (Figure 1). Clinical performance of the VTLi POC assay was acceptable and equivalent to CL hs-cTnT: Area Under Curve (AUC) 0.92 (0.89-0.96), 0.98 (0.96-0.99) and 0.93 (0.87-0.98) at presentation (Figure 2), 1 and 3 hours respectively. However, clinical performance was inferior to CL hs-cTnI: AUC 0.96 (0.95-0.98) and 0.96 (0.93-0.98) at presentation (p=0.0007) and 3 hours (p<0.0001) respectively. Conclusion The Siemens Altellica VTLi hs-cTnI POC assay has imprecision levels consistent with a high sensitivity troponin assay. It has acceptable clinical performance though inferior to the equivalent CL hs-cTnI. Further validation of this assay, particularly with optimised single sample rule-out, could facilitate its use in routine clinical practice.

Performance of an automated echocardiographic artificial intelligence model. to detect subclinical heart failure with preserved ejection fraction (HFpEF) in community-dwelling older adults

Abstract Background Heart failure (HF) with preserved Ejection Fraction (HFpEF) is common among older adults and associated with a high burden of morbidity and mortality. Early identification of subclinical HFpEF, defined by abnormalities in cardiac structure and function without symptoms of HF, can prompt early initiation of evidence-based therapies to prevent HFpEF. However, scalable strategies for the identification of subclinical HFpEF are lacking. Purpose To evaluate the performance of a validated, automated echocardiographic artificial Intelligence algorithm (Ultromics, UK) to identify subclinical HFpEF among community-dwelling individuals without HF. Methods The study included participants of the Dallas Hearts and Minds Study without HF who underwent cardiovascular phenotyping with resting and exercise echocardiography and maximal cardiopulmonary exercise testing. The resting apical 4C echocardiographic images were analyzed by the AI echo algorithm to identify the HFpEF phenotype (AI-HFpEF). Subclinical HFpEF was defined by E/e’ >14 and Peak exercise oxygen uptake (VO2peak) <25th percentile for the cohort. The performance of the AI algorithm to detect subclinical HFpEF was determined using the area under the receiver operating curve and decision curve analysis and was compared with the previously validated H2FpEF score. The association between the AI-HFpEF phenotype and the presence of subclinical HFpEF, VO2peak, exercise E/e’, left ventricular strain, and left atrial strain was assessed using multivariable-adjusted logistic and linear regression models. Results The study included 511 participants (mean age: 61 y, 57% women, mean VO2peak = 16.9 ml/kg/min). Using the AI echo algorithm, subclinical HFpEF was detected in 10% of participants (n=76), and 10% were non-diagnostic. The participants with (vs. without) AI-HFpEF phenotype were older and had a higher burden of CVD risk factors, left ventricular hypertrophy, and left atrial dilation. Subclinical HFpEF, as defined by the gold standard criteria, was present in 5.3% of participants. The AUROC for diagnosis of subclinical HFpEF using the AI-HFpEF algorithm was 0.85 vs. 0.78 by the H2FpEF score (see Figure). In the adjusted analysis, the AI-HFpEF phenotype was significantly associated with greater odds of subclinical HFpEF by exercise and echocardiographic phenotyping criteria, higher E/e’ with exercise, lower VO2 peak, and worse LV and LA strain (see Table). In decision curve analysis, the AI-HFpEF algorithm identified 23 additional cases of subclinical HFpEF per 1000 screened participants compared with the H2FpEF score. Conclusion The AI-HFpEF algorithm can reliably identify community-dwelling individuals with subclinical HFpEF characterized by diastolic dysfunction at rest or exercise and impaired exercise capacity. Future studies are needed to assess the utility of the AI-HFpEF algorithm in screening for subclinical HFpEF in health systems.