Abstract Background Human Immunodeficiency Virus (HIV) has become a treatable, chronic condition, but people with HIV still face an elevated risk of cardiovascular disease, including heart failure. Purpose To assess echocardiographic alterations in left ventricular (LV) function in a contemporary cohort of well-treated people with HIV compared to the general population. Methods We included 744 people with HIV frequency matched 1:1 on age and sex with controls from the general population. Both people with HIV and controls underwent echocardiography, physical examination, questionnaires and blood sampling according to similar study protocols. LV systolic dysfunction was defined as LV ejection fraction (LVEF) <50% or absolute global longitudinal strain (GLS) <16%. LV diastolic function was defined as abnormal if the following was true for half or more available parameters: (1) average E/e’>14, (2) septal e’ velocity < 7 cm/s or lateral e’ velocity <10cm/s, (3) tricuspid regurgitation velocity >2.8 m/s, (4) left atrial volume index >34ml/m2. Associations between HIV status and LV function were assessed using linear and logistic regression models adjusted for age, sex, smoking, hypertension, diabetes mellitus, total cholesterol and high-sensitivity C-reactive protein. Among people with HIV, the association between HIV-specific characteristics and LV function were assessed using logistic regression models with adjustment for the same potential confounders. Results Mean age was 53.4 years and 88% were male. For people with HIV, median time since HIV diagnosis was 18 years and 99% received antiretroviral therapy. People with HIV had lower adjusted mean absolute GLS [17.6 vs. 18.5%, p<0.001], E/A ratio [1.0 vs. 1.2, p<0.001] and average e’ [9.5 vs. 10.5 cm/s, p<0.001] than controls, while LVEF and E/e’ were not significantly different between people with HIV and controls (Figure 1). HIV was associated with impaired systolic function as assessed by GLS [odds ratio 1.70, 95% CI: 1.17-2.46, p=0.005], but not when assessed by LVEF [odds ratio 1.06, 95% CI: 0.78-1.45, p=0.69](Figure 2). Living with HIV was not associated with diastolic dysfunction compared to controls [odds ratio 0.97, 95% CI: 0.61-1.52, p=0.88], but longer HIV-duration was associated with higher odds of diastolic dysfunction among people with HIV (odds ratio 1.06, 95% CI: 1.02-1.10 per year, p=0.004). Current antiretroviral medication type, previous AIDS defining conditions, current CD4+ count and detectable viral load were not associated with LV dysfunction. Conclusion People with HIV show signs of early impairments in longitudinal LV systolic function compared to the general population. These subclinical changes may underlie the increased risk of heart failure observed in PWH.

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).

Abstract Background Large randomized controlled trials (RCT) have shown that COVID-19 vaccines are effective at preventing severe COVID-19. However, the RCT's are not powered to detect rare adverse events. It has been reported that the new mRNA based COVID-19 vaccines may increase the risk of thromboembolic and ischemic events. Likewise, thromboembolic and ischemic events are also known complications to infection with SARS-CoV-19. Currently, less is known about the risk-reward relationship of receiving an mRNA-based COVID-19 vaccine versus contracting COVID-19 infection with respect to thromboembolic and ischemic outcomes. Purpose To compare the risk of thromboembolic and ischemic events following COVID-19 vaccination to the risk following infection with SARS-CoV-19. Methods The study period was from March 2020 to August 2021. All individuals were >18 years old. The population was stratified into two different groups. The vaccinated group consisted of recipients of the first dose of either Moderna (mRNA-1273, n=488,220) or Pfizer-BioNTech (BNT162b2 mRNA, n=3,186,164) vaccines. Individuals who had previously tested positive for SARS-CoV-19 were excluded. The other group consisted of individuals who had tested positive for SARS-CoV-19 in the same period who had not yet received their first vaccination dose (n=233,926). The exposure period for both groups was set to 28 days following vaccination/testing positive for SARS-CoV-19 (Figure 1). Patient level data were obtained on all included individuals using nationwide registries. Primary outcomes were acute myocardial infarction (AMI), ischemic stroke, pulmonary embolism (PE), and deep venous thrombosis (DVT). Odds ratios were obtained from logistic regression models with the vaccinated group acting as reference. Multivariable models were adjusted for demographics and comorbidities. Results In the vaccinated group, mean age was 53±19 years and 50.3% were female. In the group of participants testing positive for SARS-CoV-19, mean age was 42.1±17.4 years and 50.2% were female. In total, 773 suffered a stroke, 472 suffered a PE, 500 suffered an AMI, and 484 suffered a DVT during the 28-day exposure period. We observed an increased absolute risk of all outcomes for participants testing positive for SARS-CoV-19 as compared to participants being vaccinated (stroke: 0.049% vs 0.019%, p<0.001), (PE: 0.91% vs 0.0072%, p<0.001), (AMI: 0.021 vs 0.013, p=0.0004), and (DVT: 0.037% vs 0.011%, p<0.001). In multivariable models, participants testing positive for SARS-CoV-19 had a significantly increased risk of all outcomes compared to participants being vaccinated: (stroke: OR: 4.0, 95% CI: [2.9–5.6], p<0.001), (PE: OR: 38.6 95% CI: [30.3–48.5], p<0.001), (AMI: OR: 3.3, 95% CI: [2.1–5.00], p<0.001), and (DVT: OR: 5.3, 95% CI: [3.8–7.5], p<0.001) (Figure 2). Conclusion The risks of thromboembolic and ischemic events were substantially higher after SARS-CoV-19 infection than after vaccination in the Danish population. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Gentofte University Hospital

Abstract Background The ratio of early transmitral filling velocity (E) to early diastolic strain rate (e'sr) (E/e'sr) has recently been proposed as a novel non-invasive measure of early LV filling pressure. Using two-dimensional speckle tracking derived e'sr instead of Doppler-derived e' circumvents several of the limitations known to the Doppler-based method including angle-dependency and the high susceptibility to sampling location. The prognostic value of E/e'sr in relation to cardiovascular morbidity and mortality has previously been demonstrated in a range of specific patient populations including patients with type 2 diabetes, heart failure, atrial fibrillation, and a smaller general population study. Purpose To investigate the prognostic value of E/e'sr in relation to major adverse cardiovascular events (MACE) in a large low-risk general population. Methods A total of 3,782 participants were included in the present study. All participants had a comprehensive echocardiographic examination performed and analyzed. Two-dimensional speckle tracking analysis was performed to determine e'sr. Additionally, participants answered a questionnaire and underwent a general health examination. The outcome was MACE defined as a composite of incident heart failure, acute myocardial infarction, and cardiovascular death. Cox proportional hazards regression models were used to assess the relationship between E/e'sr and MACE. Results The mean age of the study population was 56±17 years and 57.2% were female. Mean E/e'sr was 63.4±19.6cm, mean E/e' was 7.6±2.8, and mean left ventricular ejection fraction was 56.8±5.9%. During follow-up (median: 3.5 years, IQR: 2.6, 4.3) a total of 133 (3.5%) met the composite outcome. Increasing E/e'sr was significantly associated with MACE in a univariable model (Figure 1) with a Harrel's C-statistic of 0.73. Increasing E/e'sr remained significantly associated with MACE in a multivariable model adjusted for age, sex, smoking status, hypercholesterolemia, hemoglobin, diabetes, history of ischemic heart disease, hypertension, heart rate, LVEF <50%, systolic blood pressure, and left atrial volume index (HR=1.09 [95% CI: 1.03; 1.16], p=0.002, per 10cm increase). A total of 824 participants had an E/e' in the indeterminate zone (E/e' between 9 and 14). In this subgroup, E/e'sr remained significantly associated with MACE (HR=1.14 [95% CI: 1.01; 1.29], p=0.038, per 10cm increase). This was also the case in all participants with a E/e <14 (n=3,649) (HR=1.12 [95% CI: 1.02; 1.23], p=0.018, per 10cm increase). Conclusion In this large general population sample, E/e'sr provides independent prognostic information in relation to MACE. This was even the case in participants with normal E/e'. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Gentofte University Hospital

Abstract Background Cardiovascular disease is one of the main causes of morbidity and mortality in patients suffering from type 1 diabetes mellitus. It is of great importance to identify early signs of cardiac pathology such as elevated left ventricular (LV) filling pressure. The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) has in recent studies proved to be an accurate measure of left ventricular (LV) filling pressure. Furthermore, E/e'sr has demonstrated strong prognostic value across different study populations. Purpose The aim of this study was to assess the prognostic value of E/e'sr in a large cohort of patients with type 1 diabetes mellitus in relation to cardiovascular morbidity and mortality. Methods In this prospective study, 1082 patients with type 1 diabetes mellitus (mean age 50±15 years, 53% male, mean duration of diabetes 26 years) underwent a comprehensive echocardiographic examination including both conventional measurements and two-dimensional speckle tracking in which E/e'sr along with other echocardiographic measurements were obtained. The primary outcome was defined as a major cardiac event (heart failure, stroke, myocardial infarction or cardiovascular death). Results During follow-up (median: 6.2 years, IQR: 5.7, 6.9) 144 (13.3%) met the composite outcome. E/e'sr was significantly associated with the composite outcome (E/e'sr: HR 1.36 95% CI [1.25–1.47], p<0.001, per 0.10m increase) (figure). E/e'sr remained an independent predictor after multivariable adjustment for age, gender, duration of diabetes, BMI, HbA1c, smoking status, level of physical activity, systolic blood pressure, cholesterol level, eGFR, albuminuria, LV ejection fraction, LV dimensions and left atrial volume index (E/e'sr: HR 1.16 95% CI [1.04–1.28], p=0.006, per 0.10m increase). Interestingly, E/e'sr was especially good as a prognosticator in female patients (p for interaction = 0.008) in a univariable model: (female: HR 1.53 95% CI [1.37–1.71], p<0.001, per 0.10m increase) (male: HR 1.23 95% CI [1.10–1.38], p<0.001, per 0.10m increase). In the same multivariable model as before, E/e'sr remained an independent predictor of the outcome in female patients whereas the same was not true for male patients (female: HR 1.39 95% CI [1.18–1.66], p<0.001, per 0.10m increase) vs (male: HR 1.05 95% CI [0.92–1.21], p=0.46, per 0.10m increase). Conclusion In patients with type 1 diabetes, E/e'sr provides independent prognostic information regarding cardiovascular morbidity and mortality. Furthermore, E/e'sr seems to have stronger prognostic value in female patients with type 1 diabetes.