Higher Cardiovascular Mortality Research Articles

Cardiovascular Mortality and Leaded Aviation Fuel: Evidence from Piston-Engine Air Traffic in North Carolina

Leaded fuel used by piston-engine aircraft is the largest source of airborne lead emissions in the United States. Previous studies have found higher blood lead levels in children living near airports where leaded aviation fuel is used. However, little is known about the health effects on adults. This study is the first to examine the association between exposure to aircraft operations that use leaded aviation fuel and adult cardiovascular mortality. We estimated the association between annual piston-engine air traffic and cardiovascular mortality among adults age 65 and older near 40 North Carolina airports during 2000 to 2017. We used several strategies to minimize the potential for bias due to omitted variables and confounding from other health hazards at airports, including coarsened exact matching, location-specific intercepts, and adjustment for jet-engine and other air traffic that does not use leaded fuel. Our findings are mixed but suggestive of adverse effects. We found higher rates of cardiovascular mortality within a few kilometers downwind of single- and multi-runway airports, though these results are not always statistically significant. We also found significantly higher cardiovascular mortality rates within a few kilometers and downwind of single-runway airports in years with more piston-engine air traffic. We did not consistently find a statistically significant association between cardiovascular mortality rates and piston-engine air traffic near multi-runway airports, where there was greater uncertainty in our measure of the distance between populations and aviation exposures. These results suggest that (i) reducing lead emissions from aviation could yield health benefits for adults, and (ii) more refined data are needed to obtain more precise estimates of these benefits. Subject Areas: Toxic Substances, Health, Epidemiology, Air Pollution, Ambient Air Quality. JEL codes: Q53, I18.

Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease

Fibroblast growth factor (FGF) 23 is a phosphate-regulating hormone that is elevated in patients with chronic kidney disease and associated with cardiovascular mortality. Experimental studies showed that elevated FGF23 levels induce cardiac hypertrophy by targeting cardiac myocytes via FGF receptor isoform 4 (FGFR4). A recent structural analysis revealed that the complex of FGF23 and FGFR1, the physiologic FGF23 receptor in the kidney, includes soluble α-klotho (klotho) and heparin, which both act as co-factors for FGF23/FGFR1 signaling. Here, we investigated whether soluble klotho, a circulating protein with cardio-protective properties, and heparin, a factor that is routinely infused into patients with kidney failure during the hemodialysis procedure, regulate FGF23/FGFR4 signaling and effects in cardiac myocytes. We developed a plate-based binding assay to quantify affinities of specific FGF23/FGFR interactions and found that soluble klotho and heparin mediate FGF23 binding to distinct FGFR isoforms. Heparin specifically mediated FGF23 binding to FGFR4 and increased FGF23 stimulatory effects on hypertrophic growth and contractility in isolated cardiac myocytes. When repetitively injected into two different mouse models with elevated serum FGF23 levels, heparin aggravated cardiac hypertrophy. We also developed a novel procedure for the synthesis and purification of recombinant soluble klotho, which showed anti-hypertrophic effects in FGF23-treated cardiac myocytes. Thus, soluble klotho and heparin act as independent FGF23 co-receptors with opposite effects on the pathologic actions of FGF23, withsoluble klotho reducing and heparin increasing FGF23-induced cardiac hypertrophy. Hence, whether heparin injections during hemodialysis in patients with extremely high serum FGF23 levels contribute to their high rates of cardiovascular events and mortality remains to be studied.

Blockade of Trpm7 in the Carotid Body area attenuated intermittent hypoxia‐induced Hypertension

RATIONALEObesity leads to high cardiovascular morbidity and mortality via multiple mechanisms including obstructive sleep apnea (OSA) and hypertension. Intermittent hypoxia (IH), a hallmark manifestation of OSA, is an established cause of hypertension. The carotid body (CB) has been implicated in the pathogenesis of hypertension in IH and obesity. We discovered that obesity‐induced hypertension is mediated via the transient receptor potential melastatin 7 (TRPM7) channel in the glomus cells of CB. Here, we investigate the relevance of TRPM7 signaling in CB for the pathogenesis of hypertension by IH. We developed a novel technique allowing continuous sustained release of the TRPM7 inhibitor FTY720 into the CB area using a hydrogel formulation with a single injection abolishing hypertension in obesity for 3 weeks. We hypothesize that IH causes hypertension acting on CB TRPM7.METHODSC57BL/6J male mice (n = 9) were implanted with telemetry in the left femoral artery for continuous blood pressure monitoring and exposed to IH for 5 days. IH was administered by decreasing O2 levels from 21% to 6%, 60 cycles/hr, during the light phase, 9AM ‐9PM. FTY720 hydrogel (n = 5) or control hydrogel (N = 4) were applied locally to the CB region. Blood pressure was recorded at baseline and during IH and the measurement was repeated 2 weeks after hydrogel application.RESULTIH increased mean arterial pressure from 103.8±1.2 mmHg to 114.3±1.4 mmHg on Day 1 of IH and to 113.0±0.6 mmHg on Day 5 of IH respectively. FTY720 hydrogel abolished IH‐induced hypertension by decreasing blood pressure to 106.6±1.6 mmHg (p<0.005) on Day 1 of IH and to 101.5±1.6 mmHg (p<0.001) on Day 5 of IH. In contrast, control hydrogel had no effect on IH‐induced hypertension.CONCLUSIONOur study has shown that inhibition of TRPM7in the carotid bodies abolished IH‐induced hypertension.

Activation of Leptin‐Receptor‐Expressing Neurons in the Dorsomedial Hypothalamus Increases Hypercapcnic Ventilatory Response and Relieves Obstructive Sleep Apnea in Obese Mice

IntroductionObesity leads to obstructive sleep apnea (OSA), characterized by loss of upper airway muscle tone during sleep leading to carbon dioxide retention and intermittent hypoxemia. OSA leads to high neurocognitive, cardiovascular, and oncologic morbidity and mortality. There is no effective pharmacotherapy for OSA. We have previously shown that an adipose‐produce hormone leptin acts in the brain to abolish hypoventilation and upper airway obstruction during sleep, and, therefore may be a promising therapeutic in obese patients with OSA. Our previous data also suggest that leptin stimulates breathing acting on the leptin receptor (LEPRb) positive neurons in the dorsomedial hypothalamus (DMH), but not in the medulla. Herein, we tested the hyphotesis that leptin stimulates control of breathing and improves upper airway patency during sleep acting on LEPRb positive DMH neurons and their projections to serotonergic neurons in raphe. Aim:In this study, we examined the contribution of LEPRb positive neurons in the DMH to control of breathing and upper airway function during sleep in diet‐induced obese mice.MethodsWe expressed designer receptors exclusively activated by designer drugs (DREADD) selectively in the LEPRb positive neurons of the DMH of Leprb‐Cre‐GFP mice with diet‐induced obesity (DIO) and examined the effect of DREADD ligand, J60, on breathing during sleep.ResultsChemogenetic activation of LEPRb positive DMH neurons increased inspiratory flow, respiratory rate, and minute ventilation during REM sleep, without significant changes in sleep architecture. The effect was particularly pronounced during inspiratory flow limitation, which suggest that upper airway obstruction during REM sleep was relieved. Activation of LEPRb positive DMH neurons with a DREADD ligand, J60, increased the hypercapnic ventilatory response and this response was blunted by a serotonin receptor antagonist, methysergide. In vitroexperiments revealed that DMH LEPRb neurons project to the serotonergic neurons in the dorsal raphe and that optogenetic stimulation of DMH LEPRb neurons evoked excitatory post‐synaptic currents in ChR2 expressing neurons.ConclusionLeptin up‐regulates the hypercapnic ventilatory response and upper airway patency during sleep acting on LEPRb neurons in the DMH. Respiratory effects of leptin are likely mediated via projections of these neurons to the dorsal raphe.

Association of Mild Thyroid Dysfunction and Adverse Prognosis Among Chinese Patients With Acute ST Segment Elevation Myocardial Infarction.

AimsThyroid hormones widely affect the cardiovascular system, but the effects of mild thyroid dysfunction on the clinical prognosis of patients with acute ST segment elevation myocardial infarction (STEMI) remains unclear. Our aims were to analyze the relations between mild thyroid dysfunction at admission and clinical outcomes in Chinese patients with STEMI.MethodsA total of 1,176 STEMI patients with the available data of thyroid function and follow-up were analyzed, including 348 patients with mild thyroid dysfunction [subclinical hypothyroidism (n=81), hyperthyroidism (SHyper) (n=51), and low triiodothyronine syndrome (LT3S) (n=216)] and 828 patients with euthyroid function. During a median 4.4-year follow-up, in-hospital mortality, cardiac and all-cause mortalities were subsequently compared among the four groups.ResultsCompared with the euthyroid group, STEMI patients in the SHyper and LT3S groups faced obviously increased risks of in-hospital death [odds ratio (OR): 5.007, 95% confidence interval (CI): 1.246–20.124, p = 0.023 and OR: 2.491, 95% CI: 1.054–5.887, p = 0.037, respectively) even after adjustment for various confounding factors. During a median 4.4-year follow-up, STEMI patients with LT3S at baseline had higher cardiovascular mortality [hazard ratio (HR): 1.880, 95% CI: 1.178–2.998, p = 0.008] and all-cause mortality HR: 1.647, 95% CI: 1.072–2.531, p = 0.023] than those with euthyroid at baseline, whereas no significantly increased mortality was found for STEMI patients with SCH and SHyper at baseline.ConclusionsSTEMI patients with SHyper at admission had increased risk of in-hospital mortality, and STEMI patients with LT3S at baseline had worse prognosis and higher incidences of in-hospital mortality and cardiovascular and all-cause deaths compared with euthyroid patients.

Hyperthyroidism and the Risk of Cardiac Arrhythmias: A Narrative Review

Hyperthyroidism directly affects the cardiovascular system, altering the heart's normal function and leading to high cardiovascular mortality. Excess thyroid hormones are associated with significantly increased risk and prevalence of cardiac arrhythmias, particularly atrial fibrillation (AF). This article reviewed the hemodynamic changes and the risk of cardiac arrhythmias, including atrial and ventricular arrhythmias associated with hyperthyroidism. It has also discussed the multi-level pathophysiology of thyrotoxic AF, sinus tachycardia, and different treatment modalities such as anti-thyroid drugs, beta-blockers, and the role of cardioversion and catheter ablation. This article has explored different studies that have concluded that AF and sinus tachycardia are the most common arrhythmias associated with thyrotoxicosis.

Prognostic Outcomes in Acute Myocardial Infarction Patients Without Standard Modifiable Risk Factors: A Multiethnic Study of 8,680 Asian Patients.

BackgroundAn increasing proportion of patients with acute myocardial infarction (AMI) are presenting without standard modifiable risk factors (SMuRFs) of hypertension, hypercholesterolemia, diabetes, and smoking, but with an unexpectedly increased mortality. This study examined the SMuRF-less patients presenting with AMI in a multiethnic Asian population.MethodsWe recruited patients presenting with AMI from 2011 to 2021 and compared the prevalence, clinical characteristics, and outcomes of SMuRF-less and SMuRF patients. Multivariable analysis was used to compare the outcomes of 30-day cardiovascular mortality, all-cause mortality, readmission, cardiogenic shock, stroke, and heart failure. Kaplan–Meier curves were constructed for 30-day cardiovascular mortality, with stratification by ethnicity, gender and AMI type, and 10-year all-cause mortality.ResultsStandard modifiable risk factor-less patients, who made up 8.6% of 8,680 patients, were significantly younger with fewer comorbidities that include stroke and chronic kidney disease, but higher rates of ventricular arrhythmias and inotropic or invasive ventilation requirement. Multivariable analysis showed higher rates of cardiovascular mortality (HR 1.48, 95% CI: 1.09–1.86, p = 0.048), cardiogenic shock (RR: 1.31, 95% CI: 1.09–1.52, p = 0.015), and stroke (RR: 2.51, 95% CI: 1.67–3.34, p = 0.030) among SMuRF-less patients. A 30-day cardiovascular mortality was raised in the SMuRF-less group, with similar trends in men, patients with ST-segment elevation myocardial infarction (STEMI), and the three Asian ethnicities. All-cause mortality remains increased in the SMuRF-less group for up to 5 years.ConclusionThere is a significant proportion of patients with AMI without standard risk factors in Asia, who have worse short-term mortality. This calls for greater focus on the management of this unexpectedly high-risk subgroup of patients.

Elevations in adipocytokines and mortality in rheumatoid arthritis.

This study assessed whether circulating levels of adiponectin and leptin are associated with higher mortality in patients with RA. Participants were adults from the Veterans Affairs RA Registry. Adipokines and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum at enrolment. Dates and causes of death were derived from the Corporate Data Warehouse and the National Death Index. Covariates were derived from medical record, biorepository and registry databases. Multivariable Cox proportional hazard models evaluated associations between biomarkers and all-cause and cause-specific mortality. A total of 2583 participants were included. Higher adiponectin levels were associated with older age, male sex, white race, lower BMI, autoantibody seropositivity, radiographic damage, longer disease duration, prednisone use and osteoporosis. Higher adiponectin concentrations were also associated with higher levels of inflammatory cytokines but not higher disease activity at enrolment. Leptin was primarily associated with greater BMI and comorbidity. The highest quartile of adiponectin (vs lowest quartile) was associated with higher all-cause mortality [hazard ratio (HR): 1.46 (95% CI: 1.11, 1.93), P = 0.009] and higher cardiovascular mortality [HR: 1.85 (95% CI: 1.24, 2.75), P = 0.003], after accounting for covariates. Higher leptin levels were also associated with greater all-cause and cancer mortality. Elevations in adipokines are associated with age, BMI, comorbidity and severe disease features in RA and independently predict early death. Associations between adiponectin and inflammatory cytokines support the hypothesis that chronic subclinical inflammation promotes metabolic changes that drive elevations in adipokines and yield adverse health outcomes.

Controversial issues of type 2 myocardial infarction patients management

Highlights. The article presents relevant literary data on the epidemiology, main causes, approaches to the diagnostics and treatment of type 2 myocardial infarction patients. The authors emphasize an unfavorable prognosis in these patients due to comorbidity that leads to development of myocardial infarction. They highlight the need to improve and unify approaches to identifying this phenomenon, as well as the necessity to conduct observational and randomized studies to evaluate approaches to the treatment of type 2 myocardial infarction patients.Abstract. The article summarizes the available data from clinical trials and current guidelines, approaches to the definition and type 2 myocardial infarction (MI) differential diagnosis in clinical practice. The attention is focused on the fundamental difference between type 1 and type 2 MI and the need to consider the comorbidities for the identification of etiological factors type 2 MI development. The lack of evidencebased medical data regarding the prognosis and effective treatment of patients with type 2 MI is emphasized. Nevertheless, such patients are characterized with high rates of overall and cardiovascular mortality in hospital and long-term disease course, as well as a high rate of readmission. Thus, there is the need for multicenter observational studies of type 2 MI patients and the development of algorithms for treatment and rehabilitation of this category of patients.

Anticoagulation in coronavirus disease 2019 (COVID-19): confirmed and controversial aspects

Die Infektion mit dem „severe acute respiratory syndrome coronavirus 2“ (SARS-CoV-2) ist mit einem hohen Risiko mikrovaskulärer Immunthrombosen sowie symptomatischer und inzidenteller Thromboembolien vorrangig im venösen, aber auch im arteriellen System vergesellschaftet. Dies begründet unter anderem die hohe kardiovaskuläre Morbidität und Mortalität der Patienten. Der heutige Kenntnisstand zur Pathophysiologie der Immunthrombosen und zu derzeitigen Strategien der Antikoagulation bei an „coronavirus disease 2019“ (COVID-19) erkrankten Patienten wird in diesem Beitrag zusammenfassend beleuchtet. Gemäß den aktuellen Leitlinien sollen moderat bis schwer erkrankte Infizierte, die sich in stationärer Krankenhausbehandlung befinden, frühzeitig eine Thromboseprophylaxe mit niedermolekularem oder unfraktioniertem Heparin oder alternativ mit Fondaparinux erhalten, sofern kein deutlich erhöhtes Blutungsrisiko vorliegt. Außerhalb der etablierten Therapieindikationen sollte eine intensivierte oder therapeutisch dosierte Prophylaxe auch aufgrund vermehrter Blutungskomplikationen bei diesen kritisch erkrankten Patienten sehr zurückhaltend erwogen werden. Die routinemäßige Fortführung einer prophylaktischen Antikoagulation nach der Krankenhausentlassung wird derzeit nicht empfohlen.

IL-17A promotes vascular calcification in an ex vivo murine aorta culture

BackgroundVascular calcification is characterized by mineral deposition in the vasculature, which is triggered by chronic systemic inflammation, including psoriasis. Psoriasis is an IL-17A-mediated inflammatory skin disease that is associated with exacerbated vascular calcification and high cardiovascular mortality. Although previous studies have shown that IL-17A induces vascular dysfunction in murine psoriasis models, it has not been clarified whether IL-17A induces vascular calcification. In this study, we investigated the potential vascular calcification-inducing effect of IL-17A in an ex vivo culture system. MethodsThoracic and abdominal aortas from mice were cultured in a medium supplemented with inorganic phosphate and were treated with inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-17A). Vascular calcification was determined using micro-computed tomography (CT) and histological analyses. ResultsIL-1β, TNF-α, and IL-6 did not significantly promote vascular calcification, whereas IL-17A significantly accelerated vascular calcification of the aorta, as indicated by the increased mineralized volume based on micro-CT analysis. Micro-CT and histological analyses also revealed that the promoting effect of IL-17A on vascular calcification was concentration dependent. ConclusionsIL-17A significantly promoted vascular calcification in ex vivo cultured aortas, which suggests that this mechanism is involved in the increased risk of cardiovascular events in IL-17A-mediated inflammatory diseases.

Obstructive Sleep Apnea as a Risk Factor for Venous Thromboembolism: A Systematic Review.

Obstructive sleep apnea (OSA), is a prevalent condition characterized by repeated episodes of pharyngeal airway obstruction resulting in hypopnea and apnea episodes during sleep leading to nightly awakenings. OSA is a major contributor to the healthcare burden worldwide due to its high cardiovascular morbidity and mortality. There is growing evidence to support a pathophysiological link between OSA and venous thromboembolism (VTE). The pro-inflammatory state along with intermittent hypoxia that is invoked in OSA is associated with blood hypercoagulability, venous stasis, and endothelial dysfunction leading to deep vein thrombosis (DVT) and pulmonary embolism (PE). In this systematic review, we aim to analyze and assess the available literature on OSA and VTE (or DVT/PE) to determine whether OSA is an independent risk factor for VTE.

Age-related sex differences in the outcomes of patients with hypertrophic cardiomyopathy.

BackgroundWe aimed to clarify the sex differences in various cardiovascular and non-cardiovascular outcomes, and to investigate whether sex differences in outcomes are affected by age in hypertrophic cardiomyopathy (HCM).MethodsA cohort of 835 patients with HCM initially evaluated during 2007–2019 were followed for a median of 6.4 years. Study outcomes were all-cause death, cardiovascular and non-cardiovascular death, sudden cardiac death (SCD)/SCD equivalent events, heart failure (HF) events, and the composite cardiovascular outcome including cardiovascular death, SCD/SCD equivalent events, admission for HF, and heart transplantation.ResultsWomen were 5 years older (women 59.9±13.5 vs. men 54.9±11.4 years), had worse dyspnea, and greater left ventricular (LV) diastolic dysfunction and obstructive physiology at presentation. Women compared to men had higher all-cause mortality and cardiovascular event rates, driven by more cardiovascular deaths and heart failure (HF) events. Conversely, non-cardiovascular mortality was not different between the sexes. Female sex was independently associated with all-cause death (HR 1.88, 95% CI 1.11–3.20) and composite cardiovascular events (HR 3.60, 95% CI 2.00–6.49), independent of age, body mass index, New York Heart Association class, SCD risk score, and LV ejection fraction. When stratified by the age of 60, sex differences were not significant at <60 years; however, at ≥60 years, women had worse LV diastolic function, greater obstructive physiology, as well as worse survival and composite cardiovascular outcomes. Sex differences in outcomes remained consistent after propensity score matching for age and other clinical characteristics.ConclusionsWomen with HCM have worse cardiovascular prognosis than men, driven by higher cardiovascular mortality and HF events. The negative impact of female sex on cardiac function and cardiovascular outcome became prominent at age ≥60 years, suggesting age-related sex differences in the prognosis of HCM.

Why should we focus on high-volume hemodiafiltration?

Though noticeable technological advances related to hemodialysis (HD) have been made, unfortunately, the survival rate of dialysis patients has yet to improve significantly. However, recent research findings reveal that online hemodiafiltration (HDF) significantly improves patient survival in comparison to conventional HD. Accordingly, the number of patients receiving online HDF is increasing. Although the mechanism driving the benefit has not yet been fully elucidated, survival advantages are mainly related to the lowering of cardiovascular mortality. High cardiovascular mortality among HD patients is seemingly attributable to the cardiovascular changes that occur in response to renal dysfunction and the HD-induced myocardial stress and injury, and online HDF appears to improve such secondary cardiovascular changes. Interestingly, patient survival improves only if the convection volume is supplied sufficiently over a certain level during online HDF treatment. In other words, survival improvement from online HDF is related to convection volume. Therefore, there is a growing interest in high-volume HDF in terms of improving the survival rate. The survival improvement will require a minimum convection volume of 23 L or more per 4-hour session for postdilution HDF. To obtain an optimal high convection volume in online HDF, several factors, such as the treatment time, blood flow rate, filtration fraction, and dialyzer, need to be considered. High-volume HDF can be performed easily and safely in routine clinical practice. Therefore, when the required equipment is available, performing high-volume HDF will help to improve the survival rate of dialysis patients.

Coronary angiographic findings in renal transplant patients with chronic coronary artery disease: a pilot study.

Patients that undergo renal transplantation (RT) often suffer from high rates of cardiovascular disease-related mortality, yet, most of the studies focus on coronary angiography performed as screening to entry in a waiting list and not, as for clinical indication, after renal transplantation. This study examined coronary angiography findings from 45 patients with functional renal grafts for over 6 months that were analyzed in Anzhen Hospital (Beijing, China) from 2014-2019. For comparison purposes, we additionally examined coronary angiography findings from 45 age- and sex-matched patients undergoing chronic dialysis due to end-stage renal disease (ESRD). We used the SYNTAX score to gauge coronary artery disease (CAD) severity. The duration of ESRD in patients in the RT group was significantly longer than for that of patients in the dialysis comparison group (19.31 ± 7.83 years vs. 11.43 ± 8.04 years, p < 0.001). The SYNTAX scores for patients in the dialysis and RT groups were 17.76 ± 7.35 and 12.57 ± 5.61, respectively (p < 0.01). We found that 64.4% and 28.9% of dialysis and RT patients, respectively, exhibited the presence of moderate or severe calcified lesions upon examination. In addition, the SYNTAX scores of RT patients were correlated with ESRD duration (p < 0.001). We observed less serious CAD in RT patients relative to long-term dialysis patients even though the former group exhibited a longer mean ESRD duration. Both groups exhibited high rates of calcification of the coronary artery, even following RT.

Left ventricular diastolic dysfunction, including an impaired myocardial relaxation pattern, predicts long-term cardiovascular and non-cardiovascular mortality in the community

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Prior studies have demonstrated abnormalities of diastolic function are independent predictors of heart failure and all-cause mortality. The optimal way to classify diastolic function has continued to evolve over time, particularly in those with preserved left ventricular ejection fraction. A notable change in the 2016 American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) guidelines is that individuals with impaired myocardial relaxation and normal filling pressure can be classified as normal diastolic function. Purpose To determine whether the association of diastolic dysfunction with increased risk of all-cause mortality is driven by cardiovascular or non-cardiovascular death. Second, to evaluate if the presence of an impaired myocardial relaxation inflow pattern without other diastolic abnormalities conveys a marker of increased risk. Methods This study utilized the Olmsted County Heart Function Study (OCHFS), a well characterized prospective adult community cohort with comprehensive echocardiography between 2001 and 2004 and long-term follow-up. Only individuals with measurable diastolic function were included (n = 1,104). Those with reduced left ventricular ejection fraction, more than moderate valve disease, or a clinical diagnosis of heart failure (n = 52); or indeterminate diastolic function (n = 47) were excluded. Diastolic function was assessed by the current Mayo Clinic diagnostic algorithm (Figure). Results A total of 695 individuals were classified as normal, 265 with impaired myocardial relaxation or grade 1 diastolic dysfunction, and 45 with grade 2-3 diastolic dysfunction. Those with diastolic dysfunction were older and had more comorbidities including diabetes, hypertension and coronary disease (Table). There were 264 deaths in the median follow up period of 15.2 years (IQR 14.4 – 18.0), including 173 non-cardiovascular and 81 cardiovascular deaths. Both cardiovascular and non-cardiovascular mortality were associated with the presence and grade of diastolic dysfunction (Table 1). Individuals classified as normal by 2016 ASE/EACVI criteria, but grade 1 by the Mayo algorithm had an increased risk of all-cause mortality after univariate analysis (HR 4.35, 95% CI (3.35, 5.65), p &amp;lt; 0.0001) compared to normal subjects and remained associated after adjustment for age (HR 1.55, 95% CI (1.15, 2.09), p &amp;lt; 0.0001. Subjects with a grade 1 pattern had a higher rate of cardiovascular mortality (ꭕ2 70.1, p &amp;lt; 0.0001). Conclusions Individuals with diastolic dysfunction, including those with an impaired relaxation mitral inflow, were at increased risk of mortality, particularly cardiovascular mortality. This study highlights the importance of separating grade 1 diastolic dysfunction from normal in the assessment of diastolic function as it represents a clinically significant risk marker of myocardial disease. Abstract Figure. Abstract Figure.

Pathophysiological, haemodynamic and prognostic implications of left atrial dysfunction in cardiac amyloidosis and other cardiomyopathies with hypertrophic phenotype

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND &amp; PURPOSE. Left atrial function (LAF) is a determinant of clinical status and outcome in many cardiac disorders, including cardiac amyloidosis (CA). Aim of this study is to explores the LAF in CA and other cardiomyopathies with hypertrophic phenotype, and its consequences on cardiovascular haemodynamics, right ventricular function and survival. METHODS. We enrolled 50 patients with CA (26 AL and 24 wtATTR) and 75 with hypertrophic phenotype (LVH group) [25 hypertrophic cardiomyopathy (HCM) pts, 25 hypertensive pts (HypCM), and 25 pts with aortic stenosis (AS)]. LAF was analysed using the phasic method [LAEI as reservoir, LAPEF as conduit, LAAEF as active pump and TLAEF as total emptying function; see figure 1] by LA volumes determination. RESULTS. ATTR patients showed higher LA dimensions and impaired reservoir and total LA emptying function (TLAEF) compared to AL without differences LAF. Compared to the LVH group, CA patients showed higher LA dimension with impaired LAF in all phasic parameters, higher LV filling pressures and reduced biventricular function. We further divided CA and LVH patients into four subgroups based on the presence or absence of LA dysfunction (LADys+ for TLAEF values below the median: &amp;lt;50.2%; range 9.3-70.9%]. Among the groups, patients with CA/LADys+ showed worst clinical status, higher pulmonary pressures (sPAP) and lower TAPSE and TAPSE/sPAP ratio values. After a median follow-up of 24 months, 19 patients died from cardiovascular (CV) causes (15 in CA/LADys+ group and 4 in LVH/LADys+). The overall survival free of CV death was 64% in CA/LADys+ and 85% in LVH/LADys+ (4/26) group [log-rank χ2 29.6; p &amp;lt; 0.0001]. A sequential multivariate model was employed to assess whether LAF could predict CV deaths: TLAEF was entered together with established clinical and echocardiographic parameters (NYHA functional class, LAVI, E/Em, sPAP, TAPSE and TAPSE/sPAP ratio). At the final backward analysis, LAVI, TAPSE/sPAP and TLAEF were independent prognosticators of CV death. CONCLUSIONS. LAF is significantly more impaired in CA than LVH group and is associated with worst clinical status, RV dysfunction and higher LV filling and pulmonary pressure. Moreover, LADys is a frequent feature of CA and significantly associated with higher CV mortality. We suggests that LADys in LVH group could results from chronic pressure overload due to LA"s exposure to high LV diastolic pressure (impaired LV compliance). In CA, LADys could also be determined by direct LA infiltration. The pathophysiological result is a progressive LA remodelling with increased LA pressure, consequent backward transmission to the pulmonary venous system and, ultimately, RV dysfunction. TLAEF is parameter of LAF that correlates with increased pulmonary vascular resistance (measured elsewhere with cardiac catheterisation) and RV dysfunction. In CA, it seems promising as marker of the haemodynamic consequences of LADys and CV mortality. Abstract Figure 1 Abstract Figure 2

Aortic valve calcification and endomyocardial fibrosis determine adverse outcomes following transcatheter aortic valve replacement

Abstract Funding Acknowledgements Type of funding sources: None. Aims There is evidence to suggest that subtype of aortic stenosis (AS), degree of myocardial fibrosis (MF) and level of aortic valve calcification (AVC) are associated with adverse cardiac outcome in AS. Since little is known about their respective contribution, we sought to investigate their relative importance and interplay as well as association with adverse cardiac events. Methods 100 consecutive patients with severe AS and indication for transfemoral transcatheter aortic valve replacement (TAVR) were prospectively enrolled between January 2017 and October 2018. Patients underwent transthoracic echocardiography, multi detector computed tomography (MDCT) and left ventricular endomyocardial biopsy at the time of TAVR. Results The final study cohort consisted of 92 patients with completed study protocol comprising of 39 (42.4 %) normal ejection fraction high gradient (NEFHG), 13 (14.1 %) low EF high gradient (LEFHG), 25 (27.2 %) low EF (flow) low gradient (LEFLG) and 15 (16.3 %) paradoxical low flow low gradient (PLFLG) AS. The high gradient phenotypes (NEFHG and LEFHG) showed the largest amount of AVC (807 ± 421; 813 ± 281 mm³ respectively) as compared to the low gradient phenotypes (LEFLG and PLFLG; 503 ± 326; 555 ± 594 mm³ respectively, p &amp;lt; 0.05). Conversely, MF was most prevalent in low output phenotypes (LEFLG &amp;gt; LEFHG &amp;gt; PLFLG &amp;gt; HEFHG, p &amp;lt; 0.05). This was paralleled by larger cardiovascular mortality within 600 days post TAVR (LEFLG n = 7 &amp;gt; PLFLG n = 4 &amp;gt; LEFHG n = 2 &amp;gt; NEFHG n = 1). In Patients with high MF burden a higher AVC was associated with a lower mortality (p = 0.045, HR = 0.261, 95%CI 0.07-0.97). Within LEFLG AS, patients with larger AVC (&amp;gt;476.8 mm³) had larger MF (40.2%) and higher cardiovascular mortality (n = 5) as compared to patients with lower AVC (£476.8 mm³, 17.1% MF, p = 0.027, cardiovascular mortality n = 2). Conclusion MF is associated with adverse cardiovascular outcome following TAVR which is most prevalent in low ejection fraction situations. In the presence of large MF burden patients with large AVC have better outcome following TAVR. Conversely worse outcome in large MF and relatively little AVC may be explained by a relative prominence of an underlying cardiomyopathy while better survival rates in large AVC patients may indicate severe AS associated pressure overload relief and subsequently improved survival following TAVR.

Randomised, placebo-controlled trial on topiramate add-on therapy for weight reduction and symptomatology in overweight/obese persons with schizophrenia.

Higher cardiovascular mortality is seen with schizophrenia due to the disorder itself and antipsychotic use. South Asians are more vulnerable to developing metabolic disorders than others. Resource-limited settings in South Asia have only a few mental health professionals, and individualised case management is mostly unavailable. Therefore, there is less monitoring and personalised support for diet and physical exercise programmes. Topiramate is useful for weight reduction and improvement of psychopathology in schizophrenia. However, there has been only one previous randomised controlled trial (RCT) done in South Asia, which possesses a quarter of the world's population. We conducted a double-blind RCT in an outpatient setting in Sri Lanka. We compared topiramate 100mg/day with a placebo in overweight/obese adults with schizophrenia who have been on antipsychotics for at least a year. We obtained monthly anthropometric measurements and assessed the symptomatology using the brief psychiatric rating scale (BPRS). Fifty patients each in the topiramate and placebo arms completed the study. Topiramate add-on therapy led to significant weight/Body Mass Index reduction and improved symptomatology as measured by the BPRS compared to the placebo. The topiramate group had significantly more reporting of loss of appetite. According to available data, this is the RCT with most participants assessing the use of topiramate in schizophrenia and only the second in South Asia. Topiramate was shown to be useful for weight reduction and symptomatic improvement in persons with schizophrenia in a resource-limited setting in South Asia.

Abstract TMP103: The Heavy Burden Of Allostatic Load On Long-term Survival After Stroke And Stroke-related Mortality

Background: Measurement of allostatic load, quantified by the allostatic load index (ALI), is often utilized to evaluate the physiologic response to stress. Our objective was to assess whether allostatic load is associated with mortality after stroke or with stroke-specific mortality in the general population. Methods: Using data from the third National Health and Nutritional Examination Survey (NHANES III, 1988-1994) and the 2015 Linked Mortality File (National Death Index), we selected adults aged ≥ 25 years. Stroke was self-reported. We computed the weighted prevalence of each allostatic load index (ALI) category to obtain nationally representative estimates with higher ALI corresponding to higher stress burden. We evaluated the relationship between ALI category and mortality outcomes using the Cox proportional hazard model considering the survey design variables, adjusting for age, sex, education, marital status, and income. Results: Of 15,567 individuals included in the study, there were 48.3% ALI ≤ 1, 21.7% ALI = 2, and 30% ALI ≥ 3. Of 414 individuals with reported history of stroke there were 11.8% ALI ≤ 1, 22.1% ALI = 2, and 66.1% ALI ≥3. Higher ALI correlated with male sex, older age, lower education, married or widowed status, and lower income. In the population with history of prior stroke, those with ALI ≥ 3 had 2.7 times higher all-cause mortality and 4.5 times higher cardiovascular mortality compared to those with ALI ≤ 1 (Table). In the general population, the ALI ≥ 3 group had 1.8 times higher adjusted stroke mortality. Discussion: Baseline higher allostatic load predicts greater all-cause and cardiovascular mortality risk in stroke survivors and greater stroke mortality risk in the general population. A global approach towards addressing the modifiable indicators in the ALI may improve survival in these populations.