Classical Risk Research Articles

Repeat revascularisation following PCI in the UK Biobank prospective cohort study: incidence, independent predictors and prognostic impact

Abstract Introduction Data from the SYNTAX and EXCEL trials have previously demonstrated increased morbidity and mortality following repeat revascularisation (RR). However real-world RR rates following index PCI are poorly defined, particularly in the 'late' context of restenosis of bystander disease and de novo lesions. Purpose To identify independent predictors of RR and evaluate its prognostic impact in an unselected cohort of patients following first PCI. 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. Data are derived from an array of physical measurements, self-reported measures and biological samples, together with longitudinal linkage to hospital inpatient records and death registries. Procedural codes (OPCS-4) were used to identify patients who had undergone first PCI from 2006 onwards. RR was defined as PCI or CABG occurring at least 9 months after the index PCI, in order to preclude instances of staged revascularisation and in-stent restenosis. Data were censored at January 2021 or date of death as appropriate. Non-parametric tests are used throughout. Results A total of 12,853 participants underwent a first PCI during the study period, with 1,394 (10.8%) requiring RR over a median follow-up of 6.5 years. Of these, 1188 underwent PCI whilst 206 were elected to CABG. The average age was 64 years in the RR cohort and 1117 (80%) were male. Univariate analyses confirmed a number of established associations with RR, including for example diabetes mellitus and hypertension. Median lipoprotein(a) concentrations were 27.6 vs. 30.3nmol/L in the RR group, p=0.066. Cox regression analyses incorporating 21 biometric and clinical parameters demonstrated that lipoprotein(a) was an independent predictor of time to RR, independent of other lipids (Table 1). The strength of this association persisted when the number of covariates was reduced to include only other lipids and classical cardiovascular risk parameters. In Kaplan-Meier analyses, RR was associated with lower all-cause mortality (Figure 1). Further multivariate time-to-event analyses confirmed this association (HR 0.59, 95% CI 0.47–0.75, p<0.001). In separate models examining PCI and CABG as distinct modalities of RR, both were independently associated with prognostic benefit (HR 0.61, p<0.001 and HR 0.48, p<0.05 respectively). Conclusions Lipoprotein(a) is identified as a major independent driver of RR. In contrast to recent trial data focussing on left main stem and multivessel disease, unselected patients undergoing RR 9 or more months following index PCI attain prognostic benefit as assessed in multivariate analyses. The findings support an invasive approach, whether with PCI or CABG, in progressive coronary artery disease following initial PCI. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): 1. The Herefordshire Heart Fund, UK. 2. Postgraduate Medical Bursary, Wye Valley NHS Trust, UK. Table 1Figure 1

Association of high-sensitivity Troponin T and I blood levels with outcome of coronary artery disease – results from the INTERCATH cohort

Abstract Background High-sensitivity Troponin T and I (hsTnT/I) concentration is independently associated with coronary artery disease (CAD) severity and cardiovascular outcome. Here we explored whether hsTnT/I blood levels add predictive information irrespective of CAD severity and further confounders in unselected stable patients with angiographically characterized CAD. Methods Between 2015 and 2020, 3,012 patients undergoing coronary angiography were included in the observational Hamburg INTERCATH study. In 2,209 consecutive patients Troponin levels were quantified for hsTnT (Roche Diagnostics Elecsys) and hsTnI (Abbott Diagnostics ARCHITECT STAT). Patients presenting with acute coronary syndromes and heart transplant recipients were excluded, leaving 1,841 patients for analyses. CAD severity was graded according to the Gensini score. Major adverse cardiac events (MACE) as a composite of cardiovascular death, stroke, myocardial infarction, and coronary revascularization were defined as endpoint. Kaplan-Meier analyses stratified by hsTnT/I quartiles were performed. Multivariable Cox models were computed for the association of hsTnT/I with MACE adjusting for age, gender, arterial hypertension, hyperlipoproteinemia, smoking, diabetes mellitus, body-mass index, eGFR and Gensini Score. Results Mean age was 68.5±10.9 years (27.9% female). 81.1% were diagnosed with CAD by coronary angiography. Gensini score was 21.0±30.2. Median follow-up time was 4.42 years. hsTnT quartiles differentiated MACE across all categories (Figure 1A). For hsTnI, cardiovascular risk was differentiated between the lowest and highest quartiles as well as the 1st and 2nd quartile particularly beyond 24 months of follow-up (Figure 1B). However, MACE after 3 years was not associated with hsTnT after adjustment for classical cardiovascular risk factors and CAD severity (Figure 1C), whereas the hazard of MACE was increased in the 3rd and 4th hsTnI quartiles compared to the 1st quartile (HR 1.3, IQR 1.1–1.6 for both categories; Figure 1D). Conclusion Increasing hsTn concentration was related to intermediate term cardiovascular outcome in unselected stable patients. Only hsTnI concentration remained as independent predictor after testing for most possible confounders, including CAD severity. This data underpins the role of hsTnI in outcome prediction. Funding Acknowledgement Type of funding sources: None.

Determinants and prognostic relevance of aortic stiffness in patients with recent ST-elevation myocardial infarction

The association between aortic stiffness, cardiovascular risk factors and prognosis in patients with recent ST-elevation myocardial infarction (STEMI) is poorly understood. We analyzed the relationship between cardiovascular risk factors and arterial stiffening and assessed its prognostic significance in patients with recent STEMI. We prospectively enrolled 408 consecutive patients who sustained a first STEMI and underwent primary percutaneous coronary intervention (PPCI). Aortic pulse wave velocity (PWV), the most widely used measure of aortic stiffness, was determined by the transit-time method using velocity-encoded, phase-contrast cardiac magnetic resonance imaging. Patient characteristics were acquired at baseline and major adverse cardiac and cerebrovascular events (MACCE) were assessed at 13 [interquartile range (IQR) 12–31] months. Cox regression- and logistic regression analysis were performed to explore predictors of aortic stiffness and MACCE. Median aortic PWV was 6.6 m/s (IQR 5.6–8.3 m/s). In multivariable analysis, age [odds ratio (OR) 1.10, 95% confidence interval (CI), 1.08–1.14, p < 0.001] and hypertension (OR 2.45, 95% CI, 1.53–3.91, p < 0.001) were independently associated with increased PWV. Sex, diabetes, smoking status, dyslipidemia, and obesity were not significantly associated with PWV in adjusted analysis (all p > 0.05). High PWV significantly and independently predicted occurrence of MACCE in adjusted analysis [hazard ratio (HR) 2.45, 95% CI 1.19–5.04, p = 0.014]. In patients with recent STEMI, the impact of classical cardiovascular risk factors on aortic stiffness is mainly dependent on age and increased blood pressure. Increased aortic stiffness is associated with adverse clinical outcome post-STEMI, suggesting it as a relevant therapeutic target in this population. Trial (NCT04113356).

Plasma nesfatin-1 and DDP-4 levels in patients with coronary artery disease: Kozani study

BackgroundNesfatin-1, a novel adipokine and dipeptidyl peptidase-4 (DPP4), a mam malian serine protease, are potent factors of atherosclerosis. In the present cross-sectional study, we investigated whether the plasma nesfatin-1 and DPP4 is associated with the prevalence and severity of coronary artery disease (CAD) with and without diabetes mellitus (DM).MethodsWe consecutively enrolled a total of 240 patients with significant CAD (previous revascularization or angiographically-proven coronary artery stenosis > 50%) presented with either unstable angina (UA, N = 76) or stable chronic CAD (SCAD, N = 165). 85 patients with at least 2 classical cardiovascular risk factors but without significant CAD served as controls. The severity of CAD was assessed using coronary angiography by the Gensini score. Clinical parameters, glycemic and lipid profile, high-sensitivity CRP (hsCRP), nesfatin-1 and DPP4 levels were assayed.ResultsNo differences were found for age, sex, hypertension and diabetes distribution between groups. Low nesfatin-1 levels were found in both CAD groups (UA & SCAD) with respect to controls. The difference between UA and SCAD groups was marginally non-significant. There was a significant increase of DPP4 along UA to SCAD and control groups. Differences between groups remained unchanged in non-diabetic participants. Nesfatin-1 significantly correlated to hsCRP (r = − 0.287, p = 0.036), HOMA-IR (r = − 0.587, p = 0.007) and hyperlipidemia (r = − 0.331, p = 0.034). DPP4 was significantly associated with hs-CRP (r = 0.353 p < 0.001) and FPG (r = 0.202, p = 0.020) in univariate analysis, but those correlations were lost in multiple regression analysis. There was a negative correlation between nesfatin-1 and the severity of CAD, quantified by the Gensini score (r = − 0.511, p < 0.001), but no association was found for DPP4.ConclusionsSerum DPP4 levels are increased in patients with CAD, while serum nesfatin-1 levels have a negative association with both the incidence and the severity of CAD. These results are independent of the presence of diabetes mellitus. In addition, both peptides have a strong association with hsCRP.Trial registration ClinicalTrials.gov Identifier: NCT00306176

Inhibitory effects of amniotic fluid on the activated protein C anticoagulation system in maternal plasma.

Pulmonary thromboembolism (PTE) is one of the leading causes of maternal mortality. We previously reported that possible contamination of amniotic fluid (AF) into maternal circulation accelerated thrombin production and activated platelet function in maternal blood through the extrinsic pathway, which may be associated with the high incidence of PTE in early puerperium. However, it remains unclear whether the maternal anticoagulation system, e.g., the activated protein C (APC) pathway, contributes to the hypercoagulable condition induced by AF. Our previous study using an endogenous thrombin potential (ETP)-based assay revealed that sensitivity to APC was reduced during the postpartum first day, i.e., immediately after delivery, when parturients were supposed to be exposed to AF. Our aim is to investigate the susceptibility of maternal plasma to APC when mixed with AF. We collected plasma from 51 pregnant females and mixed with AF as well as APC. APC-sensitivity ratio (APC-sr) was calculated using the ETP-based assay. Addition of AF to maternal plasma showed a significant increase of ETP in the presence of APC. APC-sr was significantly increased, indicating decreased sensitivity to APC, after AF mixture to maternal plasma. The present APC-sr difference with AF contamination was smaller than that we reported previously in venous thromboembolism cases. The inhibitory effects of AF on the APC anticoagulation pathway may contribute, at least partly, to further promotion of thrombin production induced by AF. Combined with other classical thrombophilic risk factors, the present findings support possible involvements of AF exposure in the high incidence of PTE in early puerperium.

On the analysis of a discrete-time risk model with INAR(1) processes

This paper considers an extension of the classical discrete-time risk model for which an INAR(1) process is utilized to model a temporal dependence between the number of claims. We apply a recursive method for deriving the Laplace transform of the aggregate claims with or without discounting in this framework. This methodology is implemented for the class of INAR(1) processes with an arbitrary innovations' distribution. Three risk models via specific INAR(1) processes are studied when the distribution of the individual claim sizes belongs to the class of mixed Erlang distributions. These different models allow us to discuss the frequent manifestations of equidispersion, overdispersion and zero inflation, and to evaluate the distribution of the (discounted) aggregate claims. Numerical examples are performed in order to illustrate the results obtained in this paper.

Research Perspective on Classic and Novel Histopathologic Risk Factors for Lymph Node Metastasis in T1 Colorectal Cancer: A Systematic Review and Meta-analysis

Research Perspective on Classic and Novel Histopathologic Risk Factors for Lymph Node Metastasis in T1 Colorectal Cancer: A Systematic Review and Meta-analysis

MO420ROLE OF IL-6 ON ACUTE KIDNEY INJURY (AKI) DEVELOPMENT AFTER LIVER TRANSPLANTATION

Abstract Background and Aims Acute kidney injury (AKI) post-liver transplantation is a frequent complication with an incidence up to 70%, requiring renal replacement therapy in about 25% of transplant patients. AKI in patients with normal renal function is a recognized risk factor (FR) of chronic renal failure (CKD) de novo, associated with a 4.5 times greater mortality at 5 years post-transplant. Pathogenesis of AKI is multifactorial. Beyond the classical pre-transplant risk factors, the hypoxia of the graft and the ischemia-reperfusion injury (IRI) have recently been recognized to exert a pathogenetic role with specific mechanisms. It has been recently demonstrated in experimental setting that ischemic tissues put in place protective mechanisms in response to hypoxia aimed at increasing the release of oxygen with the activation of angiogenesis mediated by the expression of factors induced by hypoxia (HIF)-1-alpha. HIF1-alfa has been shown to promote cell survival under hypoxic conditions by switching metabolism from oxidative to glycolytic, by affecting the production of ATP to prevent excessive mitochondrial generation of reactive oxygen species, by promoting secondary release of vascular endothelial growth factor (VEGF) and transforming growth factor-beta 1 (TGF-ß1), with following activation of inflammatory cytokines responsible for systemic inflammatory response syndrome (SIRS). Tumor necrosis factor-α, IL-1 and IL-6 are the most important cytokines released in IRI and seem to play a pivotal role in the onset of AKI in SIRS and sepsis. The development of AKI after hypoxia/ischemia of the graft, as observed more frequently in the population of recipients from donors after cardiocirculatory death (DCD) compared to donation after brain death (DBD), confirms this pathogenetic mechanism. Aim of the study is to evaluate AKI occurrence among liver transplanted patients and its relationship with IRI and cytokines systemic release. Method Data of 78 patients (62 males, 79.5%) undergone liver transplantation (2007-2011) were retrieved. Results The following clinical investigations were performed: AKI patients demonstrated a progressive increasing of IL-6 after liver transplantation (AKI 34.4-37.8-88.2 ng/ml vs no AKI 30.5-21.6-23.3 ng/ml). Conclusion Patients who experienced greater ischaemia-reperfusion injury of the liver graft developed more frequently AKI. Patients with AKI experienced an increased release and circulation of IL-6, that probably is involved in AKI development with interesting implications in future therapy.

Involvement of Inflammation in Venous Thromboembolic Disease

Recent evidence has been established that the inflammatory process is involved in the pathophysiology of Venous Thrombotic Events (VTE) and may have a significant role in prediction of the disease. It is likely that classical and non-classical risk factors modulate thrombosis through inflammatory mediators. Inflammation of the venous wall promotes the release of tissue factor inhibit the release of anticoagulant factors and hamper endogenous fibrinolysis. Recent studies also indicated that increased inflammatory response (interleukin storm) is related to prothrombotic state and thromboembolic events in patients with COVID-19. Inflammatory markers are also negatively related to thrombolysis and restoration of blood flow in the acute phase of Venous Thrombosis (VT). Despite the growing evidence of the involvement of inflammation in pathogenesis of VTE, the importance of anti-inflammatory treatment of this disease was overlooked. Aspirin was shown to be effective in the prevention of recurrent venous thrombosis after treatment with anticoagulant drugs. Some anti-inflammatory drugs like nonsteroidal anti-inflammatory agents may have prothrombotic effect and increase risk of VTE. Therefore, the recent research was dedicated to searching new specific anti-inflammatory drug inhibitors of inflammatory markers, which were shown to be involved in the pathogenesis of VTE. As thrombus formation is based on the activation of coagulation system, provoked by inflammation, prevention and treatment of VTE, should include both anticoagulant and anti-inflammatory agents. To reduce bleeding complications of combined treatment, sub-therapeutic doses of both drugs should be used to improve the efficacy of management of VTE without increasing risk of bleeding.

Cardiovascular autonomic neuropathy in people with type 2 diabetes mellitus; investigation of its association with classical cardiovascular risk factors using cardiovascular autonomic reflex tests: a cross-sectional study

BackgroundPeople with type 2 diabetes mellitus (DM) are at increased risk of cardiovascular disease (CVD). Cardiovascular autonomic neuropathy (CAN) is an underdiagnosed risk factor for CVD, which is prevalent among people with 2DM and can lead to CVD and CVD-related mortality. Little is known about the risk factors associated with CAN in type 2DM. Thus, the study was aimed to assess CAN using five cardiovascular autonomic reflex tests (represented by Ewing’s score) and explore the factors associated with CAN in people with type 2DM. The studied factors include traditional and serological CVD risk factors obtained from a fasting blood sample and cardiorespiratory fitness (CRF) obtained via attainment of the highest peak of volumes of O2 (VO2Peak).ResultsUnivariate analysis revealed a significant positive correlation between resting systolic blood pressure (SBP) and Ewing’s score (r=0.47, p=.02) and an inverse correlation between VO2Peak and Ewing’s score (r=−0.64, p=.001). Multivariate linear regression revealed that a significant model that included resting SBP and VO2Peak explained 93.8% of Ewing’s score variance.ConclusionCAN was associated with two CVD parameters, including resting SBP and CRF, which may indicate the importance of controlling these two factors to prevent or reduce CAN in people with type 2DM.

Study of the activation of the RISK and SAFE signaling pathways by cyclosporin A pre- and post-conditioning in a mouse model of cerebral infarction

Cyclosporin A (CsA) has been shown to be useful in preventing ischemia-reperfusion injury in basic models of myocardial or cerebral infarction. CsA limits the opening of the mitochondrial transition pore (mPTP) through its direct interaction with cyclophilin D. However, recent studies in cardioprotection and neuroprotection suggest a role of CsA on the classic RISK and SAFE pathways, upstream of mitochondria. We aim to study the effect of CsA in ischemic pre- and post-conditioning on the RISK and SAFE pathways in a mouse model of stroke. Mice underwent 60 min ischemia and 30 min or 24 h reperfusion and received either no treatment (IR), a bolus of CsA (10 mg/kg) 10 min before the ischemia (pre-CsA) or 10 min after the reperfusion (post-CsA). Infarction of the middle cerebral artery was performed with a microfilament placed intra-arterially for the desired duration. Surgery was performed on Sham mice, but the filament was not occlusive. mPTP opening was evaluated by calcium retention capacity (CRC) on isolated mitochondria from ischemic right hemisphere and non-ischemic left hemisphere. Activation of the RISK and SAFE pathways was evaluated by determining the phosphorylation state of key proteins by Western blots: STAT3, GSK3-β, Akt and Erk. As expected, CRC was significantly reduced in the mitochondria from the right hemisphere in the IR group (Sham, 103 ± 21 vs. IR, 57 ± 18 nmol Ca2+/mg, n = 12/gp, P < 0.05). There was a slight increase in PTP resistance in the ischemic mitochondria from the pre-CsA and post-CsA groups. Experiments are ongoing to measure infarct size after 24 h of reperfusion. There was no significant change in protein phosphorylation in the left hemisphere. In the right ischemic hemisphere, there was a trend of activation of GSK3-β in post-CsA mice and STAT3 in pre-CsA mice. Our results suggest an effect of CsA upstream of the mPTP during stroke, which could correspond to a positive feedback loop.

Prognostic value of BNP in STEMI patients

Abstract Funding Acknowledgements Type of funding sources: None. OnBehalf Portuguese Registry of Acute Coronary Syndromes (ProACS) Introduction Brain natriuretic peptide (BNP) is a highly sensitive and specific biomarker on the extension of myocardial infarction, strongly related to short and long-term prognosis in patients with ST elevation myocardial infarction (STEMI). Objective To evaluate diagnostic and prognostic value of BNP levels in a Portuguese cohort of STEMI patients. Material and methods Retrospective analysis of patients admitted with STEMI included in the Portuguese Registry of Acute Coronary Syndromes between 2010-19. Patients were divided in three groups regarding BNP: Group 1 if BNP &amp;lt;100 pg/ml; Group 2 100 ≤ BNP &amp;lt; 400 pg/ml and Group 3 ≥400 pg/ml. Independent predictors of a composite of all-cause mortality and rehospitalization for cardiovascular causes were assessed by multivariate logistic regression. Results 1650 patients were included, mean age 64 ± 13 years, 75.4% male. 39.0% (n = 643) integrated group 1, 39.5% (n = 652) group 2 and 21.5% (n = 355) group 3. Group 3 patients were significantly older (58 ± 11 vs 66 ± 13 vs 72 ± 12 years, p &amp;lt; 0.001), had more classic cardiovascular risk factors, except for smoker status, and more previous history of cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease and cancer. Anterior STEMI was the most frequent location (51.1%), however group 3 patients presented with lower systolic blood pressure (136 ± 30 vs 140 ± 31 vs 131 ± 28 mmHg, p &amp;lt; 0.001) and higher heart rate (76 ± 17 vs 77 ± 19 vs 84 ± 26 bpm, p &amp;lt; 0.001) and KK class (KK class &amp;gt; I 5.6 vs 9.5 vs 28.5%, p &amp;lt; 0.001). They also presented higher levels of creatinine (1 ± 0.5 vs 1.2 ± 0.9 vs 1.5 ± 1 mg/dl, p &amp;lt; 0.001) and the lowest levels of hemoglobin (13.5 ± 1.6 vs 12.6 ± 1.9 vs 11.7 ± 2.1 g/dl, p &amp;lt; 0.001). Mean ejection fraction (EF) was lower in group 3 (58 ± 11 vs 53 ± 12 vs 44 ± 13%, p &amp;lt; 0.001). Multivessel disease was more common in group 3 (34.8 vs 44.8 vs 51.3%, p &amp;lt; 0.001), where a higher percentage was proposed to medical therapy (2.8 vs 3.5 vs 8.5%, p &amp;lt; 0.001). In the patients proposed to revascularization, although not statistically significant, there was a trend towards surgical revascularization or hybrid approach. In-hospital complications were more frequent in group 3, especially heart failure (HF) (18.9% mean vs 45.4%, p &amp;lt; 0.001), and mortality was seven times superior in group 3 versus group 1 (1.2% vs. 8.5%, p &amp;lt; 0.001). The composite endpoint of 1-year mortality and cardiovascular rehospitalization occurred in 12%. After propensity score application, the 1-year endpoint total mortality rate and cardiovascular readmission was 20.3%, and higher BNP was associated with higher rates (p &amp;lt; 0.001). Predictor factors for the composite endpoint, evaluated through Cox multivariate regression were previous HF, multivessel disease, EF &amp;lt; 30% and the use of nitrates and aldosterone antagonists. The use of aspirin was a protector factor. Conclusion BNP levels during index hospitalization were a powerful prognostic biomarker for all-cause mortality MACE in patients admitted with STEMI.

Early vascular aging in patients with metabolic syndrome: features of the course and diagnosis

Purpose: identifying the causes of early vascular aging (EVA) in patients with metabolic syndrome (MetS), assessing the relationship between vascular age and various metabolic disorders, the severity of metabolic syndrome , tissue and circulating risk markers, the severity of non-infectious inflammation, and derive a new score for calculation vascular age and predicting early vascular aging in patients with metabolic syndrome.Materials and methods: а total of 750 patients aged 35 to 80 years with metabolic syndrome were examined. Early vascular aging syndrome was detected in 484 patients with metabolic syndrome and carotid-femoral pulse wave velocity (cfPWV) values exceeding expected for average age values by 2 or more SD.Results: Multiple logistic regression shown, that presence of type 2 diabetes and IR were associated with greater risk of early vascular aging, the risk of having early vascular aging increased by 76% with an increase in HOMA-IR by 1 unit, by 17% with an increase in carotid-femoral pulse wave velocity by 1 mg/l, by 4% with an increase in DBP by 1 mm Hg, and by 1% with each 1 pmol / L increase in the level of UA. For vascular age, calculated from carotid-femoral pulse wave velocity, SCORE scale, QRISK-3 scale and Framingham scale, respectively. Diabetes mellitus and clinical markers of IR (yes/no), HOMA-IR and UA level were used to develop a new VAmets score for EVA prediction providing a total accuracy of 0.830 (95% CI 0,799 to 0,860).Conclusion: parallel efforts for effective integration simple clinical score into clinical practice have been offered. Our score (VAmets) may accurately identify patients with metabolic syndrome and early vascular aging on the basis of widely available clinical variables and classic cardiovascular risk factors can prioritize using of vascular age in routine care.

Classic cardiovascular risk factors improve in very elderly hypopituitary patients treated on standard hormone replacement in long term follow- up

BackgroundHypopituitarism in the elderly population is an underdiagnosed condition and may increase comorbidities related to glucose metabolism, dyslipidemia, and cardiovascular risk factors. Optimization of hormone replacement that considers alterations in clearance rates of hormones, interaction with other medications, and evaluation of the risk-benefit ratio of treatment is a big challenge for clinical practice.ObjectivesThis study aimed to evaluate classic cardiovascular risk factors in hypopituitary septuagenarians and octagenarians by diagnosis and after long-term hormone replacement.MethodsThis is a retrospective observational study, with patients recruited and selected from a registry in a tertiary medical center. We included patients aged 70–99 years with hypopituitarism, evaluated hormonal and biochemical parameters, and cardiovascular risk scores were calculated by diagnosis and compared after long-term follow-up. All patients gave informed consent. Patient data were compared to a sex and age-matched control group, with long-term geriatric follow-up, without endocrine diseases.ResultsThirty-five patients were included, 16 patients aged 70–75 years (72.61), 12 patients 76–80 years (72.28), 7 patients 81–99 years (89.28). Pituitary macroadenomas were the main cause of hypopituitarism, mean maximal diameter 3.4 cm (2.9–4.3), and invasive craniopharyngiomas. At the moment of diagnosis, most patients were overweight, and abdominal adiposity was observed in 76.9% of women and 36.4% of men, primarily in octagenarians and nonagenarians. Comorbidities were frequent; 85.7% presented hypertension, 37.1% diabetes, 53.1% low HDL, 51.5% hypertriglyceridemia. Most patients presented more than two combined pituitary deficiencies; hypogonadism in 88.6%, central hypothyroidism in 82.9%, GH deficiency in 65.7%, and adrenal insufficiency in 25.7%. Analysis of cardiovascular risk prediction in the total cohort showed that 57.1% of patients presented a reduction in the General Cardiovascular Disease (CVD) Risk Prediction Score and 45.7% in atherosclerotic CVD risk estimated by ACC/AHA 2013 Pooled Cohort Equation, despite being submitted to conventional hormone replacement, during the mean follow-up of 14.5 years. This reduction was not observed in the control group.Discussion and conclusionIn this study, aged hypopituitary patients presented a reduction in estimated general CVD risk during long-term follow-up, despite replacement with corticosteroids, levothyroxine, or gonadal steroids. Early diagnosis and treatment of hypopituitarism in the elderly remain challenging. Larger studies should be performed to assess the risk-benefit ratio of hormone replacement on the metabolic profile in septuagenarian and octogenarian patients.

Abstract P442: The Association of Amyloid and Tau Burden With Centrum Semiovale Perivascular Spaces in Cerebral Amyloid Angiopathy

Background: The mechanisms linking cerebral amyloid angiopathy (CAA) to enlarged perivascular spaces in centrum semiovale (CSO-EPVS) and whether other Alzheimer’s Disease (AD) pathologies might affect CSO-EPVS are unclear. We hypothesized that amyloid but not tau load would independently correlate with CSO-EPVS in CAA. Methods: Fifty prospectively enrolled nondemented probable CAA patients underwent high-resolution structural MRI, Pittsburgh compound B (PiB, for amyloid), and 18 F-flortaucipir (FTP, for tau) PET imaging. Microbleeds (all lobar, LMB) were counted and white matter hyperintensity volume (WMH) was quantified. CSO-EPVS were counted on T 2 -MRI sequence and graded using a previously validated scale (range 0-4). A multivariate ordinal regression model was used to assess the independent associations between CSO-EPVS and mean cortical amyloid as well as tau deposition, after adjusting for relevant covariates. Results: Patients had a mean age of 69.3±7.2. Age, sex, presence of hypertension, intracerebral hemorrhage (ICH), LMB counts, and WMH were not associated with CSO-EPVS grades (p&gt;0.2 for all comparisons). Higher PiB uptake significantly correlated with increased CSO-EPVS (rho=0.45, p=0.001). Higher FTP showed a trend for correlation with CSO-EPVS (rho=0.26, p=0.069). In an ordinal regression model with CSO-EPVS grade as the dependent variable and both amyloid and tau levels included as predictors along with covariates presented above, the association of CSO-EPVS remained significant with higher PiB uptake (β=3.97, 95%CI 1.1-6.8, p=0.007) but not with FTP uptake (p=0.167). Conclusion: Results of this study suggest that CSO-EPVS is independently associated with amyloid but not with tau deposition in CAA. CSO-EPVS was not associated with age or classical vascular risk factors or presence of ICH. Our results support the view that vascular amyloid but not other AD pathologies such as tau might contribute to EPVS in patients with CAA.

The relationship of indoxyl sulfate and p-cresyl sulfate with target cardiovascular proteins in hemodialysis patients

Protein-bound uremic toxins (Indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) are both associated with cardiovascular (CV) and all-cause mortality in subjects with chronic kidney disease (CKD). Possible mechanisms have not been elucidated. In hemodialysis patients, we investigated the relationship between the free form of IS and PCS and 181 CV-related proteins. First, IS or PCS concentrations were checked, and high levels were associated with an increased risk of acute coronary syndrome (ACS) in 333 stable HD patients. CV proteins were further quantified by a proximity extension assay. We examined associations between the free form protein-bound uremic toxins and the quantified proteins with correction for multiple testing in the discovery process. In the second step, the independent association was evaluated by multivariable-adjusted models. We rank the CV proteins related to protein-bound uremic toxins by bootstrapped confidence intervals and ascending p-value. Six proteins (signaling lymphocytic activation molecule family member 5, complement component C1q receptor, C–C motif chemokine 15 [CCL15], bleomycin hydrolase, perlecan, and cluster of differentiation 166 antigen) were negatively associated with IS. Fibroblast growth factor 23 [FGF23] was the only CV protein positively associated with IS. Three proteins (complement component C1q receptor, CCL15, and interleukin-1 receptor-like 2) were negatively associated with PCS. Similar findings were obtained after adjusting for classical CV risk factors. However, only higher levels of FGF23 was related to increased risk of ACS. In conclusion, IS and PCS were associated with several CV-related proteins involved in endothelial barrier function, complement system, cell adhesion, phosphate homeostasis, and inflammation. Multiplex proteomics seems to be a promising way to discover novel pathophysiology of the uremic toxin.

Poor cardiovascular health is associated with subclinical atherosclerosis in apparently healthy sub-Saharan African populations: an H3Africa AWI-Gen study

BackgroundThe cardiovascular health index (CVHI) introduced by the American Heart Association is a valid, accessible, simple, and translatable metric for monitoring cardiovascular health in a population. Components of the CVHI include the following seven cardiovascular risk factors (often captured as life’s simple 7): smoking, dietary intake, physical activity, body mass index, blood pressure, glucose, and total cholesterol. We sought to expand the evidence for its utility to under-studied populations in sub-Saharan Africa, by determining its association with common carotid intima-media thickness (CIMT).MethodsWe conducted a cross-sectional study involving 9011 participants drawn from Burkina Faso, Ghana, Kenya, and South Africa. We assessed established classical cardiovascular risk factors and measured carotid intima-media thickness of the left and right common carotid arteries using B-mode ultrasonography. Adjusted multilevel mixed-effect linear regression was used to determine the association of CVHI with common CIMT. In the combined population, an individual participant data meta-analyses random-effects was used to conduct pooled comparative sub-group analyses for differences between countries, sex, and socio-economic status.ResultsThe mean age of the study population was 51 ± 7 years and 51% were women, with a mean common CIMT of 637 ± 117 μm and CVHI score of 10.3 ± 2.0. Inverse associations were found between CVHI and common CIMT (β-coefficients [95% confidence interval]: Burkina Faso, − 6.51 [− 9.83, − 3.20] μm; Ghana, − 5.42 [− 8.90, − 1.95]; Kenya, − 6.58 [− 9.05, − 4.10]; and South Africa, − 7.85 [− 9.65, − 6.05]). Inverse relations were observed for women (− 4.44 [− 6.23, − 2.65]) and men (− 6.27 [− 7.91, − 4.64]) in the pooled sample. Smoking (p < 0.001), physical activity (p < 0.001), and hyperglycemia (p < 0.001) were related to CIMT in women only, while blood pressure and obesity were related to CIMT in both women and men (p < 0.001).ConclusionThis large pan-African population study demonstrates that CVHI is a strong marker of subclinical atherosclerosis, measured by common CIMT and importantly demonstrates that primary prevention of atherosclerotic cardiovascular disease in this understudied population should target physical activity, smoking, obesity, hypertension, and hyperglycemia.

Patients with coronary heart disease, dilated cardiomyopathy and idiopathic ventricular tachycardia share overlapping patterns of pathogenic variation in cardiac risk genes

BackgroundVentricular tachycardia (VT) is a major cause of sudden cardiac death (SCD). Clinical investigations can sometimes fail to identify the underlying cause of VT and the event is classified as idiopathic (iVT). VT contributes significantly to the morbidity and mortality in patients with coronary artery disease (CAD) and dilated cardiomyopathy (DCM). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility screening for disease-predisposing variants could improve VT diagnostics and prevent SCD in patients.MethodsNinety-two patients diagnosed with coronary heart disease (CHD), DCM, or iVT were included in our study. We evaluated genetic profiles and variants in known cardiac risk genes by targeted next generation sequencing (NGS) using a newly designed custom panel of 96 genes. We hypothesized that shared morphological and phenotypical features among these subgroups may have an overlapping molecular base. To our knowledge, this was the first study of the deep sequencing of 96 targeted cardiac genes in Kazakhstan. The clinical significance of the sequence variants was interpreted according to the guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015. The ClinVar and Varsome databases were used to determine the variant classifications.ResultsTargeted sequencing and stepwise filtering of the annotated variants identified a total of 307 unique variants in 74 genes, totally 456 variants in the overall study group. We found 168 mutations listed in the Human Genome Mutation Database (HGMD) and another 256 rare/unique variants with elevated pathogenic potential. There was a predominance of high- to intermediate pathogenicity variants in LAMA2, MYBPC3, MYH6, KCNQ1, GAA, and DSG2 in CHD VT patients. Similar frequencies were observed in DCM VT, and iVT patients, pointing to a common molecular disease association. TTN, GAA, LAMA2, and MYBPC3 contained the most variants in the three subgroups which confirm the impact of these genes in the complex pathogenesis of cardiomyopathies and VT. The classification of 307 variants according to ACMG guidelines showed that nine (2.9%) variants could be classified as pathogenic, nine (2.9%) were likely pathogenic, 98 (31.9%) were of uncertain significance, 73 (23.8%) were likely benign, and 118 (38.4%) were benign. CHD VT patients carry rare genetic variants with increased pathogenic potential at a comparable frequency to DCM VT and iVT patients in genes related to sarcomere function, nuclear function, ion flux, and metabolism.ConclusionsIn this study we showed that in patients with VT secondary to coronary artery disease, DCM, or idiopathic etiology multiple rare mutations and clinically significant sequence variants in classic cardiac risk genes associated with cardiac channelopathies and cardiomyopathies were found in a similar pattern and at a comparable frequency.

Reduced insulin clearance is linked to subclinical atherosclerosis in individuals at risk for type 2 diabetes mellitus

Hyperglycemia and insulin resistance contribute to vascular damage and are regulated by different pathophysiological processes. The aim of the study was to systematically investigate the relative contributions of multiple fasting state- and oral glucose tolerance test (oGTT)-derived glycemic traits to carotid intima-media thickness (cIMT), a surrogate parameter of subclinical atherosclerosis, in individuals with increased risk for type 2 diabetes mellitus (T2D). 667 volunteers (417 women and 250 men, mean age 44.1 years), who were free of cardiovascular disease (CVD), were included in this cross-sectional study. Glucose tolerance, insulin sensitivity, insulin secretion and insulin clearance were assessed by frequently sampled 75 g oGTT. CIMT was measured by high-resolution ultrasound. Insulin clearance was associated with cIMT in univariate analysis (ßst = − 0.17, p < 0.0001) and in a stepwise regression analysis on 15 variables possibly affecting cIMT, age (r2 = 0.3923, p < 0.0001), insulin clearance (r2 = 0.4564, p < 0.0001), systolic blood pressure (r2 = 0.4733, p < 0.0001), body mass index (BMI) (r2 = 0.4804, p = 0.002), gender (r2 = 0.4831, p = 0.013), and fasting insulin clearance (r2 = 0.4857, p = 0.030) turned out to be significant determinants of cIMT. In a cross-validated model resulting from this analysis, insulin clearance was found to be an independent determinant of cIMT (ßst = − 0.16, p < 0.0001) even after adjusting for traditional CVD risk factors. Reduced insulin clearance may be an early marker of damage on the vasculature, independent of classical CVD risk factors. Reduced insulin clearance should be considered with regard to vascular insulin resistance.

Abstract 12811: Clinical Outcomes and Prognostic Impact of Triglyceride Deposit Cardiomyovasculopathy Among Hemodialysis Patients Suspected of Coronary Artery Disease

Introduction: Hemodialysis (HD) has been reported as a strong prognostic factor in patients with cardiovascular disease. It is unknown how much triglyceride deposit cardiomyovasculopathy (TGCV), a novel identified rare cardiovascular disorder, is associated with cardiovascular mortality among HD patients. Hypothesis: We hypothesized that comorbidity of TGCV in HD patients who suspected of CAD plays a critical role for cardiovascular outcomes in this population. Methods: We examined the data obtained from 83 consecutive HD patients suspected of coronary artery disease who underwent both [123I]-β-methyl-iodophenyl-pentadecanoic acid (BMIPP) scintigraphy and subsequent coronary angiography (CAG). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke up to 5 years of follow-up. The key secondary endpoint was a composite of cardiovascular death, non-fatal MI, non-fatal stroke, target vessel revascularization, or any hospitalization for heart failure. Results: A total of 83 HD patients were grouped into either the definite TGCV (17 patients), the probable TGCV (22 patients), or the non-TGCV control group (44 patients). At the end of the follow-up period for a median of 4.7 years, a primary endpoint event occurred in 58.8% of the definite TGCV patients (hazard ratio, 8.06; 95% confidence interval [CI], 2.52-25.8, Log-rank p&lt;0.001) and 27.3% of the probable TGCV patients, as compared to 9.1% of the non-TGCV control patients; the corresponding rates of the key secondary endpoint were 88.2% for the definite TGCV patients (hazard ratio, 6.36; 95% CI, 2.89-14.0, Log-rank p&lt;0.001) and 59.1% for the probable TGCV patients. In the multivariate Cox proportional hazard analyses after adjustment for confounding factors, various variables related to mortality on HD patients, or variables known as a classical cardiovascular risk, the definite TGCV was significantly and independently associated with cardiovascular mortality and outcomes in any of the three models. Conclusions: Comorbidity of TGCV in patients on HD was associated with increased risk of cardiovascular events including cardiovascular death, which might highlight the potential therapeutic target.