Cohort Of Patients Research Articles

Cardiovascular mortality with oral potassium-binders in patients with CKD and heart failure

Abstract Introduction Hyperkalemia is an inherent consequence of advancing chronic kidney disease (CKD) as a result of the kidney’s decreased ability to excrete potassium. Heart failure patients with concomitant CKD may not tolerate maximum doses of guideline-directed medical therapies (GDMT) like ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), angiotensin receptor/neprilysin inhibitors (ARNI) and mineralocorticoid receptor antagonists (MRA) due to dose-limiting hyperkalemia. Many randomized controlled trials in heart failure exclude patients with advanced CKD. Two oral therapies exist to manage hyperkalemia - patiromer sorbitex calcium and sodium zirconium cyclosilicate. This study aims to identify the potassium-binder with better outcomes as defined by less readmissions, hyperkalemia episodes, and death. Purpose This project was undertaken to better understand the impact of using potassium-binders in CKD patients with heart failure. Improved management of hyperkalemia will be an avenue for optimization of GDMT in this population. Methods and materials The TriNetX research network was used for this study. Two cohorts of patients were created by using International Classification of Disease 10 (ICD-10) codes and CPT codes. Both cohorts consisted of patients with no prior history of hyperkalemia within 30 days of hospital discharge at which time one cohort was prescribed patiromer and the other received sodium zirconium cyclosilicate. Each cohort was prohibited from exposure to the other medication. The cohorts were balanced by propensity score matching and the greedy nearest neighbor algorithm for age, race, gender, ethnicity. They were also balanced for systolic and diastolic heart failure diagnoses, and for each individual stage of CKD (1 through 5 and end stage). They were also balanced for use of ACEi, ARBs, and MRAs. This resulted in 8,921 patients in each arm. They were then evaluated for the outcomes of hospital readmission, hyperkalemia episodes (>6.1 mmol/L), and death within 12 months. Results Patients treated with patiromer were more likely to be hospitalized over the following twelve months (44% vs 40%, RR 1.11, 95% CI (1.07,1.15), p value <0.0001). They were also more likely to experience hyperkalemia (11.7% vs 9.2%, RR 1.27, 95% CI (1.16,1.38), p value <0.0001). Patiromer was also associated with slightly greater all cause mortality (27% vs 25%, RR 1.08, 95% CI (1.03,1.13), p value 0.0021). Discussion This study demonstrates patiromer has more readmissions and hyperkalemia episodes along with greater mortality. In conclusion, sodium zirconium cyclosilicate was found to have better outcomes compared to that of patiromer. Further studies are necessary to better understand the utility of using sodium zirconium cyclosilicate as maintenance therapy for hyperkalemia in order to maximize GDMT in CKD patients with heart failure.

Lipoprotein(a) and atherosclerotic cardiovascular disease in a Brazilian tertiary hospital population

Abstract Background/Introduction Elevated levels of lipoprotein(a) [Lp(a)] are a strong risk marker of atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction (MI), ischemic stroke, and peripheral arterial disease, as well as of aortic valve calcification and stenosis. However, few studies have assessed the prevalence of high Lp(a) levels in patients followed at a tertiary hospital specialized in cardiovascular diseases (CVD). In addition, there is scant information about Lp(a) concentrations in Brazilian individuals. Purpose The aim of the study was to describe the demographic characteristics and comorbidities of patients with at least one measure of Lp(a) at a tertiary treatment center for CVD in our city – Brazil. Methods Patients treated at a heart institute had their data extracted between the years 1999 and 2021. Data were obtained through direct electronic extraction of patients' medical records. The patients were categorized according to different Lp(a) cutoff levels (> 50 and < 70, > 70 and < 90, and > 90 mg/dL) and by quartiles. Results Of 4,970 unique patients included in the study, the mean age at baseline was 59.9 years (SD ± 14.5), 2,634 (53%) were male, and the median Lp(a) was 23.2 mg/dL (interquartile range 8.9 - 56.8 mg/dL). In the whole cohort, 460 (9.3%) had Lp(a) > 50 and < 70, 344 (6.9%) > 70 and < 90, 612 (12.3%) > 90 mg/dl and 138 (2.8%) > 150 mg/dL. Established ASCVD was reported in 1,223 (24%) of the individuals, with a progressively higher prevalence across the Lp(a) categories above (31.2%, 33.8%, 34.2%, respectively) (table 1). Moreover, the Lp(a) median (interquartile range) in mg/dL was significantly higher in those with baseline history of ASCVD (31.4 [10.8-71.2] vs 21.2 [8.3-52]), MI (27.8 [10.6-65.9] vs 22.3 [8.5-54.7]) and stroke (24.9 [10-69.5] vs 23.1 [8.9-56.5]), all p < 0.05 (table 2). Lp(a) was also significantly higher among those with LDL-C ≥ 100 mg/dL relative to LDL-C < 100 mg/dl (25.5[9.5-63.2] vs 21.4[8.4 vs 52.2] p < 0.05). Conclusions In this cohort of patients followed at a tertiary center specialized in CVD, approximately a third had Lp(a) levels above 50 mg/dL, a cutoff robustly associated with ASCVD. This finding likely represents an important source of cardiovascular residual risk, particularly in those with established ASCVD, exposing the need of further therapies.

Comparison of cardiovascular outcomes in patients with diabetes treated with tirzepatide versus semaglutide: a multi-institutional analysis

Abstract Introduction Glucagon-like-peptide-1 (GLP-1) receptor agonists have been demonstrated to have cardiovascular benefits in patients with diabetes. Two of the most prescribed medications in this class are tirzepatide and semaglutide. Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, while semaglutide is a selective GLP-1 receptor agonist. Tirzepatide and semaglutide have previously been directly compared to assess efficacy in glycemic control as the primary endpoint. However, there is limited data directly comparing cardiovascular outcomes between the two medications in patients with diabetes. This retrospective cohort study compares the incidence of major adverse cardiovascular events (MACE) in patients with diabetes treated with tirzepatide or semaglutide. Purpose The purpose of this study is to identify differences in cardiovascular outcomes between patients with diabetes treated with tirzepatide as compared to semaglutide. Materials and Methods The TriNetX research network was used for this study. Two patient cohorts were generated using International Classification of Disease 10 (ICD-10) codes and medication codes in the TriNetX system. Both cohorts of patients had a history of diabetes (E08-E13) and no prior history of cerebral vascular accident (I63) or myocardial infarction (I21). One cohort received semaglutide and the other tirzepatide. Each cohort was prohibited from receiving the other agent. The cohorts were balanced for age, race, gender, and ethnicity by propensity score matching and the greedy nearest neighbor algorithm resulting in 36,212 patients in each arm. They were then evaluated for the 3-year outcomes of major adverse cardiovascular events (myocardial infarction, cerebral vascular accident, and death). Results Tirzepatide was associated with statistically significantly fewer MACE outcomes compared to semaglutide for each of the individual endpoints as well as the overall composite endpoint over the 3 year follow up period. Table 1. MACE events for semaglutide and tirzepatide. Table 2. Relative risks for semaglutide MACE endpoints compared to tirzepatide. Conclusions In this retrospective cohort study, tirzepatide was associated with a lower incidence of major adverse cardiovascular events compared to semaglutide in patients with diabetes. These findings suggest that tirzepatide offers superior cardiovascular protection for primary prevention compared to semaglutide and warrant further investigation in future studies and clinical trials.Table 1Table 2

Predictors of adverse cardiac events in a large cohort of patients with antiphospholipid syndrome

Abstract Background Non-valvular cardiac disease in antiphospholipid syndrome (APS) has been modestly evaluated. Aim We wanted to assess the prevalence and evolution of major adverse cardiovascular events(MACE) in a cohort of APS patients. Material and Methods From a large cohort of 181 APS patients included in a study from 2011-2012.year data for the occurrence of MACE in 10 years of follow-up were evaluated in 82 patients (86.6% females, 62.2% with primary (PAPS), and 37.8% patients with APS associated with systemic lupus erythematosus (SLE) (sAPS)). At the inclusion in all patients, a transthoracic echocardiography study for the assessment of dimensions and functionality of the left and right heart along with valvular functions and morphology. Standard atherosclerotic risk factors prevalence was analyzed. Antiphospholipid antibodies(aPL) analysis included the detection of aCL (IgG/IgM), ß2GPI (IgG/IgM), and LA, and all patients were treated according to the valid guidelines by the rheumatologist. Data regarding the occurrence of new myocardial infarction (MI), cerebrovascular events (CVI), arterial and/or venous thrombosis, heart failure (HF), and cardiovascular death (considered as MACE) have been collected 10 years after inclusion. Results The prevalence of standard atherosclerotic risk factors was less than 40% in both study groups. Left ventricle ejection fraction(LVEF) was over 45% in more than 90% of patients in both groups (p=0.246) with valvular dysfunction present in 49% of PAPS and 58.1% of sAPS patients (p=0.426). 9.8% PAPS and 12.9% sAPS had coronary artery disease(CAD) (p=0.724) and HF was present in 7.8% PAPS and 3.2% sAPS (p=0.645). MACE occurred in 17.6% of PAPS and 22.6% of sAPS (p=0.585). The new MI occurred in 9.8% of PAPS and 9.7% of sAPS (p=1.000), CVI in 5.9% of PAPS and 3.2% of sAPS (p=1.000), HF in 5.9% of PAPS and 3.2% of sAPS (p=1.000) and cardiovascular death in 9.8% of PAPS and 12.9% of sAPS (p=0.724). New thrombotic events (arterial and/or venous) occurred in 15.7% of PAPS and 17.2% of sAPS (p=1.000). During the follow-up period, 66.7% of PAPS and 55.2% of SAPS (p=0.313) were treated with aspirin, 25.5% of PAPS and 25.0% of sAPS with warfarin, and chloroquine was administered in 46.8% of PAPS and 53.6% of sAPS (p=0.571). Age (p=0.008), gender (p=0.034), thrombotic APS (p=0.033), hypertension (p=0.003), diabetes mellitus (p=0.043), and cardiovascular manifestations present at the time of APS diagnosis (p=0.035), namely CAD (p=0.001) and HF (p=0.005) were significantly associated with 10y MACE. aPL type and category were not associated with 10y MACE. In a multivariate logistic model, age. hypertension, and HF were independent predictors for 10y MACE. Conclusions APS patients develop new cardiovascular events despite optimal medical therapy. Cardiovascular evaluation at the time of diagnosis and proper cardiologist follow-up with the rigorous treatment of standard atherosclerotic risk factors is of utmost importance.

Potential hematopoietic effects of SGLT2 inhibitors in patients with cardiac amyloidosis

Abstract Introduction Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been revealed to have potential hematopoietic effects in patients with heart failure (HF), leading to an improvement in clinical outcome. However, these benefits have not been studied in patients with cardiac amyloidosis (CA), despite CA often causing symptoms of heart failure (HF) and contributing to an iron-deficient state, which further complicates by limiting erythropoiesis and lowering haemoglobin and haemotocrit levels. We aimed to determine the potential of SGLT2i in improving haematological parameters and functional capacity (FC) in amyloidosis patients. Methods A prospective analysis was conducted to compare the effects of SGLT2i in a cohort of patients who received the best medical therapy (BMT) alongside SGLT2i (n=20), as opposed to patients receiving only BMT without SGLT2i (n=20). All of patients underwent blood testing and cardiopulmonary exercise testing (CPET) at baseline and after 6 months (IQR:5.0 – 6.0). Results The SGLT2i-based therapy resulted in a significant improvement and difference in hematological parameters upon follow-up assessment compared to the control group. In the SGLT2i group, the mean haemoglobin level increased from 13.3 g/dL to 14.5 g/dL, whereas in the control group, it decreased from 12.7 g/dL to 10.9 g/dL (P < 0.001). Furthermore, the haematocrit difference showed a significant increase in the SGLT2i group (+3.8%) compared to a decrease in the control group (-4.4%) (P < 0.001). Additionally, the iron status improved in the SGLT2i-treated group (+6.7 µg/dL) compared to a decrease in the control group (-14.9 µg/dL), although the difference was significant only with a p-value of 0.034. However, neither group demonstrated significant improvement nor regression in CPET parameters. The peak oxygen consumption (peak VO2, (ml/min)/kg) showed no significant change in either group (P = 0.286), as well as VE/VCO2 slope (P = 0.295). Conclusions Treatment with SGLT2i could be utilized in the treatment of patients with amyloidosis. This potential benefit in improving hematological parameters warrants further investigation and consideration in clinical practice.

GLASGOW-BLATCHFORD AND ROCKALL SCORE UTILITY IN PREDICTING FINDINGS ON VIDEO CAPSULE ENDOSCOPY IN PATIENTS ADMITTED WITH OVERT SMALL BOWEL BLEEDING

Background and Aims Glasgow-Blachford (GBS) and Rockall scores are recognised tools to prioritize patients with upper gastrointestinal bleeding. Its utility in predicting findings on capsule endoscopy (CE) in patients with overt small bowel bleeding (OSBB) remains unclear. The aim was to assess the use of these scores in predicting relevant findings on CE and outcome among patients with suspected OSBB. Methods Retrospective analysis from January 2019 to June 2022. Clinical parameters and scores were collected at presentation and at 24 hours. Univariate analysis used simple logistic regression, chi-squared test or Mann-Whitney as needed. ROC analysis was performed selecting the optimal cut-off point maximized by the Youden index. Results 79 patients were included. 62% had relevant findings. The predictor showing the highest discrimination ability was the Initial GBS (AUC 0.625 95%CI 0.49 – 0.76). The optimal cut-off point was at least 4, with a sensitivity 98%, specificity 30% and accuracy 72%. Multivariable regression analysis showed inpatient status on CE (OR 117.27; CI 11.32 – 4492.93; p=0.001), shorter time to CE (OR 1.02; CI 1.01 – 1.04 p=0.018), higher initial GBS (OR 1.22; CI 1.06 – 1.43 p=0.009) and higher GBS within 24 hours (OR 1.19; CI 1.04 – 1.37 p= 0.013) were predictive factors for relevant findings on CE, with a model AUC 0.802, Sensitivity 91.8% and Specificity 63.3%. Conclusions GBS and Rockall score were useful in predicting relevant findings on CE in this cohort of patients with suspected OSBB. In patients with GBS 5 or higher, an early CE during the same admission, is warranted.

Right atrio-ventricular strain as a predictor of death in left-sided heart failure

Abstract Background Right ventricular (RV) strain is an established outcome predictor in heart failure (HF). However, the role of right atrial (RA) strain in the setting of left-sided HF is incompletely understood. Purpose We sought to evaluate the RV, RA and combined right atrio-ventricular (RAV) strain using speckle-tracking echocardiography in a cohort of patients with left-sided HF and to assess their prognostic role. Methods 121 consecutive patients (mean age 59±14 years, 74% men) with HF with reduced ejection fraction (HFrEF) referred to our echocardiography department were prospectively enrolled. The main endpoint was all-cause death. RV strain was measured as the average longitudinal strain of the basal, mid, and apical segments of the RV free wall and was reported as a positive value, thus a lower RV strain reflecting a greater longitudinal dysfunction. RA strain was defined as the maximal longitudinal displacement of the atrial wall at end-systole, corresponding to atrial reservoir function. RAV strain was defined as the sum of RV strain and RA strain. Results During a median follow-up of 19±11 months, 26 patients (21%) died. Patients who reached the endpoint had lower left ventricular ejection fraction (LVEF) (21±7% vs. 26±7%, p=0.001), lower tricuspid annular plane systolic excursion (16±3 vs. 18±5, p=0.02) and lower RA strain (13± 10% vs. 18±11%, p=0.03). In univariable Cox regression, RV, RA and RAV strain were all predictors of death: HR=1.05 [95% CI, 1.00-1.11], p=0.045 for RV strain, HR=0.95 [95% CI, 0.91-0.99], p=0.02 for RA strain, HR=0.97 [95% CI, 0.94-0.99], p=0.01 for RAV strain. We constructed a multivariable model with well-established event predictors in HFrEF and one strain index at a time. After adjustment for LVEF, maximal left atrial volume, tricuspid regurgitation severity and pulmonary artery systolic pressure, only RAV strain remained an independent predictor of death (HR=0.97 [95% CI, 0.94-1.00], p=0.04), while RV strain and RA strain did not (p=0.07 for both). LVEF did not emerge as a predictor of death in multivariable regression (p=0.57). Conclusion In left-sided HF, RV and RA strain were predictors of death. Combining the longitudinal strain of both right heart chambers might improve risk stratification, since RAV strain remained the only independent predictor of adverse outcome after adjustment for confounders.

Assessment of right ventricular function in patients with severe secondary tricuspid regurgitation, following to the TVARC recommendations: association with outcome

Abstract Introduction Severe tricuspid regurgitation (TR) is associated with increased mortality if left untreated. Recently, the Tricuspid Valve Academic Research Consortium (TVARC) has published standardized definitions of disease aetiology and severity, as well as endpoints for future clinical trials. Right ventricular (RV) function assessment represents one of the cornerstones for risk stratification in these patients, but current guidelines do not propose specific cut-off values for the echocardiographic measures. Also, the thresholds proposed by the TVARC have been derived from normative value and not yet validated in large cohorts of TR patients. Purpose To test the prognostic value of the TVARC proposed echocardiographic cut-offs for grading RV-dysfunction (figure1) in a large real-world cohort of patients with severe secondary TR (STR). Methods Consecutive patients from a single centre with first diagnosis of severe secondary STR, and without a cardiac implantable electronic device, were included. Tricuspid annulus plane systolic excursion (TAPSE), RV global and free wall strain (RVGLS and RVFWLS) and fractional area change (FAC) were used to measure RV function. The study endpoint was all-cause mortality, censored for tricuspid valve intervention. Results A total of 1043 patients (mean age 69 ± 13 years, 43% male), were included. Approximately half of the population (45%) was in NYHA class III or IV and 52% was treated with loop diuretics. Overall patients showed mild RV-dilatation (RV end-diastolic area indexed 12.2 [10.1-15.2cm2/m2]) and moderate-to-severe right atrial dilatation (right atrial maximal area indexed: 13.9 [11.0-17.5cm2/m2]). Using the proposed cut-off values, strain analysis identified a higher number of patients with impaired RV function as compared to standard echocardiographic parameters (89% based on RVGLS; 80% based on RVFWS, 61% based on TAPSE and 54% based on RVFAC). During a median follow-up of 51 [IQR 6 - 98] months, 445 (43%) patients died. The Kaplan-Meier survival curves for each echocardiographic parameter of RV-function are shown in Figure 1. TAPSE, which is the most widely used RV-function parameter, was able to clearly identify patients at high and intermediate risk when mildly, moderately and severely impaired. However, patients with normal TAPSE were still at intermediate risk when RVFWLS was (even mildly) reduced (figure 2). We therefore propose a stepwise practical approach including the measure of RVFWLS when measuring normal TAPSE, in order to possibly re-stratify patients into a higher risk group (Figure 2). This novel grading approach remained independently associated with all-cause mortality after correcting for relevant clinical and echocardiographic variables on multivariable analysis. Conclusion Novel TAVRC cut-off values for RV function show prognostic value in patients with severe STR; particularly the combination of TAPSE and RVFWLS could be use in clinical practice for risk stratification.Figure 1Figure 2

Tafamidis for the treatment of transthyretin cardiac amyloidosis (ATTR-CM) - Real-world data from a tertiary center

Abstract Introduction Tafamidis 61mg was shown to be the first treatment to reduce cardiovascular hospitalizations and to improve survival in patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM). Real-world data on the efficacy of transthyretin (TTR) stabilizers in patients with Heart Failure (HF) due to ATTR-CM is scarce. Purpose We aimed to assess the use of tafamidis in our center, that features a dedicated Cardiomyopathy Clinic. Methods We conducted an all-comers single-centre prospective study of consecutive patients with symptomatic HF due to ATTR-CM followed up to November 2023. As per site protocol, the diagnosis was established according to the ESC algorithm and all patients were assessed at least twice yearly. Disease management plans include HF treatment tailored to ATTR-CM (CHAD-STOP) and treatment with disease-modifying tafamidis 61mg. The latter is considered in patients who meet the local protocol criteria, including key inclusion criteria - NYHA class I-II - and none of the exclusion criteria - e.g. estimated glomerular filtration rate (GFR) <25mL/min. The primary endpoint was time to cardiovascular hospitalization or all-cause death. Results A total 226 ATTR-CM patients were identified, of whom 181 had a follow-up of at least 6 months and were included in the analysis (mean age 84 ± 7 years; 81% males, 16% hATTR-CM). Overall, there were 84 patients treated with tafamidis. Compared to non-treated patients, those receiving tafamidis were younger (mean age 83 vs. 86 years, p=0.007), more often with a lower NYHA functional class (e.g., NYHA I-II: 92 vs. 62%; p<0.001), scored higher on performance scales (e.g., Karnovsky >70: 67 vs 33%; p<0.001), and had less comorbidities (e.g., GFR: 40 vs. 30mL/min; p<0.001). Over a median follow-up of 16 months, 68 (37.6%) patients met the primary endpoint (49.5% vs. 22.6%, respectively; p<0.001). In multivariate analysis, treatment with tafamidis was an independent predictor of the primary endpoint (HR 0.24; 95%CI 0.13-0.43; p<0.001), adjusted for NYHA functional class (HR for NYHA I-II vs. III-IV: 0.54; 95%CI 0.32-0.92; p=0.023), NT-proBNP (HR 1.83; 95%CI 1.09-3.08; p=0.023) and high-sensitivity Troponin T (HR per 10 units: 1.01; 95%CI 1.01-1.02; p=0.024). These findings were consistent in multivariate analysis with any combination of the prior variables with either creatinine, GFR, albumin, or TTR type (wild-type vs. mutated). These results were primarily driven due to association of tafamidis treatment with increased survival. Conclusion The use of tafamidis in a cohort of patients with symptomatic HF and ATTR-CM was shown to be independently associated with reduced cardiovascular hospitalization or all-cause death. The effect had a similar magnitude of effect to that of the ATTR-ACT trial, suggesting that our local protocol based on the key criteria from this trial may allow for appropriate patient selection.

LV reverse remodeling after SAVR in patients with severe symptomatic aortic stenosis: impact on the clinical outcome

Abstract Introduction Surgical aortic valve replacement (SAVR) is the treatment of choice for young patients with severe aortic stenosis (AS) and low surgical risk. Left ventricular (LV) reverse remodeling (RR) after surgery is expected to occur. However, this is not always the case following afterload relief, and this may impact the prognosis. We aimed to assess the prognostic effect of distinct definitions of LV RR after SAVR in the long-term outcome of patients with severe AS. Methods Single-centre prospective study including patients referred for SAVR due to severe symptomatic AS, with no previous history of ischemic cardiomyopathy. Both pre- and post-operative transthoracic echocardiographic (TTE) and cardiac magnetic resonance (CMR) study (at the 3rd to 6th month after SAVR) were performed. LV RR was defined when in presence of at least one of the imaging criteria: >15% decrease in end-diastolic volume (EDV) by CMR; >15% decrease in LV indexed mass (LVM) by CMR; >10% decrease in geometric remodeling (LV mass/EDV ratio) by CMR; >10% increase in LV ejection fraction (LVEF) by CMR; >50% increase on global longitudinal strain (GLS) by TTE. We assess the prognostic value of RR definitions for the outcome after SAVR using Cox regression and Kaplan-Meier analysis. The primary endpoint was defined as all-cause mortality, heart failure (HF) hospitalization or worsening HF. Results We enrolled 140 patients – mean age 71±9 years-old, 49% male, predominantly high-gradient-normal flow AS (mean gradient 65±18mmHg, aortic valve area 0.7±0.2cm2, index stroke volume 47±11mL/m2) submitted to SAVR. At a mean follow-up (FUP) of 34±12 months, 23 (16%) patients met the primary endpoint: 4% (5 patients) died immediately after surgery; three patients died at the FUP (overall mortality rate of 6%). 12 patients (9%) were admitted for HF and 7 (5%) had at least one episode of worsening HF. 118 patients had complete pre and post-surgery imaging study (mean FUP: 36±10 months): 103 patients (87%) had at least one RR parameter (Table 1). Post-operative RR was not independently associated with the clinical outcome (Figure 1A). LVM was the sole independent predictor of the outcome at univariate analysis (Figure 1B–F). Conclusions LV RR after SAVR is highly prevalent in a cohort of patients with classical severe symptomatic AS. However, only LVM regression independently predicts the clinical outcome after surgery. This may stand the greater importance of structural reverse remodeling, rather than LV functional improvement, after pressure overload relief.

Prediction of cardiovascular risk in patients type 2 diabetes using the SCORE2-Diabetes risk score

Abstract Background/Introduction The SCORE2-Diabetes risk score was developed to predict the risk of cardiovascular events (CV-death, non-fatal MI and non-fatal stroke) in patients with T2DM without known cardiovascular disease. Current ESC guidelines recommend the use of this risk score to tailor treatment strategies in this population. Purpose We sought to determine whether the SCORE2-Diabetes risk score was able to appropriately stratify an international cohort of patients from recent cardiovascular clinical outcomes trials. Furthermore, we sought to determine the accuracy and precision of the model including in patients with and without known cardiovascular disease. Methods Patients from 4 randomized cardiovascular outcome trials (DEVOTE, LEADER, PIONEER-6, SUSTAIN-6) were included (n=23,464). Mean follow-up was 2.6 years and outcomes were adjudicated. The SCORE2-Diabetes risk score was calculated using the uncalibrated version which does not account for risk-region. Patients were stratified into low (<5%), moderate (5-<10%), high (10-<20%), and very high risk (≥20%) groups. The SCORE2-Diabetes risk predication model was designed to predict 10-year risk; however, given the mean follow-up from the cohort, outcomes were reported at 36 months. The Brier score, which evaluates estimated risk, and c-index, which evaluates the ability to discriminate between participants, were used to evaluate the precision of the risk score. We further compared the risk score with an estimated risk of MACE calculated using a cause specific Cox model that accounts for competing risk. Results Most patients in the cohort did not have prior myocardial infarction or stroke (57.4%, n=13,467). The SCORE2-Diabetes risk score was able to stratify patients into low, moderate, high, and very high risk cohorts (Figure 1). Observed cardiovascular events at 36 months were higher than the SCORE2-Diabetes risk score predicted (Table 1). The risk score, when included in a regression model, independently predicted cardiovascular death, myocardial infarction, or stroke (HRadj 1.03, p<0.001) and non-cardiovascular death (HRadj 1.05, p<0.001). Including the score in models with only age and sex improved the discrimination and performance of the model. The c-index for the risk score in the overall cohort was 0.62 and was 0.66 in the cohort without known cardiovascular disease. When using the Brier score to evaluate the utility of the model, the Brier score of the SCORE2-D model was 0.08 which is no different than a null model which assumes a baseline risk of 10% in all patients. Conclusion In a cohort of patients that was older, more geographically diverse, and at higher risk of cardiovascular events, the SCORE2-D risk score appropriately stratified patients into categories of risk. However, the overall risk prediction underestimated the risk of cardiovascular events and the discrimination of the risk score was modest.Figure:CV events over timeTable:CV events by risk group

DNA methylation in the TXNIP gene is associated with type 2 diabetes in Pacific Peoples living in NZ

Abstract Background Pacific Peoples living in Aotearoa New Zealand (NZ) have higher rates of type 2 diabetes (T2D) and have benefited less from improvements in cardiovascular health outcomes when compared with other populations in NZ. DNA methylation markers of T2D have been identified in non-Pacific populations and could be used to monitor the cumulative effects of T2D on cardiovascular disease risk. However, no study has yet investigated the relationships between T2D and DNA methylation in Pacific Peoples living in NZ. Purpose This study aimed to quantify the relationship between DNA methylation and T2D in two cohorts of Pacific Peoples living in NZ. Methods Whole-blood DNA methylation at over 850,000 loci was measured on Illumina MethylationEPIC arrays in 288 Pacific participants from the Pasifika Heart Study (PHS, n=191), a community cohort, and the Multi-Ethnic NZ Study of Acute Coronary Syndromes (MENZACS, n=97), a cohort of patients with acute coronary syndromes. In the PHS, the median age was 41 years, and 98 (51%) participants were female. In MENZACS, the median age was 53 years, and 18 (19%) participants were female. In both cohorts, T2D cases were defined by either previous diagnosis (n=58) or had an HbA1c measurement >58 mmol/mol (n=7). We compared 65 participants with T2D and 223 participants without T2D of Samoan (n=116), Tongan (n=66), Fijian (n=61), Cook Island Māori (n=22), Niuean (n=9), or of Other/Multiple Pacific (n=14) ethnicity in a meta epigenome-wide association study (EWAS). EWAS comparisons were adjusted for age, sex, and imputed blood cell composition. We compared the difference in means at differentially methylated loci between the European and Pacific MENZACS participants using a two-sample z statistic. For the 525 European participants, 85 had T2D, the median age was 57 years, and 149 (28%) were female. Results One locus cg19693031, in the thioredoxin interacting protein (TXNIP) gene, exhibited differential methylation between those with T2D and those without in the meta EWAS (false discovery rate =6.9x10-9). In the PHS we observed a mean reduction in cg19693031 methylation of 7.0% (95% CI, 5.0, 8.9) between those with T2D and those without. Similarly in the MENZACS Pacific participants we observed a mean reduction in cg19693031 methylation of 10.9% (95% CI, 7.6, 12.4) between those with T2D and those without. The MENZACS European participants with T2D had a mean reduction in cg19693031 methylation of 6.5% (95% CI, 5.3, 7.7, p<0.001) compared to those without T2D. The difference in means in T2D cases and controls between MENZACS Pacific and European participants was non-significant (p =0.08). Conclusion DNA methylation at cg19693031 is associated with T2D in Pacific Peoples living in NZ and may be a sensitive marker of T2D in Pacific Peoples with acute coronary syndromes. DNA methylation at this locus may provide valuable information on the relationship between T2D and cardiovascular disease.Miami plot of Pacific T2D EWAST2D methylation by population in MENZACS

Predictors of LV reverse remodeling after SAVR: insights from a prospective TTE and CMR study in patients with severe aortic stenosis

Abstract Background Left ventricular (LV) remodeling in patients with severe aortic stenosis (AS) is believed to be reversible after pressure overload relieve, as provided by both surgical (SAVR) or transcatheter aortic valve replacement. However, LV reverse remodeling (RR) is far from uniform in patients with AS and the same clinical indication for treatment. Aim To determine the prevalence and imaging predictors of LV RR after SAVR in patients with severe symptomatic AS. Methods single-center, prospective cohort study enrolling 119 patients with severe symptomatic AS (age 71±8y, 49% male; mean transaortic gradient 62±18mmHg, mean indexed aortic valve area (AVAi) 0.40±0.10 cm2/m2, mean LV ejection fraction by TTE 58±9%), with no previous history of ischemic cardiomyopathy, undergoing SAVR between 2019 and 2022. All patients underwent serial imaging assessment beyond clinical characterization (transthoracic echocardiogram – TTE, and 1.5T cardiac magnetic resonance - CMR) prior to surgery and at the 3rd to 6th month post-SAVR. Endomyocardial biopsy (EMB) for myocardial fibrosis quantification (Masson ́s Trichrome histochemistry) was performed during SAVR. LV RR was defined when in presence of at least one of the imaging criteria: > 15% reduction in LV end-diastolic indexed volume (LVEDV) by CMR; > 15% reduction in LV indexed mass (LVM) by CMR; > 15% reduction in LV geometric remodeling by CMR; >10% increase in LV ejection fraction (LVEF) either from TTE or CMR; > 50% increase in global longitudinal strain (GLS) at TTE. Clinical, imaging and histology derived data were compared in patients with post-SAVR LV RR and for each of the defined criteria. Results 107 patients (90%) met at least one criteria of LV RR. Morphological criteria were more prevalent than LV functional improvement after SAVR (Figure 1). In patients who met at least one criteria of LV RR, no differences were found between NT- proBNP, LV tissue characterization (by CMR) or myocardial fibrosis at EMB. Yet, those with LV RR had significantly smaller preoperative AVAi (0.4±0.9 vs 0.5±0.9 cm2/m2, p=0.007) and higher mean valvular gradients (62±18 vs 49±12 mmHg, p=0.017). Considering individual LV RR criteria, patients with higher NT-proBNP levels met LVEF and morphological (LVEDV and LVM) LV RR criteria (p=0.027, p=0.016 and p= 0.003, respectively). Patients with higher % of late gadolinium enhancement on pre-operative CMR [7.8 (IQR 2.5-11.3) vs. 1.6 (IQR 0-5.2)%, p=0.017] had significant GLS improvement after SAVR. Conclusion In a cohort of patients with classical severe, symptomatic AS, LV RR is common after SAVR, occurring in almost 9 out of every 10 patients. Both indexes of worse valve narrowing and pre-operative LV adaptation are associated with favorable RR after surgery. This underlines the benefits of a timely intervention even in patients with more advanced disease.

Insights into cardiac amyloidosis screening in TAVI from a Greek/Cypriot Cohort: the GRECA-TAVI registry

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a disease with a poor prognosis and an unknown prevalence in the general population. Specific patient subgroups are at higher risk, such as patients with severe aortic stenosis (AS). Purpose To investigate the prevalence of ATTR-CM in Greek and Cypriot patients with severe AS that undergo Transcatheter Aortic Valve Implantation (TAVI). Methods A total of eight (n=8) tertiary hospital centers from Greece and Cyprus formed part of the GRECA-TAVI registry to evaluate the prevalence of ATTR-CM in patients undergoing TAVI. The inclusion criteria were diagnosis of severe AS in the presence of left ventricular hypertrophy (i.e. ≥12mm). Patients were referred for ATTR-CM screening by Tc99m-DPD or Tc99m-PYP bone scintigraphy. A complete hematologic workup was performed in all patients to rule out plasma cell dyscrasias. Cases with equivocal bone scintigraphy findings were not included in analysis. Results A total number of n=303 AS patients were screened from January 2023 until February 2024. Screening for CA with Tc99m-DPD/PYP bone scintigraphy and hematological tests was complete for all the patients included in the study. A positive bone scan (i.e. Perugini scale 2 or 3) was found in n=31 or 10.2% of the patients. The mean age of patients was not significantly different between AS patients with and without ATTR-CM (82,25 ±1,8 vs. 81,21 ±0,44 respectively, p=0.478). A male predominance was found in the ATTR-CM subgroup, although this was not statistically significant compared to non-ATTR-CM patients (%male: 64.5% vs. 49.3%, respectively, p=0.13). ATTR-CM patients had a lower LVEF compared to non-ATTR-CM patients (47.5% ±2.13 vs. 55% ±0.75, p=0.046). Conclusions The prevalence of ATTR-CM in this cohort of patients with severe AS undergoing TAVI was ~10%. These findings call for the implementation of national screening strategies for ATTR-CM which still remains significantly underdiagnosed in many geographic parts of the globe.

Prognostic value of additional midwall late gadolinium enhancement in patients with ischemic cardiomyopathy

Abstract Background Although several studies have reported the additional presence of midwall late gadolinium enhancement (LGE) using cardiac magnetic resonance (CMR) in patients with ischemic cardiomyopathy (ICM), its prognostic value is not well established. Purpose To assess the prognostic value of the additional presence of midwall-LGE in a large cohort of patients with ICM and reduced left ventricular ejection fraction (LVEF). Methods Between 2008 and 2022, all consecutive patients referred for myocardial viability assessment using CMR with an history of ICM (≥70% stenosis in ≥1 epicardial coronary vessel on angiography and/or history of myocardial infarction and/or coronary revascularization) and LVEF <50% were included. Midwall-LGE was defined by non-ischemic LGE corresponding to non-specific myocardial fibrosis. All patients with a history of acute myocarditis and/or sub-epicardial LGE were excluded. The primary outcome was all-cause death. Nested Cox proportional hazard models were used to assess the prognostic value of additional midwall-LGE including its location (lateral and/or septal and other location) and extent (1 or ≥2 segments), above the presence of ischemic-LGE and traditional prognostic factors. The incremental prognostic value of midwall-LGE extent and location was assessed by the C-statistic increment, the continuous net reclassification improvement (NRI), the integrative discrimination index (IDI) and the global Chi-2. Results Among the 6,082 included patients (65±12 years, 73% males), 702 (11.5%) had an additional midwall-LGE. During a median follow-up of 9 (IQR, 7-12) years, 652 (11%) patients died. The presence of midwall-LGE alone was strongly associated with the risk of death compared to patients without midwall-LGE (p<0.001, Figure 1A). Among these patients with midwall-LGE (N=702), survival curves showed an increased risk for midwall-LGE in lateral and/or septal location (p<0.001), for larger extent (p<0.001) and the presence of ischemic-LGE (p<0.001, Figure 1B). In this population with midwall-LGE (N=702), after adjustment for risk factors and extent of ischemic-LGE, midwall-LGE with septal and/or lateral location (adjusted HR: 2.6; 95%CI: 1.8-3.6) and extent ≥2 segments (adjusted HR: 2.6; 95%CI: 1.8-3.7, both p<0.001) were independently associated with all-cause death. A comprehensive LGE model combining all the characteristics of midwall-LGE showed the best improvement in model discrimination and reclassification above traditional prognosticators (C-statistic improvement: 0.13; NRI=46%; IDI=19%, Chi-2 global=261, all p<0.05; LR-test p<0.001, Figure 2). Conclusion In a large cohort of ICM patients, the presence of an additional non-ischemic midwall-LGE is an independent prognosticator of all-cause death, particularly for larger extent or when present in the septal and/or lateral location.Prognostic value of midwall-LGEIncremental prognostic value

Machine-learning phenotyping of patients with functional mitral regurgitation undergoing transcatheter edge-to-edge repair - the MITRA-AI study

Abstract Background Severe functional mitral regurgitation (FMR) may benefit from transcatheter mitral valve repair (TMVR), but selection of patients remains to be optimised. Objectives The aim of this study was to use Machine-Learning (ML) approaches to uncover concealed connections between clinical, echocardiographic, and hemodynamic data associated with patients' outcomes. Methods Consecutive patients undergoing TMVR from 2009 to 2020 were included in the MITRA-AI registry. Eleven relevant clinical and echocardiographic variables were selected in a clustering-based model. The primary endpoint was a composite of cardiovascular death or heart failure hospitalisation at one year, while its single components were secondary endpoints. External validation was performed on the Mitrascore dataset and comparison between clustering and Mitrascore was performed with Net Reclassification Index (NRI). Moreover cluster assignment was performed also on a cohort of patients with moderate-to-severe MR treated with medical therapy alone. Results 822 patients were included in the derivation cohort. The composite primary endpoint occurred in 250 (30%) patients. Four clusters with decreasing risk of the primary endpoint were identified (42%, 37%, 25% and 20% from cluster 1 to cluster 4, respectively). Clusters were combined into a high-risk (clusters 1 and 2) and a low-risk phenotype (clusters 3 and 4). High-risk phenotype patients had larger LVs (> 107 ml/m2), lower LVEF (< 35%) and more prevalent ischemic aetiology (51% to 60% vs. 30% to 40%) compared to low-risk phenotype patients. Moreover, within the high-risk group, patients with diabetes mellitus and with advanced age were at increased risk. Within the low-risk group, ischemic aetiology increased the risk of cardiovascular death, while permanent atrial fibrillation amplified that of HF hospitalizations. In the Mitrascore validation cohort of 1119 patients, incidence of the primary end point varied consistently (48%, 52%, 35% and 42%). Clustering achieved a NRI in 27% of the patients in the derivation cohort and 7% in the validation group compared to Mitrascore. In the validation group of 207 patients treated medically, the incidence of the primary endpoint decreased from the first to the fourth cluster (53%, 42%, 30% and 30%). Conclusions A ML analysis identified meaningful clinical phenotypic presentations in FMR undergoing TMVR, with significant differences in terms of cardiovascular death and heart failure hospitalizations, confirmed in an external validation cohort. ML phenotyping also discriminated prognosis of medically treated patients with severe MR.Central Figure

Preserved left ventricular ejection fraction with abnormal myocardial work in sepsis

Abstract Background Sepsis is a life-threatening condition associated with a dysregulated response to infection, leading to an increased risk of multi-organ dysfunction and death. Left ventricular (LV) dysfunction has been reported in up to 60% of patients with sepsis. Still, it’s true incidence is difficult to determine as defined by standard methods like left ventricular ejection fraction (LVEF) due to its dependency on loading conditions. Myocardial work (MW) is a validated novel parameter informing true LV contractility. MW is calculated using echocardiography strain data, noninvasive BP measurements, and GE Healthcare proprietary software. There are four MW indices; here, we evaluated the global work index (GWI), the indexed total work performed by the LV through mechanical systole, including isovolumic relaxation and contraction. Purpose To describe our patient population diagnosed with sepsis with GWI calculated as part of their echocardiography. We also sought to compare the GWI values with GWI normal reference values reported in current literature to determine whether our observed mean GWI in a cohort of patients with sepsis deviates significantly from these established benchmarks in an average healthy population. Methods This report was a retrospective analysis of 179 consecutive patients ≥18 years with sepsis as defined by the Third International Consensus Definitions for Sepsis and Septic Shock who presented at our center from January 2020 to October 2023. LVEF (%) and GWI (mm Hg%) were reported as mean (±SD). A one-sample t-test was used to determine if the mean MWI for males and females diagnosed with sepsis at our center significantly differed from the reported GWI literature of reference patients without sepsis. Results Males (n=90, 50.3%) from our center had a significantly lower GWI mean (1353.06 ± 490.75) than the literature-reported male reference value of 2062 (P < 0.001) and a 95% confidence interval (1250 to 1455.84). See the Table. In 89 (49.7%) females with sepsis, mean GWI was also significantly lower, 1511 ± 595.79 (P < 0.001), than the normal reported female reference GWI value 2155 with a 95% CI (1385.57 to 1636.58). The pooled GWI mean was 1440.0±561.8 (ref: 2118±277). Septic males and females had preserved mean LVEF values of 51.6±13.11 and 56.8±14.4, respectively. The pooled mean LVEF was 54.0±13.8. Conclusion These findings revealed preserved LVEF alongside decreased global work index in patients with sepsis. To our knowledge, this is the first description of MW indices in septic patients. The results highlight the importance of further investigations into the role of MW indices in sepsis and the potential for these indices to enhance our understanding and clinical approach to myocardial dysfunction in sepsis.

A digital, decentralized trial of exercise therapy in patients with cancer

We developed and evaluated the Digital Platform for Exercise (DPEx): a decentralized, patient-centric approach designed to enhance all aspects of clinical investigation of exercise therapy. DPEx integrated provision of a treadmill with telemedicine and remote biospecimen collection permitting all study procedures to be conducted in patient’s homes. Linked health biodevices enabled high-resolution monitoring of lifestyle and physiological response. Here we describe the rationale and development of DPEx as well as feasibility evaluation in three different cohorts of patients with cancer: a phase 0a development study among three women with post-treatment primary breast cancer; a phase 0b proof-of-concept trial of neoadjuvant exercise therapy in 13 patients with untreated solid tumors; and a phase 1a level-finding trial of neoadjuvant exercise therapy in 53 men with localized prostate cancer. Collectively, our study demonstrates the utility of a fully digital, decentralized approach to conduct clinical trials of exercise therapy in a clinical population.

Elderly patients with decompensated heart failure: prospective analysis from the LECRA-HF registry

Abstract Background/Introduction Heart failure (HF) presents as a clinical syndrome associated with an adverse prognosis, increased mortality risk, and recurrent hospitalizations for HF (HHF). In Poland, there has been a persistent increase in the overall prevalence and hospitalizations of HF among patients. Each subsequent HHF is associated with progressively worsening prognosis. In Europe, HF is most prevalent in elderly individuals, rendering this patient group particularly susceptible to HF exacerbations. Purpose The aim of this study was to conduct a comprehensive analysis of the oldest patients (≥80 years) hospitalized due to HF decompensation, compared to the rest of the evaluated cohort, including overall mortality after median 46 months of observation. Methods The prospective registry of patients with HF decompensation (LECRA-HF) is an ongoing registry conducted at a tertiary cardiology center specializing in HF treatment. Patients enrolled in the registry (n=1394) were evaluated for the presence of cardiovascular risk factors, HF phenotype, laboratory, and echocardiographic findings, as well as overall mortality. Due to the frequent occurrence of HF in elderly patients, we arbitrarily chose to compare two cohorts of patients: those above (n=306) vs. below 80 years of age (n=1088). Results Median age of elderly patients was 84 [82-86] years, of which only 7.8% were >90 years of age. HFrEF was the most common HF phenotype, which, occurred less frequently in the elderly (54.4 vs 74.4%, P<0.001). In turn, HFpEF was more prevalent in elderly group (39.2 vs 17.7%, P<0.001). Elderly patients were more often female (45.1 vs 30.2%, P<0.001) and had more comorbidities: arterial hypertension (85.6 vs 78.6%, P=0.007), atrial fibrillation (61.1 vs 45.7%, P<0.001), renal failure (49.7 vs 28.5%, P<0.001) as well as peripheral arterial disease (17 vs 9.8%, P=0.005). Those patients had more frequently implanted cardiac pacemakers (28.6 vs 12.6%, P<0.001), but less often implantable cardioverter-defibrillators (7.9 vs 14.3%, P=0.003). During HHF they were less often qualified to elective coronary angiography (24.2 vs 31.5%, P=0.039). At discharge mineralocorticoid receptor antagonist were less often prescribed in that group (42.4 vs 50.3%, P=0.010). During long-term observation patients ≥80 years had a higher all-cause mortality (81 vs 67.4%, P<0.001, Panel A). Moreover, it was also higher elderly with NT-proBNP>4497 pg/mL (P<0.001) and LVEF<41% (P=0.014) (Panel B). Conclusion(s) Patients aged ≥80 years were characterized by a higher burden of comorbidities. They were more often qualified to cardiac pacemakers, but less often to implantable cardioverter-defibrillators and invasive coronary procedures. The most common HF phenotype was HFrEF, however with a significant increase in HFpEF. They exhibited significantly higher overall mortality compared to those <80 years old, which was associated with both LVEF and NT-proBNP levels.

Mortality and survival rate in a scottish cohort of adults with congenital heart disease

Abstract Background Adult patients with congenital heart disease (ACHD) experience higher rates of morbidity and reduced long-term survival in comparison to the general population. The care of this cohort of patients requires specialist expertise which is mainly delivered at tertiary centers. Aims We aim to report the clinical characteristics, mortality rates and causes of death in a contemporary cohort of ACHD patients followed up in a North- East Scottish Health Board. Methods We prospectively followed up ACHD patients aged ≥17 years (n=645) under review at the Regional NHS ACHD Clinic in a North- East Scottish Health Board between the years 2020 and 2023. We recorded the number and the causes of death as documented on our electronic records and on correspondence with primary care physicians. Survival analysis was performed according to the 2020 ESC Guidelines classification of congenital heart disease complexity (Table 4) classes using Kaplan-Meier method with log-rank (Mantel-Cox) test done in IBM SPSS v.24. Results Our ACHD cohort (n=645, 54% females and 46% males) included patients of all three ESC complexity classes (30% mild, 60% moderate and 10% severe). Between 2020 and 2023, 18 patients (2.8%) died, with a total incidence of 0.93 deaths/100 patient years. Median age of death was 59 years (IQR 45–71), and the majority of deceased patients were males (56%). There were 2 deaths in the mild complexity group, 11 deaths in the moderate complexity group and 5 deaths in the severe complexity group (See Table 1). This was found to correspond to an incidence of 0.34, 0.95 and 2.64 deaths/100 patient years respectively. The leading causes of death were heart failure (28%) and malignancy (22%). Using Kaplan-Meier survival analysis we found that the survival distributions for the mild, moderate and severe ACHD complexity groups were statistically significantly different by log-rank test (χ2(2) = 11.47, p < .005) (See Figure 1). Patients with moderate ACHD complexity had a median survival age 67 years (95% CI 58.1-75.9), patients with severe ACHD had median survival age 57 years (95% CI 44.7-69.2). Median survival could not be calculated for the mild group due to lack of data points. Conclusion The ACHD patient group is characterised for a variety of pathophysiology and clinical presentations. They require lifelong medical input and in spite of the local and national expertise, the mortality and morbidity rates are still high. Heart failure was the leading cause of death in this cohort which is similar to previous reported data. Mortality rates were proportional to the complexity of the underlying ACHD diagnosis. The survival rate of patients in the severe complexity group was ten years less than the moderate complex group. ACHD patients in the moderate and severe complexity groups have significantly reduced life expectancy and require access and clinical expertise from National ACHD Specialty Centers.