Glomerular Filtration Research Articles

Subgroup results from KARDIA-2: impact of demographic and baseline disease characteristics on zilebesiran response in patients with hypertension uncontrolled by a standard oral antihypertensive

Abstract Background Zilebesiran is an investigational RNA interference therapeutic targeting hepatic angiotensinogen synthesis. In KARDIA-1, a single subcutaneous (SC) dose of zilebesiran monotherapy significantly reduced 24-hr mean ambulatory and office systolic blood pressure (SBP) from baseline to Months 3 and 6 versus placebo. The Phase 2 KARDIA-2 study assessed efficacy and safety of zilebesiran with a standard oral antihypertensive in patients with uncontrolled hypertension. Purpose Uncontrolled hypertension is a leading cause of cardiovascular morbidity and mortality, and medication non-adherence affects blood pressure control. Developing effective, long-lasting treatments is crucial for patients with hypertension uncontrolled by standard therapy. Methods KARDIA-2 enrolled adults with mild-to-moderate hypertension who were untreated or receiving stable therapy with ≤2 antihypertensives. Patients discontinued prior antihypertensive medication and were randomized 10:7:4 to open-label, once-daily oral treatment with 40 mg olmesartan, 5 mg amlodipine, or 2.5 mg indapamide. After ≥4 weeks on protocol-specified medication, patients with a 24-hr mean ambulatory SBP of 130–160 mmHg were randomized 1:1 in a double-blind manner to a single SC dose of zilebesiran 600 mg or placebo as add-on therapy. The primary endpoint was change from baseline to Month 3 in 24-hr mean ambulatory SBP versus placebo for each group. Efficacy and safety were also assessed in pre-specified subgroups: age (<65; ≥65 years), sex, race (Black; other), baseline 24-hr mean ambulatory SBP (<145; ≥145 mmHg), and baseline estimated glomerular filtration rate (≥60; <60 mL/min/1.73m2). Results The primary analysis included 667 patients (median age [range] 59 [27–75] years; 57% male, 28% Black). At Month 3, least-squares mean differences (LSMD) (95% confidence interval [CI]) between zilebesiran and placebo for the olmesartan, amlodipine, and indapamide groups were −4.0 (−7.6, −0.3), −9.7 (−12.9, −6.6), and −12.1 (−16.5, −7.6) mmHg, respectively, for 24-hr mean ambulatory SBP (all p<0.05). LSMD (95% CI) in office SBP for the same groups were −7.0 (−10.4, −3.6), −10.2 (−13.5, −6.9), and −18.5 (−22.8, −14.2) mmHg, respectively, (all p<0.001). SBP reductions were consistent across subgroups, except for a trend towards an attenuated response observed in Black patients (Figs 1, 2). More patients receiving zilebesiran (49–58%) than placebo (39–48%) experienced ≥1 adverse event through Month 6, with low rates of hyperkalaemia, hypotension, or acute kidney injury reported across all groups. Conclusion In KARDIA-2, a single dose of zilebesiran significantly reduced SBP versus placebo at Month 3 on top of a standard oral antihypertensive, with encouraging safety data. SBP reduction was consistent across most subgroups. Treatment with zilebesiran combined with standard antihypertensives may be effective for a broad population of patients with hypertension uncontrolled on monotherapy.

Association between self-care behaviour and multiple frailty domains in older patients with heart failure

Abstract Background/Introduction Heart failure (HF) self-care is important for the effective management of HF, reducing clinical events such as all-cause mortality and hospitalizations. HF self-care behaviours encompass comply with a regimen involving medication, diet, and exercise, symptom monitoring, and seeking assistance when symptoms occur. Frailty, prevalent among older patients with HF, involves physical, social, and cognitive domains. Identified factors influencing self-care behaviours in patients with HF include age, social support, and knowledge of the condition. Despite research on the association between self-care behaviours and frailty, there is a notable gap in studies that explore the relationship between self-care behaviour and multiple domains of frailty, particularly with adjustments for clinical characteristics. Purpose The aim of this study was to assess the association between self-care behaviour and multiple domains of frailty in older patients with HF. Methods The study included 182 patients with HF who were aged 65 years or older. Self-care behaviour was assessed 5 months after their discharge using the European Heart Failure Self-Care Behaviour Scale (EHFScBS), a self-report questionnaire. Frailty was assessed using the revised Japanese version of the Cardiovascular Health Study criteria (J-CHS) for physical frailty, and using Makizako’s five items for social frailty, and using Mini-Cog for cognitive decline. We used multiple regression analysis to assess the association between self-care score and multiple frailty domains and the number of frailty domains. The adjusted model was constructed based on age, gender, body mass index, New York Heart Association Classification, left ventricular ejection fraction, log-transformed B-type natriuretic peptide, estimated glomerular filtration rate and history of HF. In addition, we used multiple regression analysis to assess the association between the EHFScBS subitems score complying with regimen, asking for help, and adapting activities and multiple frailty domains and the number of frailty domains. Results According to the results of a multiple regression analysis, poor self-care behaviour was significantly associated with physical and social frailty and the number of frailty domains (all p < 0.05), even after adjusting for clinical characteristics. Poor complying with regimen was also significantly associated with physical and social frailty and the number of frailty domains (all p < 0.05). Poor asking for help was significantly associated with social frailty and the number of frailty domains (all p < 0.05). Conclusion The study indicates that poor self-care behaviour is linked to physical and social frailty, in addition to the cumulative number of frailty domains in older patients with HF, even when clinical characteristics are taken into consideration. This underscores the importance of factoring in the frailty status when guiding patients with HF in disease management.

Non-linear causal effects of kidney function on the risk of heart failure: a Mendelian randomization study

Abstract Background Kidney insufficiency is defined as the early stage of heart failure, but Mendelian randomization (MR) analyses based on several large heart failure cohorts suggest no linear causal effect between kidney function and heart failure (HF), inconsistent with observational studies evidence. However, whether there is a non-linear causal relationship between kidney function and HF has not been reported. Methods and Results Observational and non-linear MR analyses were performed using individual-level data from a UK Biobank cohort of white British ancestry subjects (N = 386,304). There were non-linear observational associations of between kidney function as assessed with estimated glomerular filtration rate (eGFR) and HF (P for nonlinear <0.001). Non-linear MR analyses showed a U-shaped association between genetically predicted eGFR values (both creatinine- and cystatin C-based eGFR) and the risk of HF (Quadratic P value < 0.05) and the risk of HF increased with both reduced and supranormal eGFR levels (β1 = -1.70E-05, P1-value = 0.004; β2 = 3.56E-06, P2-value = 0.004). Conclusion This study observed a non-linear U-shaped genetic relationship between eGFR and HF outcomes, indicating that both reduced and supranormal eGFR may be causally linked to a higher risk of HF.Central Illustration

Comparative analysis of muscle sympathetic nerve activity in patients afflicted with orthostatic hypertension versus conventional hypertension

Abstract Introduction Standing places a significant hemodynamic burden on the cardiovascular system. In healthy individuals, neurohumoral reflex mechanisms, particularly the arterial baroreflex, maintain blood pressure during standing. However, in some cases, the counterregulatory response can be excessive, resulting in a condition known as orthostatic hypertension (OrthoHT), which appears to be linked to an increased cardiovascular risk. Epidemiologically, orthostatic hypertension has been reported in 5-30% of hypertensive patients. Furthermore, in recent years, it has garnered attention as a responder group in renal denervation therapy. Purpose In hypertensive patients, sympathetic hyperactivity is expected to exacerbate cardiovascular risk. However, the relationship between OrthoHT and sympathetic nerve activity remains poorly understood. This study aims to assess the differences in sympathetic nerve activity between OrthoHT and conventional hypertensive patients using muscle sympathetic nerve activity (MSNA) measurements. Methods We conducted an examination of hypertensive patients undergoing drug treatment at our clinic between April 1, 2023, and June 30, 2023, to identify cases of OrthoHT. Only patients with essential HT were included in the HT group; patients diagnosed with secondary HT were excluded. HT patients with other active CV diseases (i.e., symptomatic cerebral/coronary artery diseases or heart failure) and/or severe renal dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m2) were also excluded. OrthoHT was defined as a sustained increase in systolic blood pressure ≥20 mmHg and/or diastolic blood pressure ≥10 mmHg within 3 minutes of standing. MSNA was recorded from the left peroneal nerve using a tungsten microelectrode at supine position. We measured MSNA in the cases for which consent was obtained. Statistical analyses were performed using SPSS software. Results Among the 183 cases, 31 were diagnosed with OrthoHT, and 7 of them consented to MSNA measurement. Of the 11 cases of hypertensive patients who consented, two groups were well age-matched. We assessed body mass index, resting systolic blood pressure, diastolic blood pressure, heart rate, blood glucose level, creatinine, cholesterol, brain natriuretic hormone, and ejection fraction measured by echocardiography, but found no significant differences between the two groups. OrthoHT patients exhibited elevated MSNA burst frequency (28.3 +/- 5.7 vs. 38.4 +/- 12.2 bursts/min, P < 0.05) and burst incidence (44.6 +/- 11.1 vs. 61.1 +/- 21.3 bursts/100 heartbeats, P < 0.05) at rest. Conclusions OrthoHT is associated with sympathetic hyperactivity compared to normal hypertensive patients, contributing to an increased cardiovascular risk.

In-hospital initiation of Vericiguat and short-term cardiovascular function improvement in heart failure patients with worsened renal function

Abstract Background and Aims Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, is approved for treating heart failure (HF) with reduced ejection fraction (HFrEF). This study aims to assess the short-term improvement in cardio-function resulting from in-hospital initiation of Vericiguat among patients with chronic kidney dysfunction (CKD), utilizing real-world data from a single-center experience in western China. Method Data were obtained from the Biobank of our hospital, spanning from January 2023 to December 2023. A total of 213 HF patients with Vericiguat initiation were screened for eligibility. Echocardiography was employed to evaluate cardio-function after 1- and 3-month short-term follow-up in each patient. Statistical analyses were conducted using one-way ANOVA (followed by Geisser-Greenhouse correction and Tukey’s multiple comparison) to assess significance between different timepoints. Results Among the 213 patients randomized in this study, baseline characteristics were compared based on estimated glomerular filtration rate (eGFR) ≤ 30 (worsened renal function group, WRF, n = 20) and >30 mL/min/1.73 m2 (n = 193). No significant differences were observed in age, gender, and other biochemical parameters expect hemoglobin and creatine between the two groups (Table 1). Analysis of cardiac function after 1- and 3-month follow-up revealed a promising increase in left ventricular ejection fraction (EF) (37.2% vs. 43.9%, Mean diff -6.7, 95% CI -12.78 to -0.62, p = 0.03), fractional shortening (FS) (20.9% vs. 25.3%, Mean diff -4.42, 95% CI -8.57 to -0.27, p = 0.04), and a significant decrease in left ventricular end-diastolic dimension (LVEDD) (65.0mm vs. 60.6mm, Mean diff 4.35, 95% CI 0.33 to 8.38, p = 0.03) after 3-month follow-up compared to Vericiguat initiation in WRF patients. However, no significant changes were observed between the beginning and 1-month follow-up in echocardiographic measurements (Figure 1). Conclusion In this real-world single-center study, Vericiguat demonstrated effectiveness in short-term improvement of cardiac function among HF patients with worsened renal function. The long-term efficacy in reducing major cardiovascular events in this subgroup, based on real-world experience, warrants further exploration.

Identifying clinical phenotype clusters for coronary artery disease: a novel approach using clustering by unsupervised machine learning

Abstract Background Guideline recommendations for the prevention of cardiovascular (CV) events in patients with coronary artery disease (CAD) are one-size-fits-all. Clinically identifiable phenotypes needing specific considerations might exist. Purpose To identify phenotypes in patients with CAD based on clinical characteristics and their relationship with the risk of new CV events and treatment benefits. Methods Unsupervised machine learning through latent class analysis (LCA) was performed on patients with CAD included in the UCC-SMART cohort (n = 5,888) and SWEDEHEART registry (n = 67,428), to identify patient clusters (i.e., phenotypes) based on clinical characteristics: age, sex, body-mass-index, diastolic blood pressure, history of diabetes, myocardial infarction, atrial fibrillation, polyvascular disease, current smoking, non-high density lipoprotein cholesterol, estimated glomerular filtration rate, and C-reactive protein. Number of clusters was determined using the Bayesian information criterion. Event free survival and hazard ratios (HR) for major adverse cardiovascular events (MACE) as primary endpoint, including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, were estimated per cluster. The LCA were performed in each respective cohort and cross-validated in the other cohort to assess impact of variations in clustering variables on cluster reproducibility. In UCC-SMART, bootstrapping was performed the assess stability of the LCA model and impact on cluster assignment. Results In UCC-SMART four distinct phenotypes within the CAD population could be distinguished: Phenotype A (16%) of mostly males with isolated CAD, phenotype B (30%) of older patients with polyvascular disease, Phenotype C (28%) of only women with limited traditional risk factors and Phenotype D (27%) young, current smokers with a premature event (Figure 1). Cross-validation in SWEDEHEART identified roughly the same four phenotypes, i.e., phenotype A (39%) with 100% males and 3.8% polyvascular disease, phenotype B (8%) with average age of 71 years and 30% polyvascular disease, phenotype C (19%) with 100% women, and phenotype D (34%) 54 years and 25% current smokers. Notably, although age was comparable between phenotype A and C, MACE-free survival was worse for the female-only cluster. Similarly, although patients where on average 9 years younger in phenotype D when compared to phenotype A, MACE-free survival was worse (Figure 2). No significant changes in clustering models were observed in the bootstrap samples. Conclusion Phenotypes can be distinguished within patients with CAD. These phenotypes are related to differences in the risk of recurrent events. These findings suggest that specific guideline recommendations for these groups could be considered.Cluster interpretation in SMARTSurvival along cluster lines

Imaging signs of carotid plaque vulnerability predict subclinical neurological events in asymptomatic patients: the carotid artery multi-modality imaging prognostic study

Abstract Background Carotid artery plaques should be considered for invasive treatment if diameter stenoses is ≥60%, in the presence of clinical and/or imaging characteristics associated with an increased risk of ipsilateral stroke, such as intraplaque haemorrhage (IPH) or lipid-rich necrotic core (LRNC). However, little is known about plaque’s characteristics in patients with <60% stenoses. Purpose To evaluate the prevalence and significance of imaging signs of plaque vulnerability in patients with asymptomatic <60% carotid artery stenoses. Methods In the Carotid Artery Multi-modality imaging Prognostic (CAMP) study (granted by Bando Ricerca Salute 2018 - Regione Toscana) we prospectively enrolled 200 patients with asymptomatic, mild/moderate (40-60%) carotid artery stenoses, as assessed at Doppler ultrasound (DUS). All patients were evaluated with multimodality imaging, including computed tomography angiography (CTA), magnetic resonance angiography (MRA) and brain magnetic resonance imaging (MRI), whenever not contraindicated. A subgroup of 75 patients underwent also a 18[F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). A thorough clinical, biochemical, cardiological and neurological evaluation was performed in all patients. Results Imaging signs of plaque vulnerability were frequent (IPH and/or LRNC at MRA were found in 26.3% patients, plaque ulceration at CTA was found in 36.7% of patients). No difference in the prevalence of cardiovascular risk factors was noted in those with and without signs of vulnerability. Subclinical embolic brain infarctions at brain MRI were found in 8.8% of patients at enrollment. These patients had more frequently a LRNC at MRA than patients without subclinical embolic brain infarctions (50% vs 17%, p<0.05), lower estimated glomerular filtration rate (55±8 vs 73±23 mL/min/1.73mq, p<0.001), higher troponin HS values (16±4 vs 12±8 ng/ml, p<0.05). Presence of LRNC at MRA was the only predictor of embolic lesions at MRI (odds ratio 4.86, 95% confidence interval 1.08-21.8, p<0.05). Conclusions Imaging signs of vulnerability are highly prevalent in patients with asymptomatic intermediate carotid artery stenosis. Presence of a LRNC at MRA is associated with subclinical embolic brain infarcts. The use of non-invasive multi-imaging can better characterize carotid plaques, independent of the degree of stenosis, and help identifying a subgroup of patients at higher risk of events.

Estimated plasma volume in heart failure with reduced ejection fraction: ACE inhibitors versus angiotensin receptor/neprilysin inhibitor in follow up

Abstract Background Estimated plasma volume status (ePVs) has been considered a biological surrogate for congestion and has been shown to be associated with post-discharge outcomes in patients with heart failure with reduced ejection fraction (HFrEF). The plasma volume status can be easily estimated by the index of the PVs according to the haemoglobin and haematocrit levels. Purpose The aim of the study was to examine the change in ePVs and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels during the 12-month follow up of HFrEF patients treated with ACE inhibitors (ACEi) and angiotensin receptor/neprilysin inhibitor (ARNI). Methods We included all patients treated or diagnosed with HFrEF in our hospital from May 2021 to February 2022 and prescribed with either ACEi or ARNI among complete guideline-directed medical therapy (GDMT). We used Strauss-derived Duarte formula [ePVs= (100-Hct%) ÷ Hb] to estimate PVs during the initiation of GDMT and after 12-month follow up. Results This registry-based study included 619 patients with HFrEF, out of which 278 were prescribed with ACEi (ACEi group) and 273 with ARNI (ARNI group). There were no differences between the groups regarding age (ACEi 68 vs. ARNI 67 years, p=0.09), however, ACEi group had significantly more women (30% vs. 26% of patients, p=0.02). Patients in ACEi group were more likely to have ischemic cardiomyopathy (61 vs. 49%, p<0.01), higher estimated glomerular filtration rate (72 vs. 64 L/min/1.73m², p=0.01), while patients in ARNI group were more likely to be NYHA III class (40 vs. 48%, p=0.04). Initial ePVs (4.23 for ACEi vs. 4.20 for ARNI, p=0.46), NT-proBNP levels (3357.5 for ACEi vs. 2786 for ARNI, p=0.08), and left ventricular ejection fraction (median 35% for ACEi vs. 35% for ARNI, p=0.49) did not significantly differ between the groups. After the 12-month follow up, the change in ePVs was similar between the groups (-0.22 for ACEi vs. -0.19 for ARNI, p=0.93). Reduction of NT-proBNP levels was more prominent in ACEi group (1750.5 vs. 858.5 pg/mL, p=0.01). Mortality rate did not differ between the groups during 12-month follow up (9.71% in ACEi vs. 8.42% in ARNI, p=0.60). Conclusion In HFrEF patients both ACEi and ARNI reduced ePV and NTproBNP levels during 12-month follow up. ACEi were more potent in reducing NT-proBNP levels. Despite the more prominent reduction in NT-proBNP levels, no significant difference was observed in mortality rate during follow up between the groups.

Undiagnosed impaired glucose tolerance/diabetes mellitus and relationship with aortic stiffness in patients with acute coronary syndromes

Abstract Background Patients admitted with an acute coronary syndrome (ACS) often have unknown cardiovascular risk factors, such as impaired glucose tolerance (IGT) or diabetes mellitus (DM). Detecting these conditions is crucial to intensify appropriate therapies. Increased aortic stiffness, assessed by aortic pulse wave velocity (PWV), is associated with higher mortality in patients at high cardiovascular risk. Purpose Estimating the prevalence of IGT and DM and their relationship with increased aortic stiffness in patients admitted with an ACS. Methods Seventy-five consecutive patients admitted for ACS (21% women, mean age 63.6±11.1 ys), with fasting plasma glucose (PG) and glycated hemoglobin (HbA1c) not diagnostic for diabetes mellitus, underwent a fully standardized oral glucose tolerance test. All patients were also evaluated with the Arteriograph device, which applies a brachial cuff-based oscillometric method for the estimation of aortic PWV and arterial pulse waveform features. The automated vascular studies and OGTTs were performed after patient stabilization, at least 96 hours after admission. Results Forty-one patients (55% of the total study population) showed an abnormal OGTT response: 14 patients had a 2-h PG-OGTT ≥ 200 mg/dL, uncovering a diagnosis of DM, and 27 patients had a 2-h PG-OGTT ≥ 140 mg/dL, uncovering a diagnosis of IGT. Patients with DM showed no differences in terms of age, cardiovascular risk factors, Framingham risk score, C-reactive protein values, whereas a significant difference was observed in the number of diseased coronary vessels (2.2±0.8 vs 1.6±0.9, p=0.016) and PWV values (10.0±1.3 vs 8.8±1.6 m/s, p=0.028). Similarly, when considering all patients with an abnormal OGTT, a significant difference was observed in PWV values compared to patients with a normal OGTT (9.5±1.5 vs 8.4±1.7 m/s, p=0.032), as well as in estimated glomerular filtration rate (78±18 vs 83±23 mL/min/1.73mq, p=0.05), and peak troponin values (3698±2905 vs 2124±2561 ng/ml, p=0.02). At follow-up (mean time 51.7 months), no patients had died, but 5 patients had a new major cardiovascular event. Aortic pulse wave velocity values were different between patients with and without events (10.6±2.3 vs 8.6±1.4 m/s, p=0.024), and PWV was a significant predictor of events at univariate regression analysis (hazard ratio 1.93; 95 confidence intervals 1.01-3.69, p=0.047). Conclusions An unknown diagnosis of DM and/or IGT is very frequent in patients with ACS. Undiagnosed dysglycemic conditions are linked to a higher prevalence of coronary multivessel disease and increased aortic stiffness, which is also predictive of future cardiovascular events. A systematic screening with OGTT may help identifying patients at even higher cardiovascular risk, and tailoring secondary prevention strategies through personalized aggressive therapeutic interventions.

Predictors of discordance in estimating the presence of chronic kidney disease among patients with atrial fibrillation and impact on prescription of anticoagulants and cardiovascular outcomes

Abstract Background In patients with atrial fibrillation (AF), the prevalence, predictors and clinical implications of a potential discordance in estimating the presence/absence of chronic kidney disease (CKD) according to Cockroft-Gault (CG) and CKD-EPI formulas remain unclear. Objective To examine patients characterized by discordance in evaluation of renal function, specifically with regard to the threshold for defining the presence of CKD according to an estimated glomerular filtration rate (eGFR) < 60 ml/min, in a large cohort of European AF patients, and to assess the association with prescriptions of oral anticoagulants (OAC) and the risks of adverse outcomes. Methods Data related to AF patients enrolled in a large European observational prospective registry with an average follow up of 645.2 days were analysed. We evaluated renal function for assessing the presence of CKD according to CG and CKD-EPI formulas and we categorized the population in four groups: eGFR ≥ 60 ml/min according both to CG and CKD-EPI (Concordant ≥ 60); < 60 ml/min according to both formulas (Concordant <60); CG <60 ml/min and CKD-EPI ≥60 ml/min (Discordant-CKD-EPI), CG ≥ 60 ml/min and CKD-EPI <60 ml/min (Discordant-CG). Logistic regression analyses were used to assess factors associated with a Discordant assessment of CKD and its association with OAC therapy. Cox regression analysis was used to determine association between categories and the risk of adverse outcome. The primary endpoint was a composite of all-cause death and major adverse cardiovascular events (MACEs). Results 8.786 patients with AF (mean age 68.70, SD 11.58 years; 40.9% female) were included in the analysis. 1360 (15.5%) of them had Discordant CKD assessment: 577 (6.6%) with Discordant-CKD-EPI and 783 (8.9%) with Discordant-CG. Increasing age, female sex and coronary artery disease (CAD) were associated with Discordant-CKD-EPI, while BMI and heart failure (HF) showed an inverse association (Figure 1). Conversely, BMI and HF were factors significantly associated with Discordant-CG. Discordant-CKD-EPI patients showed lower odds of being prescribed with OAC therapy (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.54-0.95) with no significant differences regarding the type of OAC therapy (warfarin or direct oral anticoagulants). At Cox regression analysis, patients with Discordant-CKD-EPI showed a higher risk of composite endpoint events (Figure 2) and both Discordant-CKD-EPI and Discordant-CG patients were associated with a higher risk of all-cause death. Conclusions Age, BMI, female sex and comorbidities associated with AF (CAD and HF) significantly influenced the probability of having a discordant assessment of the presence of CKD, according to estimation of renal function impairment using CG or CKD-EPI formulas, respectively. A discordant assessment of CKD influenced the probability of being prescribed with OAC and was associated with a higher risk of adverse outcomes.Figure 1Figure2

Mavacamten in a real-world hypertrophic cardiomyopathy population: how many may be eligible?

Abstract Introduction Mavacamten is a newly approved drug for obstructive hypertrophic cardiomyopathy (oHCM) and is currently being studied in non-obstructive HCM (nHCM). Our goal was to evaluate how often patients with oHCM and nHCM in a real-world cohort would be eligible for the main mavacamten trials: EXPLORER-HCM, VALOR-HCM and MAVERICK-HCM. Methods Single-centre retrospective study enrolling consecutive patients with confirmed HCM, as per the 2023 ESC Guidelines, with at least yearly follow-up in our center, from 2017-2023. Key inclusion criteria from the three trials were considered: NYHA class II-III for all; obstructive forms (defined as peak left ventricle outflow tract [LVOT] gradient ≥50 mmHg at rest, after Valsalva manoeuvre or exercise) for EXPLORER-HCM and VALOR-HCM; left ventricular ejection fraction (LVEF) ≥55% for EXPLORER-HCM and MAVERICK-HCM; LVEF ≥60% and formal criteria for septal reduction therapy for VALOR-HCM, and NT-proBNP ≥300pg/mL for MAVERICK-HCM. Key exclusion criteria (estimated glomerular filtration rate [eGFR] <30mL/kg/1.73m2, QTc using the Fridericia’s formula >500ms, paroxysmal or intermittent atrial fibrillation present on screening electrocardiograph) were also considered. Results Overall, 410 patients were diagnosed with HCM, of whom 361 (88%) were alive at follow-up and included in the analysis: mean age of 63 ± 16 years, 196 (54%) were male, 272 (75%) with septal HCM and 60 (17%) with oHCM. According to the criteria of EXPLORER-HCM, VALOR-HCM and MAVERICK-HCM, 35 (10%), 6 (2%) and 27 (7%) patients would be eligible for enrolment, respectively. In patients with oHCM, 35 (58%) would be eligible for the EXPLORER-HCM trial. In the overall cohort, 65 (18%) would have criteria for at least one of the trials. The main reasons for exclusion were as follows: 191 (53%) NYHA I, 43 (12%) with NYHA IV, 12 (3%) had a LVEF <55%, 8 (2%) had both HCM and infiltrative myocardial disease and/or moderate-to-severe aortic stenosis and 8 (2%) had an eGFR <30mL/kg/1.73m2. In patients with nHCM, 16 (5%) would have been excluded due to NT-proBNP <300pg/mL and 8 (3%) due to paroxysmal atrial fibrillation. Conclusion In a real-word HCM cohort, we found that approximately 1 in every 5 patients would have criteria for either of the mavacamten trials, with more than half of oHCM being potential candidates for the EXPLORER-HCM. The main reasons for non-eligibility were NYHA I and LVEF <55%.

Real-world evidence for patient phenotypes in heart failure with preserved ejection fraction

Abstract Background Heart failure (HF) with preserved ejection fraction (HFpEF) presents a high mortality risk due to its heterogeneous and multifactorial nature, coupled with limited treatment options. The incompletely understood pathophysiology is influenced by various comorbidities, resulting in different clinical phenotypes. Identifying these could be crucial for tailored HFpEF treatments. While previous studies focused on small, well-characterized patient populations, electronic health records (EHRs) offer the potential to unveil HFpEF phenotypes in larger real-world patient groups. Purpose We aimed to establish a sizable, unselected HFpEF patient population using real-world data. Employing cluster analysis, we intended to uncover distinct groups with varied disease aetiology and medical needs based on comorbidity profiles and prognoses. Methods From EHRs of n = 1,610,101 HF patients, we identified an HFpEF cohort of n = 32,009 patients, by applying thresholds for the LVEF and data availability, and by excluding confounding conditions. Clustering by the relative frequency of common comorbidities aimed to reveal patient populations with unique prognoses, comorbidity profiles, and clinical and demographic characteristics. Results Six clusters of different sizes, comorbidity prevalence, clinical presentation, and all-cause mortality were identified. About 50% of patients (n = 15,445) were predominantly hypertensive, with varying extents of coronary heart disease and diabetes mellitus (DM), and a 5-year mortality of about 30%. Around 22% (n = 7,089) exhibited a cardiometabolic comorbidity profile, with an increased prevalence of obesity and sleep apnea, but also DM and hypertension, and a 5-year mortality of 22.5%. Over 15% of patients (n = 5,298) had a 5-year mortality rate of 45.0%, marked by highest rates of anaemia and chronic kidney disease (CKD) but also DM, elevated N-terminal prohormone of brain natriuretic peptide levels, and a reduced estimated glomerular filtration rate. Conclusion Despite the favourable prognosis, a significant proportion of patients represent a cardiometabolic HFpEF phenotype with notable unmet medical needs regarding cohort size and multimorbidity. Patients simultaneously suffering from CKD, anaemia, and the highest mortality rates may represent a previously underrecognized phenotype. Our study demonstrates that distinct medical needs can be identified in a large, unselected real-world HFpEF cohort. In contrast to clinical trials, this approach enabled access to a broader patient population, revealing novel phenotypes to be targeted by precision medicine in the future.

Association of Triglycerides, HDL, and Waist Circumference with eGFR in patients in private practice

Background: Chronic kidney disease (CKD) is one of the leading causes of mortality and morbidity all over the world. On the other hand, metabolic syndrome has been reported to be associated with adverse renal outcomes. Among the components of metabolic syndrome, diabetes and hypertension are established causes of renal impairment. However, the association of Triglycerides (TGs), High density lipoprotein (HDL), and Waist Circumference (WC) with renal function independently remains understudied. Objectives: The objective of this study was to determine the association of triglycerides, HDL, waist circumference with estimated glomeruar filtration rate (eGFR). Materials and Methods: This cross-sectional study enrolled 100 subjects attending as outpatient in Ibn Sina Diagnostic Centre, Uttara from July 2023 to December 2023. Renal impairment was measured by estimated glomerular filtration rate (eGFR). The eGFR was calculated using the modified modification of diet in renal disease (MDRD) equation. Statistical analyses were performed by using SPSS 25.0 (Statistical Package for Social Science, Inc., Chicago, IL, USA). Continuous variables were expressed as means±standard deviation, and categorical variables as frequencies and proportions. The relationships between renal function with triglycerides, HDL and WC were assessed by correlation coefficient. A p-value <0.05 was considered significant. Results: Among 100 subjects the overall incidence of renal impairment is 13 (13%). Waist Circumference (WC) and high Triglyceride (TG) have inverse relation with eGFR means significant association in developing renal impairment. Conclusion: This study suggests triglyceride and central obesity progress with renal impairment. Therefore, early monitoring and management of triglycerides and central obesity in CKD patients may help in decreasing the progression of the disease and, hence, mortality in CKD patients. EWMCJ Vol. 12, No. 1&2, January-July 2024: 4-8

Impaired systemic microvascular function in patients with resistant arterial hypertension and microalbuminuria: an observational study

Abstract Background Systemic arterial hypertension (SAH) is one of the most prevalent diseases worldwide and is known to be associated with alterations of microvascular function. It is well known that microalbuminuria (MAU) is considered an early marker of renal and cardiac injury in SAH and is an independent risk factor for cardiovascular events in this population. Additionally, it is associated with altered endothelial function, which occurs from the early stages and can be considered an early marker. In some cases, SAH presents as resistant arterial hypertension (RAH), resulting in a worse prognosis compared to individuals with non-resistant hypertension. Moreover, MAU is associated with higher mortality, independent of glomerular filtration rate. Endothelial dysfunction is also a risk marker found in different conditions and can add to MAU in patients with RAH. Purpose To investigate systemic microvascular function in patients with RAH, with or without MAU. Methods 64 patients with RAH, of both genders (50% men), were evaluated, with 32 having MAU and 32 without MAU (defined as a urinary albumin/creatinine ratio between 30 and 300 mg/g in a routine urine sample). Microvascular function assessment was performed using a laser speckle system, allowing analysis of cutaneous microvascular flow. Flow measurements were expressed in arbitrary perfusion units (APU) divided by the mean arterial pressure to obtain cutaneous vascular conductance (CVC). A post-occlusive reactive hyperemia (PORH) test was performed, with brachial artery occlusion using a sphygmomanometer 50 mmHg above systolic pressure for 3 minutes; cutaneous flow was measured after release of the occlusion. Results Patients with or without MAU did not differ in terms of age, frequency of diabetes, and chronic kidney disease. The peak CVC values during PORH were 0.64 ± 0.15 and 0.55 ± 0.15 APU/mmHg in RH and RH + MAU patients, respectively (P=0.03). The delta values (peak – baseline) during PORH were 0.31 ± 0.11 and 0.25 ± 0.09 APU/mmHg in RH and RH + MAU patients, respectively (P=0.04)(Figure 1). Conclusions PORH-induced vasodilation was found to be reduced in patients with RAH and MAU compared to patients without MAU. This finding shows alteration of endothelium-dependent vasodilation mechanisms in these patients, indicating reduced systemic microvascular endothelial function. Endothelial dysfunction may be associated with glomerular permeability changes, contributing to MAU and further increasing the risk for these patients. This suggests the need for more intensive therapeutic interventions and better risk stratification for these patients, as endothelial dysfunction can be found in the early stages of the disease.Figure 1

Exploring heart failure prevalence and overlooked dimensions: a comprehensive NT Pro-BNP study in high-risk primary care patients

Abstract Background Heart failure (HF) is a prevalent syndrome linked to significant morbidity and mortality, especially in those with comorbid conditions like diabetes, hypertension, and atherosclerotic cardiovascular disease. Early detection and intervention are crucial. Natriuretic peptides, particularly NT-proBNP, are promising biomarkers for identifying at-risk individuals, but their use in primary care settings is not fully understood. Methods This prospective cohort study enrolled 874 participants aged 40 and above with documented risk factors for HF, such as diabetes mellitus, hypertension, metabolic syndrome, obesity, atherosclerotic cardiovascular disease, genetic variants for cardiomyopathy, or exposure to cardiotoxic agents. NT-proBNP levels were measured in blood samples collected at primary care clinics, and participants underwent comprehensive cardiac evaluations at a referral hospital. Clinical characteristics, laboratory findings, electrocardiography, and echocardiography results were recorded. Results The study included 874 patients with at least one risk factor for HF, with a mean age of 62.5 ± 9.1 years and 51.9% female. According to the 2022 AHA/ACC/HFSA HF Guideline, 69.1% were Stage A HF, 21.9% Stage B HF, and 9% Stage C HF. Clinical characteristics, laboratory and echocardiographic findings are shown in Picture 1. The majority had hypertension (71.1%), while other prevalent comorbidities included diabetes mellitus (43.4%), dyslipidemia (35.2%), obesity (27.1%), and atherosclerotic cardiovascular disease (26.2%). Laboratory findings showed a significant decrease in HbA1C, eGFR, LDL, triglycerides, and hemoglobin from Stage A to C HF. Median NT-proBNP levels rose from Stage A to C HF (46.4 pg/mL in Stage A, 219 pg/mL in Stage B, and 268.5 pg/mL in stage C), with 84.8% of Stage B HF patients exhibiting elevated levels. NT-proBNP levels were correlated positively with left atrial volume index, left ventricular mass index, age, E/e’, and estimated systolic pulmonary artery pressure levels. Conversely, NT-proBNP levels showed a negative correlation with estimated glomerular filtration rate and left ventricular ejection fraction. Among Stage C patients, 92.4% had HFpEF. The Picture 2 depicted the study's design and outcomes, providing a comprehensive visual representation. Conclusion NT-proBNP screening in primary care settings identified a substantial proportion of individuals with undiagnosed HF, particularly those in Stage B and Stage C. The high prevalence of HFpEF underscores the need for comprehensive evaluation and management strategies targeting this population. Early detection facilitated by NT-proBNP screening may lead to timely interventions and improved outcomes in individuals at risk for HF.

Efficacy of sotagliflozin by diabetes duration: a secondary analysis of SCORED

Abstract Background Sotagliflozin is a sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibitor. SCORED randomized patients with type 2 diabetes (DM) and high cardiovascular (CV) risk to sotagliflozin or placebo. Purpose We evaluated if diabetes duration affects HF and CV outcomes when comparing sotagliflozin with placebo in SCORED, as diabetes duration can modify CV risk. Methods SCORED enrolled patients with DM (hemoglobin A1c ≥7%), chronic kidney disease (glomerular filtration rate of 25-60 mL/minute per 1.73 m2), and CV risk factors. Patients were randomized to sotagliflozin compared with placebo. Patients in SCORED were stratified by diabetes duration, into categories of <10 years, 10-19 years, or ≥20 years. The primary endpoint was total CV death, hospitalization for HF, or urgent visit for HF. Secondary endpoints were total hospitalization for HF or urgent visit for HF, as well as total CV death, nonfatal myocardial infarction, and nonfatal stroke (MACE). Outcomes were assessed using marginal proportional hazard models stratified according to HF criteria and geographic region where non-CV death was a competing terminal event. Subgroup analyses were assessed with natural cubic splines of interaction between treatment and continuous diabetes duration. Results In SCORED, 10,579 (99.9%) of 10,584 patients had complete data on diabetes duration, with 2412 (22.8%), 4424 (41.8%), 3743 (25.9%) having diabetes duration of <10, 10-19, and ≥20 years respectively. Median (Q1, Q3) diabetes duration was 16.4 years (10.4, 22.4 years), while mean hemoglobin A1c was 8.6%, 8.7%, and 8.7% respectively by diabetes duration. The rate of the primary endpoint was lower in the sotagliflozin group (5.6 events per 100 patient-years [p-y]) compared with the placebo group (7.5 events per 100 p-y) (HR: 0.74; 95% CI: 0.63, 0.88). Event rates among diabetes duration subgroups indicated that rates in both the placebo group and relative treatment benefit increased with increasing diabetes duration, with 5.6 vs 5.8 events per 100 p-y, 6.1 vs 7.4 events per 100 p-y, and 4.6 vs 8.5 events per 100 p-y for diabetes duration <10, 10-19, and ≥20 years respectively. Spline analysis indicated increasing treatment benefit with increasing duration when modeled continuously (Figure Panel A; PSpline=0.02). Similar findings were observed for the secondary HF outcome of hospitalization for HF or urgent visit for HF, with increased treatment benefit with duration (Figure Panel B; PSpline=0.10). Total MACE was lower in the sotagliflozin group (4.8 events per 100 patient-years) than in the placebo group (6.3 events per 100 patient-years) (HR: 0.77; 95% CI: 0.65, 0.91), without significant difference in relative treatment benefit by duration (Figure Panel C; PSpline=0.30). Conclusions Sotagliflozin improved HF and MACE outcomes in patients with high CV risk, with increasing treatment benefit for HF outcomes among patients with longer diabetes duration.

Comparison of the clinical chemistry score to other biomarker algorithms for rapid rule-out of acute myocardial infarction and risk stratification

Abstract Background The clinical chemistry score (CCS) comprising high-sensitivity (hs) cardiac troponins (cTn), glucose and estimated glomerular filtration rate has been previously validated with superior accuracy for detection and risk stratification of acute myocardial infarction (AMI) compared to hs-cTn alone. Methods The CCS was directly compared to other biomarker-based algorithms for rapid rule-out and prognostication of AMI including the hs-cTnT limit-of-blank (LOB, <3 ng/L) or limit-of-detection (LOD, <5 ng/L) and the dual marker strategy (DMS) (copeptin <10 pmol/L and hs-cTnT ≤14 ng/L) in 1506 patients presenting to the emergency department (ED) with symptoms suggestive of acute coronary syndrome. Negative predictive values (NPV) and sensitivities for rule-out of AMI were assessed and outcomes included rates of the combined end-point of all-cause mortality, myocardial re-infarction and stroke within 12 months. Results NPVs of 100% (98.3-100%) could be found for a CCS=0, hs-cTnT LoB and hs-cTnT LoD with rule-out efficacies of 11.1%, 7.6% and 18.3% as well as specificities of 13.0% (9.9-16.6%), 8.8% (7.3-10.5%) and 21.4% (19.2-23.8%), respectively. A CCS≤ 1 achieved a rule-out in 32.2% of all patients with a NPV of 99.6% (98.4-99.9%) and specificity of 37.4% (34.2-40.5%) compared to a rule-out efficacy of 51.2%, NPV of 99.0 (98.0-99.5) and specificity of 59.7% (57.0-62.4%) for the DMS. Rates of the combined end-point of death/AMI within 30 days ranged between 0.0% and 0.5% for all fast-rule-out protocols. Conclusions The CCS enables a reliable rule-out of AMI with low outcome rates in short and long-term follow-up for a specific population of ED patients. However, compared to a single or dual biomarker strategy, the CCS rule-out is attenuated by a loss of specificity and lower efficacy. Thus, the clinical benefit of the CCS in clinical practice seems to be negligible.

An examination of co-existence of metabolic dysfunction-associated liver disease and chronic kidney disease and its effect on long-term mortality in patients with acute myocardial infarction

Abstract Background Metabolic dysfunction-associated liver disease (MASLD) and chronic kidney disease (CKD) are both diseases that can cause increased cardiovascular risk. Recent studies have revealed that the combination of both is a more potent risk factor for ischemic heart disease. However, the mortality and outcomes of patients presenting with acute myocardial infarction (AMI) with varying combination of these two risk factors have yet to be examined. Aims Our research aims to examine the effects of concomitant MASLD and CKD on mortality in patients presenting with AMI. Methods This research examined the features and outcomes of individuals experiencing AMI at our institution. The patients were stratified into 4 groups – patients without MASLD or CKD (MASLD(-)/CKD(-)), patients with MASLD without CKD (MASLD(+)/CKD (-)), patients with CKD without MASLD (MASLD(-)/CKD(+)), and patients with both MASLD and CKD (MASLD(+)/CKD(+)). MASLD was identified as hepatic steatosis along with at least one of five metabolic criteria, and hepatic steatosis was assessed using the Hepatic Steatosis Index. CKD is defined as estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m². A Kaplan-Meier curve was generated to analyse long-term all-cause mortality, and Cox regression analysis was used to identify independent predictors of mortality. Results A total of 6757 patients who presented with AMI were examined over 3.2 ± 2.4 years. Of whom, 3766 (55.7%) individuals were in the MASLD(-)/CKD(-) group, 1945 (28.8%) in the MASLD(+)/CKD (-) group, 675 (10.0%) in the MASLD(-)/CKD(+) group and 371 (5.5%) in the MASLD(+)/CKD(+) group. The MASLD(+)/CKD(+) group had the highest risk of cardiogenic shock compared to their counterparts (p<0.001). The highest 30-day mortality rates were found in the MASLD(+)/CKD(+) group (17.8%), followed by MASLD(-)/CKD(+) (11.6%), MASLD(+)/CKD(-) (4.6%) and MASLD(-)/CKD(-) (4.0%) (p<0.001). In terms of long-term mortality, the Kaplan-Meier curve demonstrated that both MASLD(-)/CKD(+) and MASLD(+)/CKD(+) groups had unfavorable survival following an AMI. Conclusions Patients with AMI, in the presence of concomitant MASLD and CKD, had the highest 30-day mortality rates. They were at the highest risks of AMI-related complications such as heart failure and cardiogenic shock. This study highlights the prognostic impact of cardiovascular-liver-kidney-metabolic health on AMI, and future studies are warranted to mitigate this risk.Figure 1:30 – day all cause mortalityFigure 2:Long term mortality

Long term outcomes of patients with decompensated aortic stenosis undergoing urgent transcatheter aortic valve implantation: a TAVI-NOR subs-study

Abstract Background Aortic stenosis (AS) is a progressive disease, which untreated leads to irreversible myocardial damage and potentially death. Patients with AS may present with acute decompensation (ADAS) even during active surveillance. Purpose In this TAVI-NOR sub-study, we investigate the clinical profile, risk factors, epidemiology and long-term outcomes of patients treated with TAVI after presenting with ADAS compared to stable patients who underwent elective TAVI (no ADAS). Method A total of 600 patients with severe AS consecutively treated with TAVI between January 2012 and July 2019 were enrolled in TAVI-NOR study. Predictors and long-term clinical outcomes were explored in binary logistic and Cox regression models. Results A total of 68 patients (11.3%) received urgent TAVI due to acute hospitalization with ADAS. Age (80±8.0 years vs 81±6.0 years, p=0.662), gender (56% males vs 50% males, p=0.361) and other comorbidities at baseline such as cardiovascular disease, chronic lung disease and atrial fibrillation (AF) were comparable in patients with ADAS and no ADAS (n=532) (p>0.05 for all). However, patients with ADAS had greater symptom burden (NYHA III-IV 81% vs 51%, p<0.001), lower blood pressure, higher heart rate and lower estimated glomeruli filtration rate (52.0±10.8 vs 54.6±9.8 mL/min/1.73m2, p<0.045). They had also higher prevalence of ECG left ventricular (LV) hypertrophy (40% vs 27%, p=0.027), more often reduced LV ejection fraction (<50%) (41% vs 16%, p<0.001), lower stroke volume (39±11 ml/m2 vs 42±11 ml/m2 vs, p=0.030) a trend of abnormal ECG (p=0.055) and longer hospital stay (11.5 ±8.7 days 6.6± 4.9 days, p<0.001). Patients with ADAS were comparable with no ADAS in terms of early short-term (<30 days) all-cause mortality (p>0.05). Although 1-year mortality was comparable (1.5% in ADAS vs 2.1% in no ADAS, p>0.99), mid- to late-term mortality rates were significantly higher in patient with ADAS receiving urgent TAVI, with 3-, 5- and 7 years mortality of 22% vs 11%, p=0.008; 46% vs 29%, p=0.005; 53% vs 39%, p=0.033, respectively. In a Kaplan-Meier analysis, event-free survival was significantly reduced for patients with ADAS undergoing urgent TAVI compared with stable patients undergoing elective TAVI HR 1.63, 95% CI 1.15-2.31, p=0.006), confirmed by a multivariable-adjusted model (HR 1.54; 95% CI 1.05-2.25, p=0.026) independent of age, gender, AF, LV ejection fraction and time from diagnosis to TAVI (Fig). Conclusion Patients with AS presenting with acute decompensation and treated with urgent TAVI had excellent short-term survival. This was irrespective of increased symptom burden, adversely remodeled and functionally reduced LV at baseline. These findings might explain the observed higher mid- and long-term mortality compared with stable patients undergoing elective TAVI. It is essential to identify patients at risk of acute decompensation and treat them timely before irreversible myocardial damage occur.

Short and long-term effects of kidney donation on mineral and bone metabolism

BackgroundLiving kidney donors (LKD) experience an abrupt decline in glomerular filtration rate (GFR) resulting in abnormalities of mineral and bone metabolism (MBD), and this may have implications for skeletal health. We prospectively studied acute and long term MBD adaptation of LKD from two kidney transplant centers (São Paulo, Brazil and Miami, USA).MethodsRenal function and MBD parameters longitudinally after kidney donation (baseline – D0, day 1, 14, 180 and 360 post-operatively) were measured in 74 patients (40 y, 73% female, 54% Brazilian). A subset of 20 donors from Brazil were reassessed after 10 years of nephrectomy.ResultsAt baseline, Brazilian donors presented lower intact FGF23 (20.8 vs. 80.1 pg/mL, P < 0.01) and higher PTH (47.4 vs. 40.1, P = 0.04) than their US counterparts. GFR decreased to 63% of its baseline levels just after donation but improved 10% during the first year. PTH levels increased on D1, returning to baseline levels on D14, while FGF23 remained higher than baseline over the first year. LKD had a significant reduction of serum phosphate on D1, which returned to baseline levels on D180. A higher fractional excretion of phosphate (FEP) was noted since D14. After 10 years of donation, 20 LKD presented a sustained reduction in GFR (74.8 ± 14mL/min). There was a return to baseline in serum FGF23 [21.8 (18–30) pg/mL] and FEP, accompanied by an increase in serum calcium. PTH remained elevated (57.9 ± 18 pg/mL), whereas serum calcitriol and Klotho were lower than before the donation.ConclusionsThe abrupt decline in kidney mass is associated with an increase in PTH and FGF23 that is not explained by phosphate retention. In a long-term evaluation, LKD showed a sustained drop in GFR, with lower serum calcitriol and Klotho, and higher PTH. The effects of these changes should be investigated in further studies.