Lower Ejection Research Articles

Comparison of Evolut-R 34 mm Valve and Smaller Evolut-R Valves in Patients Undergoing Transcatheter Aortic Valve Implantation and Determination of Mild Paravalvular Leak Predictors.

The main purpose of this study was to evaluate and compare the in-hospital, 1-month and 1-year post-procedure outcomes of patients treated with Evolut-R 34 mm and Evolut-R 23/26/29 mm devices. Additionally, the study aimed to identify factors that could predict the occurrence of ≥ mild paravalvular leaks (PVL). Between April 2015 and May 2022, 269 consecutive patients who underwent transcatheter aortic valve implantation (TAVI) with Evolut-R 34 mm (n = 66, 24.5%) and Evolut-R 23/26/29 mm (n = 203, 75.5%) devices in a single center were retrospectively analyzed. Patients in the Evolut-R 34 mm group had a lower female sex ratio (16.7% vs. 66.5%, P <.001, respectively), ejection fraction (50.7 ± 10.1% vs. 54.5 ± 9.3%, P =.016, respectively), and mean aortic gradient (7.4 ± 3.3 vs. 9.2 ± 5.0, P =.026, respectively) compared to the Evolut-R 23/26/29 mm group. The groups did not exhibit any statistically significant distinctions with regard to technical success, the need for a permanent pacemaker, occurrences of stroke, major vascular complications, PVL, major adverse cardiovascular and cerebrovascular events, or mortality. Peak velocity was confirmed as a significant predictor of ≥mild PVL in both patient groups in the receiver operating characteristic curve analysis. In logistic regression analysis; In patients with Evolut-R 34 mm valve, pre-TAVI aortic valve peak velocity (odds ratio (OR) = 23.202; P =.019) and calcium volume 800 Hounsfield Units (mm3) (OR = 1.017; P <.001) were independent predictors of ≥mild PVL. The Evolut-R 34 mm valve has shown comparable in-hospital results with smaller valve sizes. Pre-TAVI aortic valve peak velocity and calcium volume predicted ≥ mild PVL in Evolut-R 34 mm patients.

Incidence and predictors of device-related thrombus after left atrial appendage closure with Watchman device.

Left atrial appendage closure (LAAC) with Watchman device prevents thromboembolism in patients with atrial fibrillation (AF). However, thrombus may develop on the atrial surface of the device. To investigate the incidence and predictors of device-related thrombus (DRT) in patients with AF who were treated with LAAC. Ninety-one consecutive patients with AF underwent LAAC procedure using first-generation Watchman 2.5 device followed by antiplatelet therapy. In our analysis we have included all patients (n = 78) who had clinical follow-up visits with transesophageal echocardiography (TEE) after the procedure. The median (IQR) CHA2DS2-VASc score was 4 (4.0-6.0) and HAS-BLED score was 3 (3.0-4.0). DRTs were observed in 5 (6.4%) patients. When compared with patients without DRT, those with DRT presented more often with lower median ejection fraction (40% (23.5-45.5) versus 55% (48.0-60.0); p = 0.005), lower emptying velocity of LAA (25 cm/s (17.5-27.0) versus 53 cm/s (26.5-78.0); p = 0.009), and with greater depth of implantation (18 mm (14.0-20.5) versus 8 mm (5.0-11.0); p < 0.001). Furthermore, patients with DRT had greater depth of LAA (35 mm (29.5-41.0) versus 29 mm (25.5-31.0); p = 0.003), greater mean (SD) dimension in 900 (22.4 mm (3.2) versus 19 mm (2.7); p = 0.02). Patients with DRT were also younger than those without DRT (67.4 years (7) versus 75 years (8.3), p = 0.045). The DRT after Watchman device implantation remains a rare complication. Its formation was related to several patient and procedural characteristics, which need to be confirmed in larger studies.

The Relationship Between Coronary Artery Angiographic Characteristics, Occupational Factors, and Return to Work.

Coronary artery disease is one of the most common causes of disability and work loss among working-age individuals. Since the ability to return to work after cardiovascular events depends on several factors, identifying these factors can be helpful in treatment planning and effective rehabilitation. In this study, we aimed to assess the employment status and related factors one year after angiography in patients with stable angina and acute coronary syndrome and to investigate the impact of occupational factors on angiographic characteristics. This retrospective study included 447 patients with coronary artery disease who underwent angiography between February 2020 and March 2021 at a teaching hospital. Data regarding employment status and other related variables, including the Job Content Questionnaire, were collected through medical record reviews and telephone interviews one year after hospital discharge. The participants' occupational factors and return-to-work status were then compared. One year after angiography, the rate of returning to work was 70%. Of these, 86.3% had resumed their previous job. Factors associated with a reduced return to work included major coronary artery involvement, a history of hypertension, lower ejection fraction, and increased hospitalization days. Occupational risk factors such as low income, longer working hours, and high job demand also decreased the likelihood of returning to employment. Various clinical and socioeconomic factors can predict the probability of returning to work after angiography in patients with coronary artery disease. Considering these factors could be useful in formulating clinical guidelines to improve employment outcomes for these patients.

Clinical characteristics and outcomes of patients requiring prolonged mechanical circulatory support after high-risk percutaneous coronary intervention.

There are limited data on the clinical characteristics and outcomes of patients who require prolonged mechanical circulatory support (MCS) after Impella-supported high-risk percutaneous coronary intervention (HR-PCI). The aim of this study is to describe the contemporary clinical characteristics, outcomes, and predictors associated with prolonged MCS support after assisted HR-PCI. Patients enrolled in the prospective, multicentre, clinical endpoint-adjudicated PROTECT III study who had undergone HR-PCI using Impella were evaluated. Patient and procedural characteristics and outcomes for those who received prolonged MCS beyond the duration of their index procedure were compared to those in whom MCS was successfully weaned and explanted at the conclusion of the index PCI. Among 1,155 patients who underwent HR-PCI with Impella between 2017 and 2020 and had sufficient data to confirm theduration of Impella support, 16.5% received prolonged MCS (mean duration 25.2±31.1 hours compared with 1.8±5.8 hours for those who only received intraprocedural MCS). Patients receiving prolonged support presented with more urgent indications (e.g., acute coronary syndromes [ACS], lower ejection fraction [EF], elevated baseline heart rate and lower systolic blood pressure). Use of the Impella CP, intraprocedural complications, periprocedural complications and in-hospital mortality were all more common amongst the prolonged MCS group. Prolonged MCS was associated with increased rates of major adverse cardiovascular and cerebrovascular events, cardiovascular death, and all-cause mortality at 90-day follow-up. Patients receiving prolonged MCS after Impella-supported HR-PCI presented with more ACS, reduced EF and less favourable haemodynamics. Additionally, they were more likely to experience intraprocedural and periprocedural complications as well as increased in-hospital and post-discharge mortality.

Serum Copeptin Level as a Predictor of One-Year Mortality after Acute Decompensated Heart Failure Hospitalization

Background: Acutely decompensated heart failure patients have variable clinical outcomes. Some predictors of mortality in acute heart failure as resting heart rate, blood pressure, Pro-BNP level, and others have been identified. This study addresses the question whether copeptin may add value in the one-year prognosis in this category of high-risk patients. Results: To assess the relationship of serum copeptin level with one year mortality, we evaluated serum copeptin at admission and after 72 hours in 106 consecutive patients hospitalized for acute decompensated heart failure between May 2021 and November 2021 in a tertiary care hospital. Twenty-four patients (23.3%) died during the one-year follow-up period. The mortality was significantly higher in patients with advancing age, male sex, smokers, NYHA class IV heart failure, lower ejection fractions, higher heart rate, higher burden of arrhythmic events, lower creatinine clearance, and higher levels of copeptin at baseline and at day 3. Copeptin level at day 1 with cutoff value of ˃25.4 pmol/l predicted mortality with sensitivity 87.5% and specificity 70.73% [hazard ratio (95% confidence interval): (0.725 - 0.898), P&lt;0.001], while copeptin level at day 3 with cutoff value ˃ 26.1 pmol/l predicted mortality with sensitivity 100% and specificity 73.17% [hazard ratio (95% confidence interval): (0.876 - 0.981), P&lt;0.001]. Finally, increase in copeptin level from bassline was independently associated with increased mortality. (p˂0.001). Conclusions: Elevated copeptin level at baseline and 72 hours post-admission is suggested to be a strong predictor of one year mortality in patients with acute decompensated heart failure.

Chronopharmacokinetic and Metabolite Studies of the Cardiovascular Medication Sacubitril

People with “heart failure with preserved ejection fraction” have heart failure, but their ejection fraction is still pretty normal (HFpEF). When it comes to heart failure, people with normal or nearly normal ejection fractions are more likely to get it than those with lower ejection fractions. In clinical trials with HFpEF, medications such as angiotensin-converting enzyme inhibitors (ACEIs), aldosterone antagonists, beta-blockers, calcium channel blockers, and angiotensin receptor blockers (ARBs) did not yield any beneficial results. Sacubitril is prescribed to peritoneal dialysis patients with end-stage renal disease in order to manage their hypertension and heart failure. The concentrations of sacubitril and its primary metabolite in plasma, urine, and peritoneal dialysis fluid were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). This method is effective because it doesn’t take much time but produces good results. Several samples of body fluids were taken with the help of protein precipitation. The positive ion mode of ionization from the UPLC-MS/electrospray MS was used to look at the extracts. With correlation values of 0.99991 for sacubitril, the suggested method was carefully tested. With this method, it is possible to find out exactly how much sacubitril are in plasma, urine, and peritoneal dialysis fluid. It is also honest, dependable, and nice. If the experiment works, we’ll know that peritoneal dialysis changed how sacubitril were cleared from the body.

Prognostic value of arterial lactate index in ST-elevation myocardial infarction treated with primary percutaneous coronary intervention: a prospective cohort study.

Aim: Limited knowledge exists on the pathophysiological cascade beyond serum lactate's association with myocardial injury. Method: Assessed the prognostic value of lactate index on periprocedural variables and its impact on 30-day major adverse cardiovascular events (MACE)in 300 prospective ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI). Results: Significant correlations were observed between admission lactate and Killip class, periprocedural time intervals, postprocedure thrombolysis in myocardial infarction (TIMI) flow and myocardial blush grade (MBG;p<0.01). Lactate levels correlated with diminished ST-deviation resolution, cardiac enzymes (CK-MB, troponin;p<0.001; 0.004), and lower ejection fraction (p<0.001). This relationship impacted 30-day MACE (p<0.001). Conclusion: Hyperlactatemia in STEMI patients undergoing pPCI is associated with worse Killip class, unsatisfactory TIMI flow, MBG, larger infarct size and higher 30-day MACE. Serum lactate aids risk stratification in pPCI for STEMI patients.

Hyponatremia in Acute ST-elevation Myocardial Infarction – A Retrospective Observational Study

Introduction: Hyponatremia is a common electrolyte disorder in hospitalized patients and has been linked to increased morbidity and mortality in various clinical settings. Patients with ST-elevation myocardial infarction (STEMI) are at risk of developing hyponatremia due to complex interplay of pathophysiological mechanisms. This study aimed to investigate the prevalence, risk factors, and prognostic value of hyponatremia in patients with STEMI. Materials and Methods: This was a retrospective study of 192 patients with STEMI who were admitted to a tertiary care hospital between July 2021 and December 2021. Patients were divided into two groups based on their serum sodium levels during hospitalization: Hyponatremia group (serum sodium &lt;135 mEq/L) and normonatremia group (serum sodium ≥135 mEq/L). The prevalence of hyponatremia, demographic variables, ejection fraction, Killip classification, type of STEMI, and in-hospital mortality were compared between the two groups. Results: 20.8% of patients with STEMI had hyponatremia during their hospital stay. Patients with heart failure, lower ejection fraction, and higher Killip classification at admission were more likely to have hyponatremia ([odds ratio (OR): 2.71, 95% confidence interval (CI): 1.23–5.97, P = 0.014], [P = 0.023] and P = 0.002). Patients with lateral STEMI were more likely to have hyponatremia compared to those with other types of STEMI (OR: 2.68, 95% CI: 1.06–6.81, P = 0.037). Patients with hyponatremia had higher in-hospital mortality rate (8 [22.9%], [OR: 4.27, 95% CI: 1.54–11.85, P = 0.005]) and longer hospital stays (P = 0.019) compared to normonatremia group. Conclusion: Hyponatremic patients with STEMI are associated with increased morbidity and mortality. Patients with heart failure, lower ejection fraction, and higher Killip classification at admission should be closely monitored for dyselectrolytemia.

Prognostic role of mitral regurgitation in patients with advanced heart failure

AimThe impact of mitral regurgitation (MR) in patients with advanced heart failure (HF) is poorly known. We aimed to evaluate the impact of MR on clinical outcomes of a real-world, contemporary, multicentre population with advanced HF. MethodsThe HELP-HF registry enrolled patients with HF and at least one “I NEED HELP” criterion, at four Italian centres between January 2020 and November 2021. The population was stratified by none/mild MR vs. moderate MR vs. severe MR. Outcomes of interest were all-cause, cardiovascular (CV) death, the composite of all-cause death or first HF hospitalization, first HF hospitalization and recurrent HF hospitalizations. ResultsAmong 1079 patients, 429 (39.8%) had none/mild MR, 443 (41.1%) had moderate MR and 207 (19.2%) had severe MR. Patients with severe MR were most likely to be inpatients, present with cardiogenic shock, need intravenous loop diuretics and inotropes/vasopressors, have lower ejection fraction and higher natriuretic peptides. Estimated rates of all-cause death, CV death, and the composite of all-cause death or first HF hospitalization at 1 year increased with increasing MR severity. Compared with no/mild MR, severe MR was independently associated with an increased risk of CV death (adjusted HR 1.61, 95% CI 1.04–2.51, p = 0.033) and recurrent HF hospitalizations (adjusted HR 1.49, 95% CI 1.08–2.06, p = 0.015), but not with and increased risk of all-cause death, first HF hospitalization and composite outcome. ConclusionsIn unselected patients with advanced HF, severe MR was common and independently associated with an increased risk of CV death and of recurrent HF hospitalizations.

Prognostic value of first pass perfusion transit time beyond the pulmonary circulation

Abstract Background Pulmonary transit time (PTT), defined as the time required for a bolus of contrast agent to pass from the right cavities to the left cavities, is an emerging parameter reflective of cardiopulmonary hemodynamics that can be measured in first-pass perfusion cardiovascular magnetic resonance (CMR). Transit times along the left heart (LHTT) and perfusion times of peripheral organs have not been explored so far. Purpose To assess the prognostic value of LHTT and peripheral organs perfusion time in a cohort of patients with left ventricular (LV) disfunction. Methods 50 consecutive patients with LV disfunction (ejection fraction ≤45%) and 56 normal controls who underwent a CMR at our institution were selected. Transit time was calculated as the peak-to-peak time interval between two different areas of the cardiovascular system. PTT was assessed between right ventricle (RV) and left ventricle. LHTT was assessed between left atrium and ascending aorta. Myocardial perfusion time (MyoPT) was measured between left ventricle and the peak of myocardial perfusion. Peripheral organ perfusion (kidney, KPT; spleen, SPT and liver, LPT) between abdominal aorta and the peak organ perfusion. The primary end point was a composite of cardiovascular death, hospitalization, ventricular arrhythmias and the need of any cardiac invasive intervention within the first year. Results Compared with controls, LV disfunction patients presented higher PTT (7.4 [5.9-8.4] vs 11.9 [9.5-13.9] s, p&amp;lt;0.001), LHTT (1.9 [1.05-2.3] vs 3.3 [1.9-4.8] s, p&amp;lt;0.01), MyoPT (9.9 [7.8-11.5] vs 13.1 [9.7-18.6] s, p&amp;lt;0.01), KPT (9.4[7.8-11.2] vs 11.5[8.3-15.5] s, p = 0.012). SPT showed a non-significant trend (9.4[8.1-11.9] vs 11.5[7.9-13.4]s , p = 0.058) . There were no differences in LPT (28.9[24.4-35] vs 33.3[23.3-41.1] s, p = 0.267). Among the patients with LV disfunction, 16 subjects reached the composite end-point; compared to those who did not, these patients had significant higher values of PTT (10.1 [8.7-13.7] vs 13.4[10-15.7] s, p = 0.04), LHTT (2.3[1.8-4] vs 4.3 [3.3-5.8] s, p = 0.008) and MyoPT (10.5[8.8-17.5] vs 13.3[11.9-20.5] s, p = 0.049). SPT showed a non-significant trend (10.3[6.9-12.6] vs 12.6[10.9-17.1] s, p = 0.078), KPT and LPT showed no significant differences. Patients with worse prognosis also presented lower LV ejection fraction (LV: 34.7± 9.5 vs 25.5±9 %, p&amp;lt;0.001) but no significant differences in RV ejection fraction: 52.9±14 vs 49.3±13.8 %, p = 0.473). Due to the small number of events we did not performed a multivariate analysis. KPT showed a weak but significant positive correlation with the creatinine measured at the time of the CMR study (r = 0.262, p = 0.024) and also at follow-up (r = 0.247, p = 0.042). Conclusions Transit time is a surrogate marker of the heamodynamic status that can be assessed beyond the pulmonary circulation. LHTT and organ perfusion times are markedly altered in patients with LV disfunction and are associated with poor prognosis.

Predicting thrombus outcome during anticoagulation for left ventricular thrombus

Abstract Background Up to 22% of embolizations have been linked to left ventricular (LV) thrombosis. Oral anticoagulation (OAC) for at least 3 months is recommended for patients with LV thrombus, according to guidelines. The purpose of this study was to predict the resolution of thrombus in patients with LV thrombus who were taking OAC for 3 months. Methods We enrolled patients prospectively from 2020 to 2022 and retrospectively from 2013 to 2019 at a national center of cardiovascular diseases in China. Patients with a history of LV thrombus &amp;lt; 3 months were included. Eligible patients were administered OAC and scheduled for 3 months of follow-up visits. The primary efficacy outcome was the rate of thrombus resolution at 3 months. Safety outcomes and major cardiovascular adverse events were collected. The hazard ratio (HR) and 95% confidence intervals (CIs) were estimated with adjustment for covariates using Cox regression models. Results We identified a total of 380 eligible patients. The median age was 53 (41, 63) years and 310 (81.6%) patients were male. The main underlying etiologies were dilated cardiomyopathy (51.6%). 204 (53.7%) patients received non-vitamin K antagonist oral anticoagulants (NOACs) while the rest were on warfarin within 3 months. In multivariable analysis, patients with NOACs had a higher likelihood of thrombus resolution than those taking warfarin (HR 1.39, 95% CI 1.08 – 1.79, P = 0.011). Lower LV ejection fraction levels and smaller diameter or thickness of thrombi were also the dominant predictors of thrombus resolution followed by a faster heart rate, a higher white blood cell count, therapy of diuretics, beta-blocker, and parental anticoagulation during hospitalization (eight variables, all P &amp;lt; 0.05). At 3 months, 29 patients (7.6%) suffered major cardiovascular adverse events, including 26 emboli and 3 deaths. One patient (0.3%) experienced an ISTH major bleeding. Conclusions Patients with systemic anticoagulation and positive treatment for heart failure achieved a greater rate of thrombus resolution at 3 months. The option of oral anticoagulation might be favorable NOACs, and further randomized controlled studies are warranted to explore.Forest plot of multivariable analysis.

3D atrial stiffness in chronic mitral regurgitation: impact of sex, regurgitation mechanism and valve geometry - the 3D-PRIME study

Abstract Background Chronic mitral regurgitation (MR) is both a cause and a consequence of progressive left atrial (LA) remodeling. The degree of LA stiffness in relation to clinical risk factors as well as atrio-valvular remodeling has not been reported in patients with MR. Aims To assess the severity and determinants of 3D LA stiffness in chronic MR. Methods In the prospective 3D-PRIME (3D Echocardiography and Cardiovascular Prognosis in Mitral Regurgitation) study, 100 patients with chronic MR (70±13years, 38% women, 55% with a history of atrial fibrillation (AF), 42% with severe MR) recruited at one heart valve center were investigated with 2D and 3D transthoracic and transesophageal echocardiography. MR severity was quantified by the regurgitant fraction and MR classified as primary (54%), atrial functional (26%) or ventricular functional (20%). 3D LA volume (LAV) was measured at end-diastole (min LAV) and end-systole (max LAV), and 3D LA function assessed in by the emptying fraction (EF) and the peak strain in the reservoir phase (LASr). LA stiffness was estimated from the ratio: mitral peak E-wave velocity divided by the mitral annular e’ velocity (E/e´) / LASr and classified as high for age if ≥ 0.55. Results High LA stiffness for age was present in 58% of patients and more often in those with a history of AF (73% vs. 45%) and in severe vs moderate MR (70% vs. 42%) (both p &amp;lt;0.01). Patients with high LA stiffness had larger LAVs with lower LA EF, lower right ventricular ejection fraction, increased mitral annulus area, and larger mitral valve leaflets (all p&amp;lt;0.05). Men had considerably larger LAVs in all MR subgroups, and highly stiff LAs in atrial functional MR compared to women (p &amp;lt;0.05, Figure) despite similar MR severity (regurgitation fraction 50% vs 52%, respectively). In multiple regression analysis, after stepwise removal of the following factors: MR severity, mitral leaflet to ring area ratio, and right ventricular ejection fraction, increased LA stiffness was independently associated with male sex, history of AF, lower LA EF and lower mitral intertrigonal diameter (R2 0.40, p &amp;lt;0.001, Table). Conclusion LA is stiff for age in over half of patients with chronic MR, excessively stiff in men with atrial functional MR, and associated with specific changes in mitral valve geometry and LA function. This gives mechanistic insights into the complex atrio-valvular interplay in chronic MR.Figure.Table.

Left atrial mechanical dysfunction and the risk for ischemic stroke in HCM patients without prior atrial fibrillation or stroke

Abstract Background Patients with hypertrophic cardiomyopathy (HCM) are at high risk of atrial fibrillation (AF) and ischemic stroke. Left atrial enlargement and dysfunction that characterize atrial myopathy may precede and promote AF and cardiac thromboembolism. In HCM patients without prior AF or stroke, whether left atrial mechanical dysfunction can improve ischemic stroke prediction is unknown. Method Patients with prior AF or stroke (n = 121) were excluded and 653 consecutive patients with HCM (mean age 47.3 ± 12.3 years, 71% male) who underwent cardiac magnetic resonance (CMR) at Fuwai Hospital between January 2012 and December 2013 were finally enrolled. LA ejection fraction, strain and strain rate indices on reservoir, conduit and booster-pump phases that represent LA mechanical function were analyzed. The primary endpoint was ischemic stroke. The secondary endpoint was new-onset AF. Result At 7.6 ± 2.4 years of follow-up, 24 (3.7%) had ischemic stroke and 73 (11.2%) had new-onset AF. Patients with stroke had an older age (p = 0.014), higher incidence of hypertension (p &amp;lt; 0.001), more LGE presence (p = 0.006) and LGE extent (p = 0.007). For LA size and function, patients with stroke showed significantly higher LA volume index and lower LA ejection fraction and LA strain (all p &amp;lt; 0.01). Age, hypertension, LGE presence, LGE extent and all LA mechanical indices were univariably associated with stroke. On multivariate model, LA reservoir strain was associated with stroke (Hazard Ratio = 0.91. 95%CI 0.85-0.97, p = 0.005) independent of Age (p = 0.292), hypertension (p = 0.002), LGE extent (p = 0.003) and LA volume (p = 0.737). In addition, LA reservoir strain was also associated with new-onset AF (Hazard Ratio = 0.93. 95%CI 0.89-0.96, p &amp;lt; 0.001) independent of Age (p &amp;lt; 0.001), hypertension (p = 0.607), LGE extent (p = 0.882) and LA volume (p = 0.002). Conclusion In HCM patients without prior AF or stroke, LA mechanical dysfunction was a strong predictor for stroke and new-onset AF independent of LA enlargement, age, hypertension and LGE extent.

Influence of sarcomeric protein mutations on myocardial function in a 3D-disease model of human iPSC-derived bioartificial cardiac tissue

Abstract Background Peripartum cardiomyopathy (PPCM) is a rare type of cardiomyopathy that occurs in women without prior history of heart disease at later stages of pregnancy or several months after childbirth (1). The disease is characterized by lowered left ventricular ejection fraction (LVEF&amp;lt;45%) and can lead to heart failure if left untreated (1). Approximately 20% of PPCM patients harbor sarcomeric mutations, from which titin truncating variants (TTNtv-s) have the highest pathogenic potential (2). However, the role of such genetic defects of the contractile apparatus on PPCM pathogenesis is not well understood. Purpose The study aims to establish an in vitro 3D disease model of PPCM to elucidate the role of sarcomeric mutations, including titin mutations, in its etiology. We hypothesize, that the disease phenotype can be uncovered in vitro via the stimulation of PPCM patient-derived Bioartificial Cardiac Tissues (BCTs), utilizing pregnancy-related factors in our custom-made bioreactors (3). Methods We selected three patients carrying previously unstudied mutations in the TTN gene for the study. The iPSC reprogramming was performed using a commercial, Sendai virus-based kit. Pluripotency was confirmed via flow cytometry and immunofluorescence stainings. The presence of mutations was confirmed by exome sequencing. Cardiomyocyte differentiation (4) and BCT generation (3) were carried out via established protocols. Following maturation, BCTs were stimulated with the pregnancy-related factors, and tissue forces were measured in the bioreactors. These forces include intrinsically generated (spontaneous) and electrically induced (paced) contraction forces (mN), as well as passive forces, which correlate with tissue stiffness. Results We successfully generated two clonal induced pluripotent stem cell (iPSC) lines from each patient. We confirmed that all of the cell lines were &amp;gt;90% positive for pluripotency markers. After differentiation, CMs contracted spontaneously from day 7 onwards and were &amp;gt;95% positive for cardiac markers (SA, MF20, cTnT). The BCTs remodeled and started contracting on days 1-2 after generation, similarly to wild-type tissues in the baseline conditions. Prolactin treatment of Patient A, harboring a missense mutation in titin, did not show significant functional effects. We confirmed, that patients B and C harbor TTNtvs, and tissues from these patients show a trend of altered stiffness after stimulation with repeated mechanical stretch cycles or β-adrenergic agonist isoprenaline. Further analysis of the underlying mechanisms investigating metabolic changes, signaling pathways, and transcriptomics are ongoing. Conclusion The established iPSC and tissue engineering technologies offer a valuable tool for the development of an iPS-CM-based 3D in vitro disease model for PPCM, which can be used for risk stratification of individual and combined sarcomeric mutations and the development of tailored therapeutic strategies.

Heart rate reduction and outcomes in heart failure outpatients

Abstract Aim Pharmacologic reduction of heart rate (HR) with beta blockers (BB) and/or ivabradine has been associated with improved survival in patients with heart failure (HF) in sinus rhythm. We analyzed the impact of different HR-reducing drug treatments on outcomes in a cohort of outpatients with heart failure (HF). Methods Consecutive patients with HF and sinus rhythm (SR) referred to a specialized tertiary HF service offering advanced therapy options including assist device and heart transplantation were prospectively enrolled from August 2015 until March 2018. Clinical characteristics were assessed at baseline. We performed Cox regression analyses to examine the effect of the resting HR and the drug regimen (BB in submaximal dose [group 1], BB in maximum tolerated dose [group 2], or BB in maximum tolerated dose plus ivabradine [group 3]) on all-cause mortality and a combined, disease-related endpoint of "death from any cause or heart transplantation". Results Of 278 patients included, 213 (76.6%) were male. Median age was 57.0 years (interquartile range 49.0-66.1). HF was due to non-ischemic origin in 167 patients (60.1%). HFrEF was present in 185 patients (73.7%). There was a decent use of guideline-recommended HF medication (MRA in 82%, RAS blocker [ARNI/ACEI/ARB] in 97%). Most patients received treatment with a BB in submaximal [n = 118, group 1], or maximum tolerated dose [n = 136, group 2]. Patients treated with BB in maximum tolerated dose plus ivabradine [n = 24, group 3] were younger (53.0 vs. 58.0 years) and had a lower left-ventricular ejection fraction on echocardiography (EF, 25 vs. 31%) than those without ivabradine. Over a mean follow-up period of 3.1 years, 30 patients died, and 11 underwent heart transplantation. Upon regression analyses, higher resting HR was associated with an increased risk of death or heart transplantation (hazard ratio HR 1.03 [1.01, 1.06], p = 0.0072, even after adjusting for age and sex. Neither the type of heart rate-reducing therapy (BB with or without ivabradine), nor the dose of BB or ivabradine affected outcome. Conclusion Our prospective study underlines the importance of heart rate reduction in HF with SR but failed to demonstrate a better risk reduction in patients with up-titrated BB doses or on a combination of BB plus ivabradine.Study profileKM-curves for the composite endpoint

Impact of new-onset versus preexisting atrial fibrillation on short- and long-term mortality in patients with STEMI treated with primary PCI

Abstract Background Comparative data on the effects of new-onset vs. preexisting atrial fibrillation (AF) on long-term mortality in patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) are scarce. Therefore, the aim of this study was to assess the impact of new-onset vs. preexisting AF on mortality over 5 years after primary PCI. Methods Our analysis included 7 955 patients referred to primary PCI in the period from 2009 to 2019, for whom data regarding the presence and type of AF were available, from a prospective electronic registry of a high-volume catheterization laboratory. Patients were stratified into three groups according to the AF status: no AF vs. new-onset vs. preexisting AF. Cumulative mortality was compared with Kaplan Meier curves. Cox regression models were created to assess the mortality hazard at 30 days and 5 years according to the presence of new-onset and preexisting AF with no AF as the reference group. 30-day follow-up was available for 7 738 and 5-year for 5 049 patients. Results Preexisting AF was found in 3.1% of patients (n=246) and new-onset AF was recorded in 7.0% (n=560). Both new-onset and preexisting AF were associated with higher crude mortality rates compared to patients without AF, at 30 days (14.4% vs 16.0% vs. 5.2%, respectively; p&amp;lt;0.001) and at 5 years as well (56.6% vs. 65.7% vs. 25.4%, respectively; p&amp;lt;0.001). Cumulative mortality rates were significantly higher for both new-onset and preexisting AF, as compared to patients with no AF (Log rank p&amp;lt;0.001, Figure). Patients with new-onset and preexisting AF were older and had a higher baseline risk profile including more frequently prior MI and stroke, more diabetes, hypertension, hyperlipidaemia, renal failure, Killip class ≥2 on admission and lower ejection fraction. When adjusted for these baseline differences, both new-onset and pre-existing AF independently predicted 5 year mortality (HR 1.6, 95%CI 1.4-1.9, p&amp;lt;0.001, and HR 2.2, 95%CI 1.8-2.8, p&amp;lt;0.001, respectively), but not at 30 days (HR 1.4, 95%CI 0.9-2.0, p=0.1, and HR 1.5 95%CI 0.9-2.5, p=0.1, respectively). Conclusion Both new-onset and pre-existing AF are independently associated with an increased risk of long-term mortality in patients with STEMI treated with primary PCI, whereas their impact on short-term mortality reflects the higher baseline risk profile of those patients.Cumulative mortality rates

Sex-related differences in the association between septal wall thickness and survival

Abstract Background Septal hypertrophy is associated with increased morbidity and mortality but data regarding the effect of sex on the association between septal wall thickness and survival is limited and uniform cutoffs in men and women are often used in clinical practice and research. Objective To investigate the differences between men and women in the association between septal wall thickness and survival. Methods A retrospective analysis of consecutive unselected patients undergoing echocardiography between March 2010 and February 2021 in a large tertiary referral center. Echocardiography studies were performed according to standard protocol. Survival data was validated against the ministry of health records. Cox regression analysis was used to evaluate the association between septal thickness and mortality. Results A total of 71,965 individuals were included. There were 32,419 (46%) female and 38,546 (54%) male examinees. Females were older than males (65 + 18 vs. 62 + 18, p &amp;lt; 0.001), less likely to have diabetes (16% vs. 19%, p&amp;lt;0.001) or ischemic heart disease (11% vs. 25%, p&amp;lt;0.001) but more frequently had atrial fibrillation (11% vs. 10%, p&amp;lt;0.001). Females had lesser septal wall thickness than males (10.3 + 2 vs. 11.1 + 2, p &amp;lt; 0.001), lower left ventricular mass index (89 + 29 vs. 102 + 33, p&amp;lt;0.001), lower left ventricular end diastolic and end systolic diameter index. Men had lower ejection fraction than women (55% + 9 vs. 58% + 6, p &amp;lt; 0.001). Over a mean follow-up of 59.1 ± 37 months there were 9631 (25%) and 8429 (26%) deaths in the male and female groups, respectively. In multivariate cox regression analysis, septal thickness was an independent predictor for all-cause mortality in both sexes (Table). When using a uniform cutoff of 12mm for septal thickness for both sexes, the multivariate adjusted HR was 1.00 (CI 95%: 0.94-1.08, p=0.83) for males and 1.15 (CI 95%: 1.07-1.25, p&amp;lt;0.001) for females. The Kaplan–Meier mortality-free survival curve by septal thickness and sex is shown (figure). Septal thickness had an incremental prognostic significance in both sexes. On multivariate analysis it became statistically significant in females at 11mm with HR 1.51 (CI95%:1.06-1.24, p&amp;lt;0.001) and in males at 13mm with HR 1.21 (CI95%: 1.12-1.36, p&amp;lt;0.001). When using indexed septal thickness for BSA, the statistically significant cutoff was 6mm/BSA for women, HR 1.08 (CI 95%: 1-1.17, p=0.04) and 6.2mm/BSA for men, HR 1.07 (CI 95%: 1-1.15, p=0.05). Conclusions In an large unselected cohort of patients, septal hypertrophy had an incremental prognostic significance in both sexes and was associated with increased mortality at a lower threshold in women than in men. This may at least partially explain the delayed diagnosis and worse prognosis reported in females in many conditions characterized by septal hypertrophy. Applying a lower absolute value or using indexed measurements may facilitate early diagnosis and improve prognostication in females.

Stress echocardiography: application of the ABCDE protocol in patients with permanent atrial fibrillation

Abstract Objectives A new standard of practice in stress echocardiography (SE) was founded with the development of the ABCDE protocol, which added functional information to conventional ischemia diagnosis. Each step showed to provide incremental prognostic information: step A, regional wall motion abnormalities; step B, B lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in the left anterior descending coronary artery; and step E, electrocardiogram-based heart rate reserve. However, the utility of SE and ABCDE protocol in patients with atrial fibrillation (AF) has never been tested. Background A growing body of evidence suggests that AF patients have a significant residual risk of myocardial infarction despite anticoagulant treatment; furthermore, they have an increased risk of heart failure and all-cause death. However, ABCDE-SE has never been applied in this population. Methods Of the 3965 patients who completed clinically indicated ABCDE-SE and with available information on rhythm stored in the shared data bank and enrolled from 13 certified centers, 3891 were in sinus rhythm (SR, Group 1) and 50 in permanent AF (Group 2) at the time of the test. ABCDE-SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). The employed stress was an exercise in 1626 (41%), vasodilator in 1864 (47%), and dobutamine in 475 (12%). Results Group 2 pts were older than Group 1 patients, more frequently hypertensives and diabetics, with lower ejection fraction, and with more signs of pulmonary congestion at rest. During stress, differences were magnified, and Group 2 patients showed more peak stress B-lines and higher values of peak WMSI compared with Group 1 (see Table). In addition, patients with AF had higher ABCDE scores (Group 1= 1.5 ±1.4 vs. Group 2= 2.6±1.6, p&amp;lt;0.0001). The distribution of the score in patients in SR and AF is shown in Figure. Conclusions Patients with AF are scarcely represented among patients undergoing SE. Patients with AF showed a higher prevalence of positivity in each step and a higher ABCDE score. More specifically, AF patients are more vulnerable than patients in SR to coronary microvascular dysfunction and chronotropic incompetence during stress.TableFigure

Cardioembolic events and death predictors in patients with intraventricular thrombus

Abstract Background There is poor evidence about the optimal medical treatment and length of anticoagulation for the management of intraventricular thrombus (IVT). Current ESC guidelines recommend continuation of anticoagulation for up to 6 months. Purpose The objective of this study was to identify predictors of events during follow-up in patients with IVT in order to infer the best therapy in this clinical scenario. Methods All patients with IVT in our tertiary hospital between 2005 and 2021 were retrospectively analyzed. Patients were classified into 2 groups, according to whether they developed (group 1) or not (group 2) the combined event of death, myocardial infarction, stroke or embolism during the first 6 months. A multivariate logistic regression analysis was performed to identify independent risk factors of clinical events. Results 195 patients were included, of whom 40 (24.1%) presented the combined event at 6 months. There were no differences in age (68.5±15.6 vs 65±13.7 years; p=0.167) or gender distribution (80% men vs 84.9%; p=0.463) between the groups. A history of peripheral vascular disease (22% vs 7.1%; p=0.007), atrial fibrillation (AF) (22% vs 6.3%; p= 0.004) and stroke (34.2% vs 11.8%; p=0.001) were more frequent in group 1. The echocardiogram showed more frequently a mobile thrombus (43.2% vs 23%; p=0.017) with the presence of outgrowths (19.4% vs 5.6%; p=0.012) in the group with events. In addition, these patients had worse ventricular function (LVEF 33.6% vs 40.4%; p=0.002). Regarding treatment, the use of P2Y12 inhibitors was lower in group 1 (36.6% vs. 58.3%, p=0.016). There were no differences in the use of anticoagulants (85.4% vs 87.4%, p=0.737) or in the time until the thrombus clearance (median 119 vs 147 days, p=0.152). The presence of outgrowths in the thrombus, the ejection fraction, and a history of stroke were independently associated with the development of events at 6 months (Table). Considering a cut-off point of one-year follow-up instead, only 7 patients more had events. The presence of outgrowths was the only factor that maintained the independent association with the development of events (OR 9.3 (95%CI 1.6-54.7); p=0.01) during this time frame. Conclusions Cardiovascular events after IVT diagnosis are concentrated in the first 6 months. The presence of outgrowths attached to the thrombus, the lower ejection fraction, and a history of stroke were independent predictors of events at 6 months. In addition, the presence of outgrowths maintained its strong association at one year. Therefore, a more aggressive antithrombotic treatment may be considered in the presence of these factors.

Influence of birth weight on later life cardiovascular structure, function and disease: unpacking influences from direct genetic effects versus intrauterine programming

Abstract Aims The cardinal risk factors for cardiovascular disease in adulthood are well-recognised. In addition to these, observational studies have suggested that intrauterine and early developmental factors might play a role. However, observational associations are liable to influence by residual confounding and bias. Additionally, observational and genetic studies to date have not been able to isolate the fetal versus maternal influences. Purpose We aim to explore the causal relevance of birth weight on cardiovascular disease and cardiac structure and function using Mendelian randomization (MR), and specifically investigate the role of fetal genetic effects (reflecting the direct causal influence of birth weight) versus maternal genetic effects (reflecting the influence of the intrauterine environment). Methods Uncorrelated (r2&amp;lt;0.001), genome-wide significant (p&amp;lt;5x10-8) SNPs were extracted from genome-wide association study summary statistics for gestational age-adjusted birth weight overall, and after isolating the indirect maternal versus direct fetal genetic effects. Inverse-variance weighted Mendelian randomisation (MR) was utilised for primary analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 15 measures of cardiac structure and function indexed to body surface area. Multivariable MR was utilised to explore potential mediation of effects observed on cardiovascular outcomes by cardiometabolic risk factors. P-values were FDR-adjusted to account for multiple testing. Results Higher genetically-predicted birth weight was associated with higher risk of atrial fibrillation (OR 1.26 [1.15-1.39], p&amp;lt;0.001), but lower risk of coronary artery disease (OR 0/78 [0.71-0.86] p&amp;lt;0.001). These associations were driven predominantly by direct fetal genetic effects. For the association with atrial fibrillation, there was no evidence of mediation through body mass index or height. For the association with coronary artery disease, there was at least partial mediation through systolic blood pressure (Figure 1). Higher genetically-predicted birth weight was associated with a greater chamber volumes, but lower ejection fraction (Figure 2), driven by direct fetal genetic effects. Conclusion The results of this study suggest that lower birthweight is associated with higher risk of coronary artery disease, partly mediated by a higher systolic blood pressure. Conversely, a greater birth weight was associated with higher risk of atrial fibrillation, and this was not mediated by body mass index or height. Higher birth weight was also associated with greater chamber volumes and lower ejection fraction. The associations were in all cases predominantly driven by direct fetal effects, suggesting a causal relevance of birth weight itself, and not of the intrauterine environment, on later life cardiovascular disease.Figure 1Figure 2