Left Ventricular Remodeling Research Articles

Clinical profiles and shortterm outcomes of women with peripartum and dilated cardiomyopathies

Background: We aimed to compare the clinical and sociodemographic characteristics, rate of left ventricular reverse remodeling (LVRR), heart failure hospitalization and allcause mortality of women with peripartum and dilated cardiomyopathies (PPCM and DCM respectively) in Nigeria. Methods: This was a prospective longitudinal study and a total of 130 patients (65 for each group) were recruited consecutively and followed up for 6 months. Results: PPCM patients were younger, but the DCM patients had higher frequency of atrial fibrillation and complete left bundle branch block, higher mean left atrial and LV dimensions, higher LV filling pressures, and worse renal dysfunction, respectively, at baseline. At the end of the 6month followup, 15 female DCM vs 21 PPCM patients (p=0.684) had achieved LVRR, 13 DCM vs 11 PPCM patients (p=0.098) were hospitalized for heart failure, and 10 DCM vs 5 PPCM patients (p=0.098) had died. The odds for achieving LVRR was independently increased by systolic blood pressure (SBP) >100 mmHg and tricuspid annular plane systolic excursion >16 mm at baseline in PPCM patients, and by use of angiotensin converting enzyme inhibitors at baseline in female DCM patients. The odds for mortality were increased by tachycardia and pericardial effusion and reduced by the use of loop diuretics at baseline in DCM patients, and SBP <90 mmHg at baseline increased it by 9fold in PPCM patients. Conclusions: Our results suggest that women with DCM and PPCM differ significantly in their demographic and clinical characteristics, and predictors of clinical outcomes.

Protein Biomarkers of Adverse Clinical Features and Events in Sarcomeric Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition that can lead to atrial fibrillation, heart failure, and sudden cardiac death in many individuals but mild clinical impact in others. The mechanisms underlying this phenotypic heterogeneity are not well defined. The aim of this study was to use plasma proteomic profiling to help illuminate biomarkers that reflect or inform the heterogeneity observed in HCM. The Olink antibody-based proteomic platform was used to measure plasma proteins in patients with genotype positive (sarcomeric) HCM participating in the HCM Registry. We assessed associations between plasma protein levels with clinical features, cardiac magnetic resonance imaging metrics, and the development of atrial fibrillation. We measured 275 proteins in 701 patients with sarcomeric HCM. There were associations between late gadolinium enhancement with proteins reflecting neurohormonal activation (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and ACE2 [angiotensin-converting enzyme 2]). Metrics of left ventricular remodeling had novel associations with proteins involved in vascular development and homeostasis (vascular endothelial growth factor-D and TM [thrombomodulin]). Assessing clinical features, the European Society of Cardiology sudden cardiac death risk score was inversely associated with SCF (stem cell factor). Incident atrial fibrillation was associated with mediators of inflammation and fibrosis (MMP2 [matrix metalloproteinase 2] and SPON1 [spondin 1]). Proteomic profiling of sarcomeric HCM identified biomarkers associated with adverse imaging and clinical phenotypes. These circulating proteins are part of both established pathways, including neurohormonal activation and fibrosis, and less familiar pathways, including endothelial function and inflammatory proteins less well characterized in HCM. These findings highlight the value of plasma profiling to identify biomarkers of risk and to gain further insights into the pathophysiology of HCM.

Shock wave-pretreated ADMSCs of cell-sheet scaffold (CSS) patched on left ventricular wall (LVW) inhibited LVW remodeling in mini-pig MI ---role CSS on counteracting Laplace's Law of LVW stress: Experimental study.

We investigated whether shock wave (SW)-pretreated autologous adipocyte-derived mesenchymal stem cells (ADMSCs) seeded in the cell-sheet scaffold (CSS) could inhibit left ventricular (LV) remodeling and improve LV ejection fraction (LVEF) in old myocardial infarction (MI). Mini-pigs (n=20) were divided into group 1 (sham-operated control), group 2 (old MI), group 3 (old MI + autologous ADMSCs/1.0×107 in CSS on LV myocardium), and group 4 [old MI + SW (0.12mJ/mm2 for total 140 shots)-pretreated ADMSCs in CSS on LV myocardium]. Treatments started on day 28 after MI induction. In vivo and in vitro studies were conducted. Cell viability/relative mitochondria DNA expression/mitochondrial cytochrome C/adenosine triphosphate concentration in ADMCSs and protein expressions of angiogenesis factors (vascular endothelial growth factor [VEGF]/stromal cell-derived factor-1 [SDF-1])/mitochondrial respiratory chain complexes I-IV/oxygen consumption rate were higher in group 4 than in group 3 (P<0.001). By day 180, LVEF and small vessel numbers in the peri-infarct or infarct area were highest in group 1, lowest in group 2, and significantly lower in group 3 than in group 4. In contrast, the LV dimension was opposite to the pattern of change in LVEF in all groups (P<0.0001). The basal/middle/apical infarct and fibrotic areas were inversely related to LVEF in all groups (all P<0.0001). Protein levels of angiogenetic markers (SDF-1α/C-X-C chemokine receptor type 4/VEGF/angiopoietin-1) were significantly and persistently increased from groups 1 to 4. In contrast, protein levels of endothelial-cell markers (von Willebrand factor or endothelial nitric oxide synthase) showed an identical pattern to LVEF in all groups (all P<0.0001). SW pretreatment of ADMSCs seeded in CSS offered significant benefits in preserving LV performance and ameliorating LV remodeling in mini-pigs with old MI.

Circulating microRNA-409-5p and USP7 are associated with left ventricular remodeling in patients with acute myocardial infarction

BackgroundOur previous study demonstrated that microRNA-409-5p (miR-409-5p) and its target ubiquitin-specific protease 7 (USP7) were involved in hypoxia-induced cardiomyocyte injury and ischemic left ventricular remodeling (LVR) in rats. This study aimed to probe into the relationship between plasma miR-409-5p and USP7 levels and LVR and dysfunction in patients with acute myocardial infarction (AMI).MethodsSixty patients with acute myocardial infarction (AMI) and 60 cases with chronic coronary syndrome (CCS) were enrolled. The clinical characteristics, echocardiographic/serum parameters of LVR, and circulating miR-409-5p and USP7 mRNA levels between the two groups and between admission and 6 weeks after discharge were compared. The correlations between circulating miR-409-5p/USP7 levels and serum/echocardiographic parameters were analyzed.ResultsThe demographic characteristics of the AMI group and CCS group were comparable. Patients with AMI admitted to the study displayed significantly higher levels of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) and growth stimulation expressed gene 2 (ST2), along with a greater left ventricular end-systolic volume (LVESV). Conversely, their left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), and global radial strain (GRS) were significantly lower compared to patients with CCS. These changes were normalized 6 weeks after discharge. Circulating miR-409-5p levels at admission were significantly decreased while circulating USP7 mRNA expression levels were significantly increased in patients with AMI compared with those with CCS (both P < 0.01). However, these changes were restored 6 weeks after discharge (both P < 0.01). Moreover, circulating miR-409-5p and USP7 mRNA levels showed varying correlations with GLS, GRS, LVESV, LVEF, and NT-proBNP in patients with AMI but not in those with CCS. Additionally, circulating miR-409-5p and USP7 levels predicted the incidence of LVR and major adverse cardiovascular events (MACE) after AMI.ConclusionSerum miR-409-5p and USP7 may influence the occurrence and evolution of LVR and left ventricular dysfunction after AMI.

The Need for New Data on Left Ventricular Remodeling and the Crucial Role of Ejection Time for our daily clinical practice.

The Need for New Data on Left Ventricular Remodeling and the Crucial Role of Ejection Time for our daily clinical practice.

Sex-specific Associations between Left Ventricular Remodeling at MRI and Long-term Cardiovascular Risk.

Background Left ventricular mass (LVM) is an established marker of cardiovascular risk; however, long-term follow-up studies in individuals with low to intermediate risk are lacking. Purpose To assess the sex-specific association of LVM measured with cardiac MRI with cardiovascular outcomes in those with a less than 20% 10-year risk of cardiovascular disease (CVD). Materials and Methods A total of 1528 volunteers older than 40 years of age with no history of CVD, a 10-year risk of CVD of less than 20%, and a B-type natriuretic peptide level greater than their sex-specific median underwent cardiac MRI between June 2008 and February 2013 as part of the Tayside Screening for Cardiac Events, or TASCFORCE, prospective study. LVM was indexed to body surface area, and the LVM-to-volume ratio was calculated. Follow-up for cardiovascular events was performed using national electronic health records. Cox proportional hazard models and Kaplan-Meier curves were applied to assess the impact of LVM. Results A total of 1495 participants (mean age, 54.5 years ± 8.3 [SD]; 925 female, 570 male) completed cardiac MRI, with a median follow-up of 10 years (IQR, 3 years). In female participants, LVM was associated with age, blood pressure, smoking status, and cholesterol level, while in male participants, LVM was associated with age and blood pressure. In female participants, the LVM-to-volume ratio was associated with cardiovascular events (hazard ratio [HR], 2.3 [95% CI: 1.1, 4.9] for the highest quartile vs the lowest quartile), while the LVM was not. In male participants, the LVM was associated with cardiovascular events (HR, 3.2 [95% CI: 1.5,7.0] for the highest quartile vs the lowest quartile), while the LVM-to-volume ratio was not. Conclusion In those with low to intermediate risk without established CVD, different remodeling patterns predict cardiovascular events, with increased LVM predictive in male participants, while LVM-to-volume ratio is predictive in female participants. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Garot and Duhamel in this issue.

Cardiac remodeling in rheumatoid arthritis: assessing the influence of anti-CCP and rheumatoid factor

Abstract Background Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF), markers of Rheumatoid Arthritis (RA) activity, are associated with adverse cardiovascular outcomes, suggesting a potential link between RA and cardiac remodeling. Purpose Our study aimed to explore the correlation between antibody levels (anti-CCP and RF) and left ventricular (LV) remodeling in RA patients without known heart disease. Additionally, it sought to identify other disease-related factors that correlate with LV remodeling. Methods A cross-sectional study of 124 RA patients aged ≥ 18 years, classified per the 2010 ACR/EULAR criteria, collected blood samples for CRP, and antibody levels (RF ≥ 20 IU/ml and anti-CCP ≥ 5 IU/ml via ELISA). Transthoracic echocardiography (TTE) was conducted using a linear method in a long-axis parasternal 2D window. Sixty-two patients exhibited LV remodeling and were matched with 62 patients without it. Echocardiographic variables included were those to calculate the relative wall thickness (RWT, cut-off value 0.42) and left ventricular mass index (LVMI, cut-off values of 43-95 g/m2 in women and 49-115 g/m2 in men) along with left ventricular end diastolic (LVIDd), and systolic volumes (LVIDs), and left ventricular ejection fraction (LVEF). Statistical analyses employed the Chi-square test, Student's t-test, or Mann-Whitney U test as applicable, with correlations assessed using Spearman's rho, an analysis was conducted on the area under the curve (AUC) and a significance level of p ≤ 0.05. Results The most common type of LV alteration in our study was concentric remodeling (74.2%). A statistically significant difference was observed in the levels of Anti-CCP titers 193.85 IU/ml (p &amp;lt; .001), RF IgM 200.00 IU/ml (p &amp;lt; .001) and IgA 185.5 IU/ml (p &amp;lt; .001) in patients with LV remodeling. Anti-CCP and RF IgA antibody levels exhibited a moderate correlation with the presence of LV remodeling, with rho 0.387 (p &amp;lt; .001) and rho 0.344 (p &amp;lt; .001), respectively. The RWT showed a moderate correlation with anti-CCP titers with rho 0.298 (p .001). AUC analysis anti-CCP titers demonstrated better diagnostic performance for the existence of cardiac remodeling (0.722, 95% CI 0.628-0.816, p &amp;lt; .001), RF IgA (0.696, 95% CI 0.602-790, p &amp;lt; .001) and IgM (0.650, 95% CI 0.563-755, p .002). Conclusion In summary, among RA patients without heart failure (HF), LV remodeling and elevated RWT correlate with antibody levels independently of traditional cardiovascular risk factors. Patients with altered LV geometry exhibit higher antibody titers, highlighting the need for RA-related biomarkers that correlate with changes in LV structure and function Recognizing association between autoimmunity and HF development holds significant implications for both prevention and treatment strategies in RA patients.

Mitral regurgitation improvement following left bundle branch pacing versus right ventricular septum pacing: a dedication to postoperative amelioration of mitral regurgitation

Abstract Background Mitral regurgitation (MR) is correlated with left ventricular (LV) remodeling and LV function in patients. Left bundle branch pacing (LBBP) exhibits a significant decline in MR in left bundle branch block (LBBB) and cardiomyopathy patients. This research aims to evaluate the influence of LBBP on MR in comparison to right ventricular septal pacing (RVSP) in patients with atrioventricular block (AVB) or sick sinus syndrome (SSS). Methods Sixty consecutive patients with SSS or AVB were enrolled if they underwent pacemaker implantation via LBBP or RVSP. Patients with a history of mitral valve surgery were excluded. Echocardiogram parameters were assessed to measure MR and LV remodeling as well as LV function at baseline and follow-up. Results Thirty-six patients (60 %; mean age: 70.39 ± 14.80 years; 61.1 % male) underwent successful LBBP, and 24 patients (40 %; mean age: 71.58 ± 10.91 years; 66.7 % male) underwent RVSP. The average follow-up duration was relatively comparable between the two groups. In comparison to RVSP, LBBP demonstrated significant changes in MR area, and severity at baseline and follow-up (P&amp;lt;0.05). LBBP independently predicted MR amelioration in patients who underwent pacemaker implantation (HR=0.289, CI=0.087–0.9961; P=0.043). At follow-up, the LBBP subgroup with moderate/severe MR exhibited significantly shorter lead-TVA-dist, higher left atrium (LA) diameters, and mitral E/A ratio (P&amp;lt;0.05) compared to the none/mild MR subgroup. In LBBP with MR amelioration, LV remodeling (ΔLVEDD) was significantly enhanced compared to baseline (P=0.016). Additionally, a non-significant trend toward better improvement in LV function (ΔLVEF and ΔE/A) was observed in patients with MR amelioration. Conclusion LBBP, considered an optimal pacing technique for SSS or AVB patients, may substantially reduce MR and subsequently enhance LV remodeling and function compared to RVSP. This open, observational pilot study warrants confirmation through further investigations.Comparison between LBBP and RVSPKaplan-Meier curves for MR amelioration

Trimethylamine N-oxide as a Novel Biomarker for Left Ventricular Diastolic Dysfunction and Functional Remodeling in ST-Elevation Myocardial Infarction Patients

Abstract Background Over the last three decades, the mortality from ST-elevation myocardial infarction (STEMI) has halved. However, the incidence of heart failure or persistent angina remains high after STEMI, and the post-STEMI left ventricular (LV) systolic and diastolic function remains unpredictable. Thus, there is an unmet need to identify patients at risk of LV diastolic dysfunction or adverse remodeling. Purpose This study aims to investigate the potential of Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite associated with heart failure, and atherosclerosis, as a biomarker for adverse LV remodeling and diastolic dysfunction following STEMI. Methods In this prospective, observational cohort study, 210 STEMI patients with multivessel coronary artery disease (CAD) were enrolled after primary PCI. At 3 months follow-up, all patients underwent complete revascularization with FFR-guided PCI. Plasma TMAO, C-reactive protein (CRP), and brain natriuretic peptide (BNP) levels at 3 months follow-up and peak troponin level at primary PCI were collected. Echocardiographies were performed within 24 hours of STEMI and at 12-month follow-ups. Diastolic dysfunction was defined according to the ASE 2016 guidelines.(1) Functional LV remodeling (FLVR) was categorized into 4 categories according to Chimed et al.(2) Receiver operating characteristic (ROC) curve analysis, including the Delong test and Youden index, was performed to compare the biomarkers' diagnostic value and determine the optimal cutoffs for predicting diastolic dysfunction and FLVR, respectively. Results Of the 210 patients enrolled, 85 (40.48%) were female, with a median age of 65 years [interquartile range (IQR): 58.00, 76.00] and a median body mass index (BMI) of 27.39 kg/m² (IQR: [24.56, 30.69]). The area under the ROC curve for predicting post-PCI LV diastolic dysfunction ≥ grade II was 0.72 (95% CI 0.63–0.81; p&amp;lt;0.001) for TMAO (Figure 1). The optimal TMAO cutoff value of 3.80 yielded a sensitivity of 0.75 (95% CI 0.63–0.86) and a specificity of 0.82 (95% CI 0.76–0.88). For FLVR grade 3 or 4, the area under the ROC curve was 0.62 (95% CI 0.50–0.74) and 0.72 (95% CI 0.62 -0.83) for TMAO and BNP, respectively (Figure 2), but the AUC was not significantly different (p= 0.191). In multivariable logistic regression analysis, TMAO was independently associated with FLVR grade 3 or 4 (OR 1.18, 95% CI 1.00-1.38, p = 0.046) and diastolic dysfunction ≥grade 2 (OR 1.30, 95% CI 1.12-1.50, p &amp;lt; 0.001). Conclusion The novel parameter of TMAO is a useful predictor for LV diastolic dysfunction after STEMI. TMAO is independently associated with an increased risk of LV diastolic dysfunction and worse FLVR. These results suggest that monitoring plasma TMAO levels could be an effective and cost-efficient strategy for monitoring patients with an elevated risk of LV diastolic dysfunction or adverse LV remodeling.Figure 1Figure 2

Left atrial and left ventricular positive and negative remodeling after catheter ablation of atrial fibrillation

Abstract Introduction Atrial fibrillation (AF) is associated with negative remodeling of left atrium (LA) and in later stages of diseases with negative remodeling of left ventricle (LV). Can radiofrequency ablation (RFA) of pulmonary veins cure AF and retain progression of arrhythmia? Purpose This study evaluated positive and negative remodeling of LA and LV after RFA of pulmonary veins and a 7-year follow-up. The patients were divided into 4 groups on the basis of Pulmonary Vein Isolation Outcome Degree (PVIOD 1-4), a new measure for the efficacy of catheter ablation of AF. Methods One hundred seventeen patients with symptomatic drug-refractory paroxysmal and persistent AF were treated with RFA. At baseline and after a 7 years of follow-up, 2-dimensional echocardiography was performed to assess LA diameter, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and left ventricular ejection fraction (LVEF). Results After a 7-year follow-up 32.5% patients with successful single RFA of AF (PVIOD 1) showed significant positive LA and LV remodeling: LA diameter 39.3±0.6 vs 36.5±0.6 mm, p=0.0007; LVEDD 53.1±0.6 vs 50.9±0.7 mm, p=0.008; LVESD 34.7±0.8 vs 32.0±0.1 mm, p=0.005 and LVEF 56.8±0.8 vs 62.1±1.1 %, p=0.000008. In 29.1% of patients with success after multiple procedures (PVIOD 2) occurred significant reverse LA remodeling: LA diameter 41.9±0.7 vs 40.2±0.6 mm, p=0.04. Clinical success (PVIOD 3) after RFA was defined as a significant reduction in the number and duration of AF episodes with or without previously ineffective antiarrhythmic drugs (AAD) class I and III. In 14.5% of subjects with long-term clinical success (PVIOD 3 and baseline LA diameter 43.2±1.0 mm) remodeling of LA and LV was not occurred. In 23.9% of patients with procedural and clinical failure after RFA (PVIOD 4) long-term follow-up showed significant negative remodeling of LA and LV: LA diameter 44.7±0.7 vs 47.4±0.7 mm, p=0.006; LVEDD 52.8±0.9 vs 57.1±0.6 mm, p=0.0006; LVESD 36.5±1.1 vs 40.7±1.2 mm, p=0.006 and LVEF 50.7±1.7 vs 43.8±1.8 %, p=0.004. Conclusions Single successful RFA of pulmonary veins in early stage of AF with normal LA diameter cure arrhythmia, which was proved with LA and LV positive remodeling after a 7-year follow-up. With increase of LA diameter, the success of RFA decrease. The multiple procedures slow the progression of AF, but are less effective because of long periods of time between them. Clinical success and role of AAD therapy are also important in AF management. If AF is not treated with RFA properly on time it becomes progressive disease.

Angiotensin-II receptor type 1 and endothelin-1 receptor type A agonistic autoantibodies in patients with STEMI: new kids on the block

Abstract Background The Prognosis after ST-elevation myocardial infarction (STEMI) remains poor. Angiotensin-II and endothelin-1 contribute to adverse prognosis after STEMI through molecular mechanisms that lead to myocardial inflammation, fibrosis and, ultimately, adverse myocardial remodeling. Functional autoantibodies against angiotensin II type 1 (AT1R-AAs) and endothelin-1 type A (ETAR-AAs) receptors bind to the same receptors as natural ligands, eliciting similar (and amplified) responses. In patients with STEMI, AT1R-AAs and ETAR-AAs have been associated with a higher risk of developing microvascular obstruction and left ventricular remodeling. Both microvascular obstruction and left ventricular remodeling are associated with a poor prognosis. Purpose To assess the prognostic role of AT1R-AAs and ETAR-AAs after STEMI. Methods Consecutive STEMI patients who underwent primary percutaneous coronary intervention within 12 h after pain onset were enrolled in this prospective study. The levels of AT1R-AAs and ETAR ETAR-AAs at the time of hospital admission were measured using an enzyme-linked immunosorbent assay (ELISA) in all patients. The incidence of major adverse cardiovascular events (MACE, defined as a composite of cardiovascular mortality, myocardial re-infarction, and hospitalizations for heart failure) during follow-up was the primary outcome. Autoantibody seropositivity was defined according to ELISA’s kit manufacturer’s instructions (levels &amp;gt; 10 U/mL). Results Two hundred patients with STEMI were enrolled. The baseline characteristics of the patients are shown in Table 1. Of these, 110 (55%) were seronegative for both autoantibodies, 44 (22%) were seropositive for one autoantibody (but not both), and 46 (23%) were seropositive for both autoantibodies. The incidence of MACE over a 14-month median follow-up was higher in patients with double (31%) and single (25%) seropositivity than in seronegative patients (13%, p=0.009 and p=0.06, respectively). Survival free from MACE was significantly different across the different degrees of autoantibody seropositivity (Figure 1). In the multivariable Cox regression analysis, adjusted for the variables that were significant in the univariate analysis (highlighted in bold in Table 1), double seropositivity was independently associated with an increased risk of MACE (hazard ratio 2.386, 95 % CI 1.471-3.864, p&amp;lt;0.001). Conclusions The degree of seropositivity for AT1R-AAs and ETAR-AAs is associated with an increased risk of MACE after STEMI. Our findings provide valuable mechanistic insights into the pathophysiology of STEMI and pave the way for future therapies focused on the improvement of long-term prognosis after acute coronary syndromes.

Relationships between 18-month kinetics and functional capacity and left ventricular remodeling and cardiac fibrosis in dilated cardiomyopathy

Abstract Introduction Myocardial fibrosis is a primary pathogenetic process in dilated cardiomyopathy (DCM) that is responsible for progressive cardiac remodeling and functional capacity impairment. We sought to verify whether there were differences between 18-month kinetics of functional capacity and left ventricular remodeling in DCM patients with different types and advancement of fibrosis who were up-titrated with guideline directed pharmacotherapy (GDMT). Methods Between May 2019 and September 2020, 99 DCM patients (88 male, mean age 45.2 ± 11.8 years, mean EF 29.7 ± 10%) underwent cardiac magnetic resonance with assessment of replacement fibrosis via late gadolinium enhancement (LGE) and interstitial fibrosis via extracellular volume (ECV). Each patient had serial (baseline, 6-, 12-, 18 month) functional assessment: NYHA class and 6- minute walking test (6-MWT) and follow-up echocardiography, including measurement of left ventricular end-diastolic volume (LVEDvol) and ejection fraction (EF). Patients were divided into LGE-negative and LGE-positive groups, whereas based on median ECV – they were divided into those with ECV below and above median values. Results Overall, LGE was identified in 44 (44%) of patients, whereas median ECV was 27.7%. NYHA class was significantly worse in patients with LGE (1.5±0.5 vs. 1.9±0.6) and with higher ECV (1.93±0.6 vs. 1.6±0.5) in comparison to those without LGE and lower ECV. However, NYHA class improved during observational period in all groups. There were no differences in 6-MWT distance in LGE positive and negative groups at all time points. Baseline 6-MWT distance in LGE positive group was 494.2±88.2 vs. 453.9±98.8 meters in LGE negative group. Baseline 6-MWT distance in upper median ECV group was (408.8±103.5 vs. 492.4±92.9 meter) was significantly lower ECV group (p=0.03). During 18 months 6-MWT distance increased only in LGE negative group but in both ECV groups (Figure 1 A-D). There were no differences in EF between patients with and without LGE and also with higher and lower ECV. Baseline EF in LGE positive group was 27.4±11.2% and 31.7±10.6% in LGE negative. Baseline indexed LVEDvol in LGE positive group was 107.7±40.7 vs. 91.8±37.8 ml/m2 (p=0.09) in LGE negative group. EF increased significantly in both groups, whereas indexed LVEDvol decreased only in LGE negative group (Figure 2 A-D). Conclusions Regardless of the presence of replacement and to some extent of interstitial fibrosis, functional and cardiac morphological improvement was observed during 18 months observation in DCM patients on GDMT. The greatest improvement occurred during the first 3 (occasionally 6) months which was associated with the greatest escalation of GDMT. Further dose escalation was not associated with a significant improvement in both functional and morphological parameters.

Sex-related differences in left ventricular geometry patterns in patients with arterial hypertension

Abstract Background Sex-specific differences in left ventricular (LV) geometry is key for tailoring management strategies for arterial hypertension. Purpose To evaluate sex-related differences in LV geometry patterns at baseline and their evolution over time in hypertension. Methods From a prospective registry, we included hypertensive patients with at least 1 year follow-up, without prevalent cardiovascular disease or incident myocardial infarction, with normal LV ejection fraction and no chronic kidney disease of stage III or more. Four LV geometry patterns were assessed: normal geometry, concentric remodeling, eccentric and concentric LV hypertrophy (LVH). Results A total of 6427 patients (age 53±11 years, 43% females) were included. At baseline, a normal geometric pattern was less common in female than in male patients (50% vs. 72%, p&amp;lt;0.001). LVH was more prevalent among female than male patients (47% vs. 23%, p&amp;lt;0.001), with a higher prevalence of eccentric LVH (40% vs. 18%, p&amp;lt;0.001). Female sex was independently associated with LV remodeling (odds ratio, 2.36, 95% confidence intervals, 2.12-2.62, p&amp;lt;0.001). At long-term follow-up (mean 6.1 years, IQR 2.8-8.6 years), the proportion of patients with LV remodeling increased in both sexes, although a normal LV geometry remained less frequent in female than male patients (43% vs. 67%, p&amp;lt;0.001), with differences persisting in eccentric (41% vs. 21%, p&amp;lt;0.001) and concentric LVH (11% vs. 5%, p&amp;lt;0.001). Conclusions We found relevant sex-related differences in LV geometry among patients with hypertension. Females have a higher risk of LV remodeling at baseline compared with men, with differences persisting at long-term follow-up.

Left ventricular dilatation in patients with significant aortic regurgitation: association with mortality

Abstract Background In aortic regurgitation (AR), left ventricular (LV) dilatation occurs as a response to volume and pressure overload. Current guidelines recommend the use of LV end-systolic diameter index (LVESDi) to give indication for intervention, but recent studies suggested that volumetric measures may be more accurate in identifying LV remodeling in AR as compared to linear dimensions. Purpose To characterize LV dilatation in patients with significant AR (≥moderate), based on linear and volumetric dimensions, and to determine their prognostic value. Methods A total of 1070 patients (56 ± 18 years,65% male) were included. Cut-off values of 20 mm/m2 for LVESDi and 45 ml/m2 for end-systolic volume index (LVESVi) were used to identify the following LV remodeling patterns: No-significant LV dilatation (N=485), when both LVESDi and LVESVi were below the cut-off values; Discordant LV dilatation (N=279) if only one positive criterion was present; and Concordant LV dilatation (N=306) when both LVESDi and LVESVi were enlarged (Figure 1). The primary endpoint was all-cause mortality. Results Baseline characteristics differed across the 3 LV dilatation groups. Compared to patients with no-significant or discordant LV dilatation, those with concordant LV dilatation were more likely to be men, had a lower prevalence of systemic arterial hypertension and were more symptomatic. Concerning the echocardiographic characteristics, patients with concordant LV dilatation showed more severe AR, worse LV systolic function and larger left atrial volumes compared to the other two LV dilatation groups. During a median follow-up of 89 (IQR,54-132) months, 168 (16%) patients died and 484 (45%) underwent aortic valve surgery (AVS). Patients with concordant LV dilatation had worse 10-year survival (72%) compared to the groups (Figure 2), but benefited more from AVS based on a landmark analysis (p=0.001). In multivariable analysis, a significant association with the risk of all-cause mortality was observed for the presence of discordant (HR 1.645, 95%CI 1.077-2.513;p=0.021) or concordant LV dilatation (HR 2.695, 95% CI 1.710 to 4.249;p&amp;lt;0.001) after adjusting for the variables significant in the univariate analysis such as, age, male gender, NYHA class III-IV, AVS as a time-dependent covariate and LV ejection fraction (LVEF) ≤55%. Moreover, the addition of LV dilatation groups to a basal model including the above mentioned clinical and echocardiographic variables led to a significant increase in the predictivity of the model (Chi-square difference=21.1,p&amp;lt;0.001). Conclusion In patients with significant AR, LV dilatation detected by linear and/or volumetric measures was independently associated with increased mortality. Combining both methods for assessment of LV remodeling may improve risk stratification of these patients.

Diagnostic and prognostic value of ECG-predicted hypertension mediated left ventricular hypertrophy using machine learning

Abstract Background Hypertension is the commonest cause of left ventricular hypertrophy (LVH). Using cardiac magnetic resonance (CMR) imaging, four distinct hypertension mediated LVH phenotypes have been reported: normal LV, LV remodelling, eccentric LVH and concentric LVH. Early detection of hypertensives with LVH can enable timely initiation of therapy however a CMR based screening strategy is costly, particularly in low resource settings. The electrocardiogram (ECG) is an inexpensive screening tool and can detect LVH but its capacity to discriminate between the 4 phenotypes is unknown. Purpose To classify hypertension mediated LVH phenotypes from the ECG using machine learning (ML) and test for associations of ECG predicted LVH phenotypes with incident cardiovascular outcomes. Methods ECG markers with a known physiological association with LVH (including QRS markers, Sokolow-Lyon, and Cornell) were extracted from the 12-lead ECG of 20,439 hypertensive participants in UK Biobank. Three classification models, logistic regression, support vector machine (SVM) and random forest, were trained in 80% of the participants using extracted ECG markers and clinical variables. The remaining 20% individuals were included in the test set for performance measurement. External validation was sought in 877 hypertensives from the Study of Health in Pomerania (SHIP). Subsequently, we tested for associations between the four ECG-predicted LVH phenotypes and incident major adverse cardiovascular events (MACE) and heart failure using Cox proportional hazard regression in the UK Biobank test set with median follow-up of 4.2 years. Results Among UK Biobank participants (mean age ± standard deviation 65 ± 7.4 years), 23,190 had normal LV, 894 LV remodelling, 218 eccentric and 103 concentric LVH. Classification performance of the three models was comparable, but SVM showed consistent results (accuracy 0.79, sensitivity 0.59, specificity 0.87, AUC 0.69) and superior prediction of eccentric LVH (AUC 0.86). In SHIP (55 ± 12.7 years), 704 had normal LV, 134 LV remodelling, 12 eccentric and 24 concentric LVH. In the external validation performed in SHIP, SVM had accuracy of 0.75 (sensitivity 0.51, specificity 0.85, AUC 0.65), with superior prediction of eccentric LVH (AUC 0.76), as shown in Figure 1. Ventricular rate and QRS amplitude (P&amp;lt;0.001) were the features most strongly associated with LVH. In the test set of UK Biobank, setting normal LV as the reference group, the ECG predicted eccentric LVH group was associated with heart failure (Hazard Ratio 3.42, confidence interval 1.06-9.86), there were no associations with MACE (Figure 2). Conclusions ECG-based ML classifiers were able to discriminate the four hypertension mediated LVH phenotypes with external validation demonstrating robustness. This automated approach enhances capabilities of non-specialists and potentially represents an accessible screening strategy for the early detection of hypertensives with LVH.

Early increase and subsequent decrease in mature BNP and early decrease and continued decrease in proBNP after sacubitril/valsartan may relate to left ventricular reverse remodeling in heart failure

Abstract Background Current BNP assays measure not only mature BNP (BNP1-32) but also precursor proBNP. Previous studies have shown that the change in BNP after sacubitril/valsartan (Sac/Val) treatment is not consistent. The reason for this may be due to the fact that the immunoreactivity of BNP consists of mature BNP and proBNP and neprilysin degrades only mature BNP but not proBNP. Purpose This study assessed changes in mature BNP, proBNP, total BNP (= mature BNP + proBNP) before and 2 and 12 weeks after administration of Sac/Val in heart failure (HF). Methods We measured mature BNP, proBNP, and total BNP levels by our developed immunoassay, NT-proBNP and ANP by conventional assay and left ventricular (LV) remodeling indices by echocargdioraphy in 34 HF patients before, 2, and 12 weeks (wk) after Sac/Val treatment. 34 HF patients were divided into two groups. Group D (n=20) was defined as the group whose mature BNP at 12wk was lower than the baseline. Whereas Group I (n=14) was defined as the group whose mature BNP at 12wk was higher than the baseline. Results In all patients, total BNP did not change after 2wk or 12wk compared to baseline. ProBNP decreased after 2wk and tended to decrease after 12wk (p=0.07). Whereas there was no change inmature BNP after 2wk or 12wk (Table 1). In group D, total BNP did not change at 2wk, but decreased after 12wk. Mature BNP did not change at 2wk, but decreased after 12wk. ProBNP decreased at 2wk and further decreased at 12wk. In contrast, in group I total BNP did not change at 2wk, but increased at 12wk. ProBNP did not change after 2wk or 12wk compared to baseline. Mature BNP increased after 2wk and further increased after 12wk. Thus, a decrease in both proBNP and mature BNP contributed to the decrease in total BNP in group D, while the increase in total BNP in group I was mainly due to the increase in mature BNP. Correlation coefficient and p value between total BNP, proBNP, mature BNP, NT-proBNP and ANP at baseline, 2wk and 12wk are shown in Table 2. A close correlation was observed between BNP molecular forms. NT-proBNP decreased and ANP increased after Sac/Val administration; however, there was a modest correlation between the two peptides. There were no significant differences in LV ejection fraction (LVEF: %), end-diastolic volume index (LVEDVI: ml/m²) or end-systolic volume index (LVESVI: ml/m²) between two groups at baseline or at 12 wk; however, the delta (at 12 wk – pretreatment) LVEDVI, and LVESVI significantly improved in group D compared with group I (-9.3±11.3 vs. 3.7±10.1, p&amp;lt;0.01; -8.2±13.5 vs. 2.7±8.9, p&amp;lt;0.01, respectively). Conclusion These results suggest that total BNP appears to be unchanged after Sac/Val administration, but its components, proBNP and mature BNP, are altered; reverse cardiac remodeling may relate to decrease of mature BNP and proBNP; and the closely correlated natriuretic peptide molecules, regardless of the degradation by neprilysin, may be regulated in the same direction.

A newly developed small-molecule ErbB4 agonist reduces reactive cardiac fibrosis and adverse ventricular remodelling after myocardial infarction in a sex-specific manner

Abstract Background The beneficial effects of the neuregulin/ErbB pathway on the diseased heart have been well-established. The anti-fibrotic and cardioprotective aspects of neuregulin are largely attributable to the activation of the ErbB4 receptor. We recently developed a small-molecule selective ErbB4 agonist, which reduced collagen production in cultured fibroblasts and prevented oxidative-stress induced cardiomyocyte death in vitro. Purpose In order to evaluate the in vivo effects of this small-molecule ErbB4 agonist (referred to as compound, Cpd), we assessed its effect on left ventricular remodelling, cardiac fibrosis and cardiac function in a murine model of myocardial infarction (MI). Since there is a potential interaction between ErbB4 and the oestrogen receptor, we also aimed to evaluate whether these effects were sex-dependent. We hypothesised that Cpd would attenuate left ventricular remodelling, reduce cardiac fibrosis and help retain cardiac function in a sex-specific manner. Methods Mice were divided by sex and then further divided into three experimental groups: a sham group, an MI group receiving Cpd (MI/Cpd), and a control MI group receiving vehicle only (MI/Veh). MI was induced by ligating the left descending coronary artery. Seven days after MI, mice started treatment with either Cpd (2mg/kg/d) or its vehicle through subcutaneous osmotic minipumps. Cardiac ultrasound was performed weekly until mice were sacrificed after four weeks of treatment. Hearts were excised and stained with Masson’s trichrome to assess reactive cardiac fibrosis in the myocardium of the left ventricle, located remote from the infarction scar. A WGA-isolectinB4-DAPI immunofluorescent stain was performed to assess cardiomyocyte cross-sectional area in order to evaluate cardiomyocyte hypertrophy. Results In females (n=25), Cpd significantly decreased left ventricular end-diastolic volume compared to vehicle (LVEDV, Fig.1A, 80±23 µl vs.108±29 µl, p=0.045) and induced a slightly increased left ventricular ejection fraction (LVEF, Fig.1B, 32±12% vs. 22±9%, p=0.086). In addition, Cpd significantly reduced reactive interstitial fibrosis myocardium (Fig.1C, fibrotic area, 1.4±1.0% vs. vehicle: 3.8±3.1%, p=0.0363). In males (n=30), Cpd had no significant effects on either of the parameters mentioned above, (Fig.1E-G). There was no significant treatment effect in either group on cardiomyocyte cross sectional area (Fig.1D, Fig.1H). Conclusion Treatment with the novel small-molecule ErbB4 agonist attenuates left ventricular dilation and reactive interstitial fibrosis after MI in female mice, but not in males. These data support the premise that small molecule-induced ErbB4 activation is a potential new therapy for heart failure, especially in female patients. The mechanisms underlying the sex-dependent effects warrant further exploration.Figure 1

Prevalence, mechanisms and prognostic impact of dynamic mitral regurgitation unmasked by handgrip exercise in patients with hypokinetic non-dilated and dilated cardiomyopathy

Abstract Background Recent studies suggest that mitral regurgitation (MR) is a dynamic condition influenced by global and regional left ventricular (LV) remodeling as well as mitral valvular deformation. Exercise testing plays a substantial role in assessing the hemodynamic relevance of MR and is recommended by current guidelines. Handgrip exercise may serve as alternative exercise intervention to bicycle exercise, as it is easy to perform even bedside. However, there are no data yet, on the prevalence, mechanisms and prognostic impact of dynamic MR in patients with dilated cardiomyopathy using isometric exercise testing. Aims We aimed to assess the prevalence, hemodynamic consequences, and prognostic impact of exercise-induced changes in MR in patients with hypokinetic non-dilated and dilated cardiomyopathy. Methods Patients with hypokinetic non-dilated and dilated cardiomyopathy and at least mild MR who underwent handgrip echocardiography at the University Hospital Duesseldorf between January 2018 and September 2021 were enrolled.Patients were followed-up for one year to assess clinical outcomes. We assessed all-cause mortality, HF-associated hospitalizations, MV surgery, transcatheter edge-to-edge repair (TEER), left ventricular assist device implantation and heart transplantation during follow-up. Results Fifty-eight patients were included (mean age 70±15 years; 41% female; mean LVEF 37±10%). At rest, 28 patients (48%) presented with mild MR, and 30 patients (52%) had moderate MR. Fifteen patients (26%) with non-severe MR at rest, developed dynamic severe MR during handgrip exercise. Patients with dynamic severe MR had advanced MR at rest, larger left atrial dimensions, and increased mitral annulus diameter (all p&amp;lt;0.01). During exercise, LVEDVi, LVESVi and parameters of local left ventricular remodeling (tenting height, tenting area) were increased in patients with dynamic severe MR compared to those with non-severe MR (all p&amp;lt;0.05). During one-year follow-up, there was no difference regarding all-cause mortality and HF hospitalizations in patients with dynamic severe MR and non-severe MR (Log-rank test Chi2 0.262; p=0.609)(Figure 1). However, patients with dynamic severe MR more often underwent mitral valve surgery/intervention than patients with non-severe MR (Log-rank test Chi2 29.41; p&amp;lt;0.001)(Figure 1). Conclusion Our results demonstrate that the evaluation of non-ischemic MR only at rest underestimates the full severity of the lesion. Handgrip exercise unmasks severe MR in every fourth patient with non-severe MR at rest. These data may have implications for therapeutic decision-making in symptomatic patients with hypokinetic non-dilated and dilated cardiomyopathy and non-severe MR at rest. TEER might present an effective treatment option to improve clinical outcomes in patients with non-ischemic cardiomyopathy and non-severe MR at rest but dynamic severe MR during exercise.Figure 1

Cocoa flavanols alleviate early diastolic dysfunction by decreasing left atrial volume in healthy elderly individuals

Abstract Background Enlargement of the left atrium (LA) predicts future cardiovascular events. Current guidelines recommend cocoa flavanol (CF) intake as it provides cardiovascular and metabolic benefits, although underlying mechanisms are not fully revealed. In this study, we hypothesized that CF intake reverses LA enlargement as a surrogate marker for diastolic dysfunction in elderly individuals without cardiovascular diseases. Methods and Results In a randomized, double-blinded trial, we investigated the effects of CF on systolic and diastolic heart function in healthy elderly individuals. Precise assessment of left-atrial and left-ventricular volume as well as strain rates, all together as emblems of early subclinical cardiac impairment, and markers of systolic function were measured by high-resolution cardiac magnetic resonance (CMR) imaging before and after CF intake. Sixty-three participants (59% male) aged ≥ 55 years received either 500 mg CF (n=30) or a placebo (n=33) twice daily for 30 days. CF counteracted subclinical cardiac dysfunction, evidenced by a reduction in maximal LA volume and LA volume index by 12.6±3.5% (p=0.0063 and p=0.0067) and LV end-diastolic volume (LVEDV) and LVEDV index by ~4.9±1.9% (p=0.049 and p=0.0413). CF intake did not influence strain, strain rate, and systolic function parameters, while the systolic blood pressure decreased by 7 mmHg [~4.7±1.9% (p=0.04)]. Conclusion We provide evidence that CF intake mitigates early changes of diastolic dysfunction and improves cardiovascular health by reversing left atrial and left ventricular remodeling. Cocoa flavanol consumption may prevent age-related cardiac changes in healthy elderly individuals and promote a health span free from cardiovascular diseases.

Percutaneous revascularization in late-presenting STEMI with absence of viability: effects on left ventricular remodeling and scar

Abstract Introduction In patients with ST-elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) should be conducted within 12 hours of symptom onset. The potential benefits attributable to late reperfusion in STEMI fall under the "open artery hypothesis" where the stunned peri-infarction zone after revascularization would restore blood supply and contractility. Purpose To estimate the differences on the LV ejection fraction (LVEF), indexed LV end-systolic volume (iLVESV) and scar in patients with STEMI without viabilitity randomized to optimal medical therapy (OMT) alone or OMT and a late percutaneous coronary intervention (PCI) performed between 24 hours and 30 days after the event. Methods Patients with non-reperfused STEMI were evaluated from September 2021 to June 2022 at a tertiary cardiology hospital. The patients underwent Cardiac Magnetic Resonance (CMR) to assess myocardial viability and were classified as non-viable if they had only 1 wall segment with less than fifty percent thickness of the affected wall with late gadolinium enhancement. The patients were randomized to PCI or OMT alone. CMR was repeated at 6 months to evaluate LVEF, iLVESV and fibrosis. This summary presents a planned partial analysis of the 6-month results (N=51). Descriptive statistics analysis included central and dispersion estimators, or absolute and relative frequencies. To explore the differences between groups and time, Mann-Whitney and Wilcoxon tests were run, and results were given as point-estimates and confidence intervals at 95% (95% CI). A significance level of 5% was adopted for inferential analysis. Results 51 patients (60±11 years, 71% male) were included in the analysis. Of this total, 24 were randomized to PCI + OMT, and 27 to isolated OMT. The groups showed balanced distribution regarding clinical characteristics and initial CMR parameters (LVEF, iLVESV, and fibrosis). The difference in LVEF at the end of 6 months between the OMT and PCI groups was 2.07%, favoring the OMT group; however, this difference was not significant (p= 0.677, 95% CI: -5 to 10). Between the groups, the difference at the end of 6 months in iLVESV was -6.82 ml/m², also without statistical significance (p= 0.858, 95% CI: -19 to 11). There was a significant reduction in the amount of fibrosis in both PCI group with -14.68g (p= 0.011) and in the OMT group with -12.57g (p= 0.009). Detailed results are presented in Table 1. Conclusion Despite a significant reduction in fibrosis in both groups, there was no superiority observed in late PCI compared to isolated OMT in reducing reverse remodeling and fibrosis in patients with non-viable STEMI when compared to isolated OMT.Remodeling changes.