Myocardial Contractility Research Articles

Gut Hormones in Heart Failure.

Heart failure (HF) is a syndrome affecting all organ systems. While some organ interactions have been studied intensively in HF (such as the cardiorenal interaction), the endocrine gut has to some degree been overlooked. However, there is growing evidence of direct cardiac effects of several hormones secreted from the gastrointestinal tract. For instance, GLP-1 (glucagon-like peptide-1), an incretin hormone secreted from the distal intestine following food intake, has notable effects on the heart, impacting heart rate and contractility. GLP-1 may even possess cardioprotective abilities, such as inhibition of myocardial ischemia and cardiac remodeling. While other gut hormones have been less studied, there is evidence suggesting cardiostimulatory properties of several hormones. Moreover, it has been reported that patients with HF have altered bioavailability of numerous gastrointestinal hormones, which may have prognostic implications. This might indicate an important role of gut hormones in cardiac physiology and pathology, which may be of particular importance in the failing heart. We present an overview of the current knowledge on gut hormones in HF, focusing on HF with reduced ejection fraction, and discuss how these hormones may be regulators of cardiac function and central hemodynamics. Potential therapeutic perspectives are discussed, and knowledge gaps are highlighted herein.

Healthy longevity-associated protein improves cardiac function in murine models of cardiomyopathy with preserved ejection fraction.

Aging is influenced by genetic determinants and comorbidities, among which diabetes increases the risk for heart failure with preserved ejection fraction. There is no therapy to prevent heart dysfunction in aging and diabetic individuals. In previous studies, a single administration of the longevity-associated variant (LAV) of the human BPIFB4 gene halted heart decline in older and type 2 diabetic mice. Here, we asked whether orally administered LAV-BPIFB4 protein replicates these benefits. In two controlled, randomized studies, 18-month-old male C57BL/6J mice and 9-week-old C57BLKS/J-Leprdb/Leprdb/Dock7 + [db/db] mice of both sexes underwent baseline echocardiography. They then received a recombinant purified LAV-BPIFB4 protein (3µg/animal, every three days) or vehicle by gavage. After 30days, the animals underwent echocardiography, and the hearts were collected post-termination for histology. All the animals completed the study except one female diabetic mouse, which was culled prematurely because tooth malocclusion caused eating problems. There was no effect of the LAV-BPIFB4 protein on body weight in the two studies or glycosuria in the diabetic study. In aging mice, LAV-BPIFB4 increased myocardial Bpifb4 expression, improving heart contractility and capillarity while reducing perivascular fibrosis and senesce. In male diabetic mice, LAV-BPIFB4 therapy improved systolic function, microvascular density, and senescence, whereas the benefit was limited to systolic function in females. This study shows the feasibility and efficacy of a variant protein associated with human longevity in contrasting pivotal risk factors for heart failure in animal models. The diabetic study revealed that sex influences the treatment efficacy.

Hydrogels in cardiac tissue engineering: application and challenges.

Cardiovascular disease remains the leading cause of global mortality. Current stem cell therapy and heart transplant therapy have limited long-term stability in cardiac function. Cardiac tissue engineering may be one of the key methods for regenerating damaged myocardial tissue. As an ideal scaffold material, hydrogel has become a viable tissue engineering therapy for the heart. Hydrogel can not only provide mechanical support for infarcted myocardium but also serve as a carrier for various drugs, bioactive factors, and cells to increase myocardial contractility and improve the cell microenvironment in the infarcted area, thereby improving cardiac function. This paper reviews the applications of hydrogels and biomedical mechanisms in cardiac tissue engineering and discusses the challenge of clinical transformation of hydrogel in cardiac tissue engineering, providing new strategies for treating cardiovascular diseases.

Regional mechanical dyssynchrony and shortened systole are present in people with Takotsubo syndrome

Background:Takotsubo syndrome is characterized by transient regional systolic dysfunction, left ventricular (LV) dilatation, and edema, often occurring without obstructive coronary artery disease. The mechanisms underlying this stress-induced condition, especially the role of mechanical dyssynchrony in affecting systolic function, remain poorly understood.Methods:In our study, we evaluated global LV function and mechanical dyssynchrony in 24 Takotsubo patients compared to 20 controls by analyzing pressure-volume loops and time-varying elastance. Additionally, we monitored changes in LV segmental volume and internal flow.Results:Here we show a significant reduction in global myocardial contractility and pronounced mechanical dyssynchrony in Takotsubo syndrome, particularly in the mid and apical LV segments, without disturbances in electrical conduction.Conclusions:Our findings reveal substantial mechanical dyssynchrony in Takotsubo patients, characterized by increased internal flow and a shortened systolic ejection time. This indicates a mechanical basis for the inefficient LV function in Takotsubo syndrome, independent of electrical conduction abnormalities.

Phosphocreatine in the treatment of chronic heart failure: Case report

Currently, there is a steady increase in the prevalence of chronic heart failure (CHF), as well as a high mortality rate associated with this condition, despite the implementation of rational pharmacotherapy. The use of quadrotherapy in clinical practice for the treatment of CHF contributes to the blocking of neurohumoral regulation by inhibiting the renin-angiotensin-aldosterone and sympathoadrenal systems, which leads to decrease in preand afterload and, respectively, to delayed and partial reverse remodeling of the heart chambers. However, these drugs don’t affect the energy metabolism of cardiomyocytes, which is still impaired in patients at the preclinical stage of CHF. In this regard, an important task of practical healthcare is the search for new schemes of a pathogenetic therapy of CHF. One of the promising directions is an adjuvant therapy, which is represented by phosphocreatine, a drug with a cardioprotective effect, proven in a large number of studies, which ensures the maintenance of myocardial energy metabolism. The use of phosphocreatin prevents further deterioration of the contractile function of the heart in patients with CHF, reduces the degree of damage to the cell membrane, improves microcirculation, and also has antiarrhythmic activity, which is especially significant in patients with a history of myocardial infarction. The drug not only improves the quality of life of patients by reducing the severity of symptoms, but also has been proven to increase myocardial contractility and reduce mortality. The purpose of the clinical case report is the description of adjuvant therapy results in a patient with CHF after using all pharmacotherapy reserves. The clinical case demonstrates the effectiveness of CHF treatment with phosphocreatine, confirmed by data from clinical, laboratory and instrumental examinations.

Phosphocreatine in the treatment of chronic heart failure: Case report

Currently, there is a steady increase in the prevalence of chronic heart failure (CHF), as well as a high mortality rate associated with this condition, despite the implementation of rational pharmacotherapy. The use of quadrotherapy in clinical practice for the treatment of CHF contributes to the blocking of neurohumoral regulation by inhibiting the renin-angiotensin-aldosterone and sympathoadrenal systems, which leads to decrease in preand afterload and, respectively, to delayed and partial reverse remodeling of the heart chambers. However, these drugs don’t affect the energy metabolism of cardiomyocytes, which is still impaired in patients at the preclinical stage of CHF. In this regard, an important task of practical healthcare is the search for new schemes of a pathogenetic therapy of CHF. One of the promising directions is an adjuvant therapy, which is represented by phosphocreatine, a drug with a cardioprotective effect, proven in a large number of studies, which ensures the maintenance of myocardial energy metabolism. The use of phosphocreatin prevents further deterioration of the contractile function of the heart in patients with CHF, reduces the degree of damage to the cell membrane, improves microcirculation, and also has antiarrhythmic activity, which is especially significant in patients with a history of myocardial infarction. The drug not only improves the quality of life of patients by reducing the severity of symptoms, but also has been proven to increase myocardial contractility and reduce mortality. The purpose of the clinical case report is the description of adjuvant therapy results in a patient with CHF after using all pharmacotherapy reserves. The clinical case demonstrates the effectiveness of CHF treatment with phosphocreatine, confirmed by data from clinical, laboratory and instrumental examinations.

Differences in left ventricular contraction in left bundle branch block with preserved and reduced ejection fraction: an evaluation using 2-dimensional speckle tracking echocardiography

Abstract Background Left ventricular (LV) contraction in left bundle branch block (LBBB) is characterized by early septal contraction and delayed contraction of the lateral wall, but the process may differ depending on myocardial contractility in addition to the degree of conduction block. Purpose This study aimed to evaluate LV contraction in patients with LBBB by analysis of longitudinal strain (LS) and to compare it between patients with preserved LV ejection fraction (pEF: EF>50%) and reduced LV EF (rEF: EF<40%). Methods We studied 87 patients with LBBB. Fifty had pEF (EF 59±7%) with a mean QRS duration of 144±12ms, and 38 had rEF (EF: 29±4%) with a mean QRS duration of 147±12ms (p=0.32 vs. pEF). We also studied 43 patients without conduction block (Narrow-QRS; pEF, n=23; rEF, n=20). Patients with a heart rate less than 60 or greater than 80 beats/min during echocardiography or with a history of myocardial infarction were excluded. Three standard apical images were recorded, and the LS of one heartbeat starting at the beginning of the QRS was evaluated in 18 LV segments. When the strain waveform showed a negative peak during the pre-ejection period, it was identified as early systolic contraction (ESC), and the first negative peak that appeared after aortic valve opening (AVO) was identified as late systolic contraction (LSC). The time from the beginning of QRS to the peak of the LSC (Q-Peak) and the strain value at the end of the QRS were measured in each segment. Results In patients with LBBB, the septum contracted early, and ESC was seen mainly in the early contracted area. The lateral wall contraction was delayed, and the difference between the maximum and minimum Q-Peak was greater than the Narrow-QRS in the same EF category. Patients with rEF and LBBB had a larger number of segments with ESC and a smaller minimum Q-Peak than those with pEF. The difference between the maximum and minimum Q-Peak was greater for patients with rEF than for patients with pEF. Conclusions Although patients with LBBB had significant dyssynchrony due to conduction block even those with pEF, LV contractile properties were altered in patients with rEF and associated with further increased dyssynchrony.

Acute hemodynamic effect of oral ketones in patients with acutely decompensated heart failure and low cardiac output syndrome: a prospective randomized study.

Abstract Background Preliminary studies showed positive inotropic effect of mild ketosis in patients with heart failure with reduced ejection fraction (HFrEF). Purpose To evaluate the acute hemodynamic effect of oral administration of beta-hydroxybutyrate (OHB) in patients with HFrEF and low cardiac output syndrome. Methods Patients with acutely decompensated HFrEF treated with inotropic therapy were randomized (1:1) to enteral bolus of OHB (25g of OHB monoester in 65 ml of solution; H.V.M.N Ketone Ester, H.V.M.N, USA) administered three times with 3-hour intervals or to euvolemic placebo. The serum concentration of OHB, biochemical markers, and invasive hemodynamics (Swan-Ganz catheter with continuous thermodilution) were repeatedly measured before and during 24 hours after administration of OHB. The primary endpoint was the maximum change in cardiac index (CI). Results The study included 20 patients with decompensated HFrEF (age: 57 ± 8 years; left ventricular ejection fraction: 21 ± 4%; non-ischemic cardiomyopathy: 16 [80%], median INTERMACS class: 3 [IQR 2 - 4]), who were treated with milrinone (0.5 ± 0.1 ug/kg/min, n=18) or levosimendan (0.1 ug/kg/min up to 25 mg, n=2). Patients in the OHB group (n = 10) did not differ from the placebo group (n = 10) in baseline clinical, biochemical, hemodynamic or echocardiographic characteristics. Baseline OHB concentration was normal (<0.6 mmol/L) in all patients. Administration of OHB increased serum concentration from 0.3 ± 0.2 mmol/L to a maximum of 2.4 ± 0.7 mmol/L (<0.001). Concentrations of OHB peaked at 1.5 ± 0.5 hours after administration of each OHB drink, and the maximum concentration was achieved at 4.1 ± 2.5 hours (Figure 1). No changes in OHB concentration were observed in the placebo group. In both study groups, there was a significant increase of CI at 3 hours compared to baseline, but the increase was significantly greater in the OHB group (OHB: 3.2 ± 0.6 vs. 2.1 ± 0.4 L/min/m2; placebo: 2.3 ± 0.4 vs. 2.0 ± 0.3 L/min/m2; both p<0.001 compared to baseline; p < 0.001 for OHB vs. placebo at 3 hours). The maximum relative increase of CI was 60 ± 24% in the OHB group (p <0.001) and 18 ± 8% in the placebo group (p< 0.01). The change of CI correlated with the change of OHB concentration in the OHB group (r = 0.58, p<0.001) but not in the placebo group (r = 0.1, p = 0.3). The changes in CI were not related to heart rate or concentration of norepinephrine, which did not change significantly throughout the study in both groups. Conclusion Oral administration of OHB leads to a significant temporary increase in myocardial contractility. This novel therapeutic concept might be a promising adjunction to inotropic support in patients with decompensated HFrEF.

Dexmedetomidine Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming.

Myocardial ischemia-reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK-MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex-treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1)phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI.

O2 consumption overshoot in patients with heart failure: crossing the line

Abstract Background Cardiopulmonary exercise testing (CPET) is among the most valuable clinical tools for evaluating disease severity and physical activity limitations in heart failure (HF) patients. Peak oxygen uptake (pVO2) reflects maximal cardiac output during exercise, and it is considered a major parameter in selecting candidates for cardiac transplantation. VO2 overshoot, a transient increase in VO2 during recovery from maximal exercise, has been frequently observed in HF patients and is attributed to the transient increase in cardiac output caused by the mismatch between cardiac contractility and afterload reduction. However, the prognostic significance of this phenomenon remains to be fully established. Purpose This study aimed to characterize the prognostic significance of VO2 overshoot following peak exercise in individuals with HF. Methods This retrospective single-center study included consecutive adult patients with chronic (>3 months) and stable HF, with left ventricular ejection fraction (LVEF) <50%, who underwent CPET between 2015 and 2020. Following maximal exercise, patients recovered over a 3-minute period (walking 2km/h for 1 minute and sitting passively for 2 minutes). VO2 overshoot kinetics during recovery were measured and described as the time until post-exercise VO2 fell below pVO2 for at least 15 seconds. Please refer to Figure 1A for an example of normal and prolonged VO2 overshoot. The study endpoint was time to cardiovascular (CV) death, urgent cardiac transplant, or left ventricular assist device (LVAD) over 1-year follow-up. Results A total of 254 patients were included (mean age 59 ± 12 years; 83% males; mean LVEF 34 ± 9%; 70% with ischemic HF; 77% in NYHA class II-III; mean pVO2 18 ± 6 mL/kg/min; mean predicted pVO2% 52 ± 16%; mean VE/VCO2 slope 41 ± 13). The VO2 overshoot had a normal distribution (Figure 1B) and lasted on average for 45 ± 33 seconds. There were no differences between patients that had an overshoot higher and below average. Overall, during follow-up, 25 patients met the composite endpoint (12 CV deaths, 9 urgent heart transplants, and 4 LVAD). Univariate analysis showed a significant relationship between VO2 overshoot and the outcome of interest (HR 1.01, 95% CI 1.00 – 1.02, p=0.027). In multivariate analysis, this association remained significant, even after adjusting for pVO2 and VE/VCO2 slope (HR 1.01, CI 95% 1.00– 1.02, p=0.026). Conclusion This study delves into the intriguing phenomenon of VO2 overshoot in patients with heart failure, shedding light on its potential prognostic significance. The independent association between VO2 overshoot and the composite endpoint suggests that this transient increase in oxygen consumption may carry prognostic value. Further studies should confirm these findings.

Arterial-myocardial coupling in primary AL amyloidosis. A validation study of vascular involvement

Abstract Background Primary AL amyloidosis is a rare yet lethal systemic disorder. Previously published own and others’ work indicated that vascular involvement in AL cardiac amyloidosis defined as low blood pressure or paradoxical vasodilation may independently affect survival. Mechanistic data will pave the way to validate the clinical role of vascular involvement in these patients. Purpose We sought to explore the presence of arterial-myocardial coupling in AL amyloidosis by investigating associations between markers of vascular and cardiac involvement. Methods We consecutively recruited n=152 newly diagnosed patients with AL amyloidosis that underwent thorough vascular examination including reactive vasodilation (flow mediated vasodilation, FMD and vasodilation in response to cold-pressor test) using high resolution ultrasonography. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (PWV) and aortic pressures and markers of arterial wave reflections were estimated using radial artery tonometry. In a subgroup of patients, transthoracic echocardiography (n=152) and cardiac magnetic resonance (CMR) (n=59) were performed. Results Vascular reactivity correlated with global longitudinal strain (GLS), left ventricle ejection fraction (LVEF)/GLS ratio and worse LV volumes. Vasodilation post-cold pressure test was correlated with LV mass. cSBP exhibited a negative correlation with markers of heart involvement, wall thickness markers, GLS, and CMR tissue characterization markers. A positive correlation between cSBP and LVEF, rotation and twist strain, myocardial work and contractility markers and late gadolinium enhancement (LGE). cDBP was associated with systolic function and contractility markers, with myocardial work indices and LGE. A negative relationship with GLS, LA strain, RV GLS and LA diameter and E/e’ was noted. In addition, T2 was negatively correlated with cDBP. SBP was correlated positively with LVEF, contractility markers, and LGE myocardium and negatively correlated with biomarkers of heart involvement, GLS, CMR structure and tissue characterization. DBP was positively correlated with LGE and myocardial work. A negative relation with NTproBNP, E/e’, RVSP, LA diameter and T2 mapping was noted. Time of wave reflections (Tr) was negatively correlated with rotation strain and positively correlated with circumferential strain, LA strain and LV structure. Ai@75 was positively correlated with myocardial work and contractility markers, and LGE. Ai@75 was negatively correlated with markers of heart involvement, LV structure, E/e’, worse GLS and adverse CMR tissue characterization. Conclusion Markers of peripheral vascular dysfunction were associated with cardiac structure and function acquired both with echocardiography and CMR in AL amyloidosis. This arterial-myocardial coupling supports the clinical role of peripheral vascular involvement in this disease and warrants further investigation.

Acute changes in right ventricular geometry and function following transcatheter tricuspid valve interventions

Abstract Background Little is known about acute changes in right ventricular (RV) function and geometry following transcatheter tricuspid edge-to-edge repair (T-TEER) or transcatheter tricuspid valve replacement (TTVR). Pressure-strain-volume loop-derived myocardial work metrics showed associations with myocardial energetics and contractility in conditions accompanied by volume overload, suggesting their potential utility in patients with tricuspid regurgitation (TR). Purpose To define acute changes in RV volumes and RV myocardial work following T-TEER and TTVR using conventional and pressure-strain-volume derived RV work metrics. Methods In this multicenter, observational study, 3D echocardiographic datasets and invasively acquired RV pressures were collected before and after transcatheter tricuspid valve procedure. Using dedicated software (ReVISION, Argus Cognitive) 3D RV volumes and strains were quantified and decomposed to longitudinal, radial and anterio-posterior motion. Forward stroke volume (SV) was calculated by subtracting TR volumes from RV 3D end-diastolic volume (EDV) and end-systolic volume (ESV) difference. Three-dimensional pressure-strain-volume loops were constructed and global RV work-index (RV-Wi) was calculated. Changes in RV parameters before and after the intervention were compared using paired-samples t test. Results Of 37 patients included in this study (65% male), 20 underwent T-TEER and 17 underwent TTVR. Compared to T-TEER patients, patients undergoing TTVR had higher prevalence of torrential TR at baseline but also achieved a higher reduction in TR volumes after the intervention (44 ± 11 ml vs 60 ± 16ml; p = 0,001). Following T-TEER there was a significant reduction in RV EDV (240 ± 93 ml vs 200 ± 80 ml; p < 0.001) and increase in SV (55 ± 34 ml vs 68 ± 26 ml; p = 0.036). Following TTVR there was a significant increase in RV ESV (121 ± 46 vs 146 ± 48, p = 0.003) and no significant change in SV (47 ± 24 ml vs 55 ± 20 ml; p = 0.143). There was significant reduction in RV strain and ejection fraction (EF) (all p < 0.001) primarily driven by reduction of radial motion component in both groups. RV-Wi increased in 35% (7/20) of T-TEER patients and in 18% of (3/17) TTVR patients. Conclusion An acute reduction in RV EF was observed in all patients and was mainly caused by decrease in RV EDV in T-TEER patients and increase in RV ESV in TTVR patients. Despite decrease of conventional metrics of RV function in both groups, an increase in RV-Wi was observed in 27% of all patients.Baseline and follow-up characteristicsCentral Figure

Post-prandial acyl ghrelin infusion in heart failure patients increases gastric emptying rate

Abstract Background Acyl ghrelin (ghrelin) increases cardiac output (CO) and contractility in patients with heart failure with reduced ejection fraction (HFrEF). In healthy humans, ghrelin increases gastric emptying rate (GER) and hunger, a potential add-on benefit for HFrEF patients suffering from cachexia with symptoms of delayed gastric emptying and loss of appetite. Aim Determine if post-prandial ghrelin infusion increases GER and hunger in HFrEF patients; compare to CO. Methods This study was a component of a double-blind placebo-controlled trial of acyl ghrelin vs. placebo in HFrEF. Patients (n=29) arrived fasted and received a 500 kcal breakfast and 1.5 g paracetamol. They next received placebo (vehicle, n=15) or ghrelin infusion (0.1 µg/kg/min, n=14) for 120 min. Blood was tapped for plasma at 0, 30, 60, 120 and 150 min into the meal. Plasma concentration of paracetamol was measured to assess GER of a liquid bolus. Hunger scores and CO were recorded. Mann-Whitney rank sum test was used for statistics. Results Paracetamol peaked at 30 min in 8 of 14 (57%) in the ghrelin treatment group versus 1 of 15 (7%) in the placebo group (P=0.004, Fig 1). Remaining patients peaked at later time points. There were no anomalous peaks at 0 min baseline or 2880 min (2 days). The ghrelin treatment group data was segregated into rapid (peak at 30 min, n=8) and slow (peak >30 min, n=6) GER subgroups. The rapid subgroup had a ghrelin treatment effect on CO (one-way repeat measures) (P<0.001, Fig 2). Baseline (t=0) CO for the rapid GER subgroup was 4.06 ±1.41 L/min (median ±SD) and 3.95 ±0.62 L/min for the slow GER subgroup (P=0.31). Data points shown are median ± SEM, each patient normalized to own baseline (100%); * P<0.05, ** P<0.01, *** P<0.001, pairwise comparison to baseline. Hunger gradually increased. The greatest increase in hunger was at 150 min, at which time median fold increase in hunger relative baseline was 1.6 (placebo), 1.7 (ghrelin, slow GER) and 2.3 (ghrelin, rapid GER). These hunger differences between groups did not reach significance. However, this trend was consistent with ghrelin induction of hunger, especially in those with potent GER and CO responses. Conclusions Ghrelin increases GER, and potentially hunger, in HFrEF patients in addition to increasing CO. Some HFrEF patients may benefit from this add-on effect.Fig 1.Time of paracetamol peak.Fig 2.Cardiac output.

Changes in echocardiographic and analytical parameters after iron replacement in stable heart failure patients. FER-STRAIN study

Abstract Background Iron deficiency replacement with intravenous ferric carboxymaltose (FCM) has demonstrated to improve clinical and prognostic parameters in patients with heart failure with reduced left ventricular ejection fraction (HFrEF). Improvement of myocardial contractility is proposed as possible hypothesis and strain could behave as an early and high sensitive parameter to assess this improvement in myocardial deformation due to increased iron availability after replacement of iron deficiency. Purpose Evaluate the effect of iron deficiency replacement with FCM in the strain of both ventricles in patients with stable HFrEF. Methods We performed an observational, analytical, longitudinal and prospective study that included 73 patients with stable HFrEF who presented iron deficiency without anemia defined as serum ferritin <100 ug/L or between 100 and 300 ug/L if the transferrin saturation was <20%. They were randomized 2:1 to iron replacement with FCM or control group. A central core lab, blinded to the treatment/control groups performed 3D echocardiograms and strain analysis. Analytical parameters and biomarkers were determined basal and four weeks after the randomization. Results Mean age of the study population was 70 years old, 77% were male, 75% had high blood pressure, 70% dyslipidemia and 41% diabetes. Of the total, 51 patients were assigned to the replacement group and 22 patients to the control group. Mean left ventricular ejection fraction (LVEF) was 33%, without basal differences between both groups. Four weeks after the randomization, a significant improvement of LVEF of 2.47±2.32% (p=0.018) was observed in the replacement group, as well as in the left ventricle global longitudinal strain (LV-GLS) of -0.96±2.08% (p=0.006). In blood tests, a significant improvement of ferritin (130.9±111.98mg/L, p<0.000), hemoglobin (0.3±0.7g/dL, p=0.027) and medium corpuscular volume (1.7±2.16fL, p=0.005), and also an increase of the biomarker myeloperoxidase (40.16±138.36pmol/L, p=0.02) were detected in the treatment group. Nevertheless, these changes were not observed in the control group. Conclusions In patients with stable HFrEF replacement of iron deficiency with FCM is associated with an improvement of myocardial contractility, of LVEF measured by 3D and LV-GLS.Variation of parametersLV-GLS before and after FCM

Genetic and phenotypic architecture of biventricular trabeculation

Abstract Introduction Cardiac trabeculae form a network of muscular strands that line the inner surfaces of the heart, and their development involves molecular pathways that regulate structural complexity. Excessive or hypertrabeculation occurs as part of normal variation in apparently healthy individuals, as an adaptation to altered loading conditions, and is observed in patients with cardiomyopathies (CMs) and heart failure (HF). Purpose In adults, trabeculation is not a prognostic factor independent of the underlying myocardial disease but may play a role in the natural history of ventricular remodelling. We sought to (i) understand the genetic and non-genetic determinants of trabeculation, (ii) understand its role in the causality of disease, and (iii) evaluate trabeculation as a biomarker for diagnosis and stratification. Methods We report genes with a burden of rare variants and novel common variant associations across the allele frequency spectrum for biventricular trabecular morphology in 47,803 participants of the UK Biobank using fractal dimension analysis of cardiac imaging (Figure 1). We assessed environmental modifiers of trabecular morphology, correlation with cardiac traits, phenome-wide association studies, and the relationship with the progression of CMs and HF. Results We identified a burden of trabeculation-associated rare variants in genes that regulate myocardial contractility and cardiac development and GWAS identified novel loci near genes implicated in CMs, conduction traits, and signalling pathways that define the early development of trabeculation. For example, we identified 56 genes with a burden of rare variants and 68 novel loci from GWAS (e.g., CASQ2, CACNA1C, MYBPC3, MYH7, NKX2-5, NOTCH1, TBX20) for the left ventricle. The strongest imaging relationships with trabeculation were with measures of volume and strain. Modifiers of trabeculation included African ancestry, alcohol intake, and physical activity. Carriers of CM-associated pathogenic variants had increased trabeculation. Of participants with CM reported after imaging, 25% had hypertrabeculation on imaging and hypertrabeculation was a risk factor for a subsequent diagnosis of HF (HR=1.3), mitral valve disorders (HR=1.4), bundle branch block (HR=1.2). Comparisons of biventricular trabeculation showed similarities in trabeculation across the ventricles in CM. Reduced right ventricular trabeculation and end-diastolic volume associated with Type-2 diabetes. Conclusions These data provide new insights into the mechanisms that regulate structural complexity in the heart. Changes in trabeculation may occur early in the pathogenesis of heart disease, can be modified by genes regulating pathways outside the sarcomere, and causality depends on the underlying cardiomyopathic substrate. Trabeculation progresses with cardiovascular disease, is a useful marker of remodelling, and identifies novel genetic modifiers of ventricular complexity.Figure 1

Improvement of myocardial contractility after iron replacement in stable heart failure patients

Abstract Background Iron deficiency replacement with intravenous ferric carboxymaltose (FCM) has demonstrated to improve clinical and prognostic parameters in patients with heart failure with reduced left ventricular ejection fraction (HFrEF). Improvement of myocardial contractility is proposed as possible hypothesis and strain could behave as an early and high sensitive parameter to assess this improvement in myocardial deformation due to increased iron availability after replacement of iron deficiency. Purpose Evaluate the effect of iron deficiency replacement with FCM in the strain of both ventricles in patients with stable HFrEF. Methods Observational, analytical, longitudinal and prospective study that included 73 patients with stable HFrEF who presented iron deficiency without anemia defined as serum ferritin <100 ug/L or between 100 and 300 ug/L if the transferrin saturation was <20%. They were randomized 2:1 to iron replacement with FCM or control group. A central core lab, blinded to the treatment/control groups, performed 3D echocardiograms and strain analysis basal and four weeks after the randomization. Results Mean age of the study population was 70 years old, 77% were male, 75% had high blood pressure, 70% dyslipidemia and 41% diabetes. Of the total, 51 patients were assigned to the replacement group and 22 patients to the control group. Mean left ventricular ejection fraction (LVEF) was 33%, without basal differences between both groups. Four weeks after the randomization, a significant improvement of LVEF of 2.47±2.32% (p=0.018) was observed in the replacement group, as well as in the left ventricle global longitudinal strain (LV-GLS) of -0.96±2.08% (p=0.006). Nevertheless, these changes were not observed in the control group. Conclusions In patients with stable HFrEF replacement of iron deficiency with FCM is associated with an improvement of myocardial contractility, of LVEF measured by 3D and LV-GLS.Variation of parametersLV-GLS before and after FCM

DPdT >1200ms predicts greater and sustained drop in ejection fraction post mitral TEER

Abstract Background The maximum rate of left ventricular pressure rise (dP/dTmax) using a CW Doppler from a mitral regurgitation (MR) curve is a simple technique which can estimate myocardial contractility, with "normal" values >1200ms. This technique has not been applied to patients undergoing mitral transcatheter edge-to-edge repairs (M-TEER). Purpose Assess if dP/dT can predict post-procedural ejection fraction (EF). Methods A retrospective review of all M-TEER's performed from January 2011 – February 2023 at a single cardiac centre with an adequate MR CW Doppler to calculate the dP/dT as well as a subsequent TTE at the institution were included. An early TTE (performed day 1-50, average 34.9) and late TTE (goal 1 year, average 354 days) were recorded. Results A total of 155 M-TEER procedures were performed; 66 for degenerative MR (DMR), 11 for atrial functional MR (AFMR) and 78 for ventricular functional MR (VFMR). Baseline characteristics: overall EF 47.9% (DMR 61%, AFMR 52% and VFMR 32%). Age DMR 75.8y, AMFR 78.9y, VFMR 75.6y), overall 31.6% female (DMR 34.6%, AFMR 45.5%, VFMR 25.8%). Surprisingly the DMR cohort demonstrated a significant drop in EF post M-TEER of 5.1% (p<0.001, figure 1). This was most marked in the group with "normal" dP/dT of >1200ms (figure 2, DMR EF drop 7.8% p<0.001). This cohort remained at the new, lower value on follow up (figure 2). The EF in the VFMR remained severely impaired despite M-TEER (figure 1). There was no significant difference between EF pre or early post (p= 0.86). When divided into groups according to baseline dP/dT. The greatest drop in EF was again seen with an apparently normal dP/dT of >1200ms (figure 2). Conclusion "Normal" dP/dT of >1200ms in patients undergoing M-TEER is likely a marker of hyper-contractile LV function as a compensatory mechanism, and may predict a greater fall in EF post correction of MR.

Cardiac contractility index, a novel biomarker of incident heart failure amongst people with normal left ventricular ejection fraction in the UK Biobank

Abstract Background Cardiac contractility index (CCI) is a simple non-invasive measure of myocardial contractility defined by systolic blood pressure divided by indexed left ventricular end-systolic volume. Although left ventricular ejection fraction (LVEF) is essential for phenotyping patients with suspected heart failure (HF), it is load dependent and insensitive to subtle subclinical ventricular dysfunction. Left ventricular (LV) strain, although more sensitive at detecting subtle disturbances in myocardial function, also does not reflect loading conditions and dependency on image quality and inter-vendor variability limit widespread use. The ability of CCI to identify patients with subclinical left ventricular dysfunction at risk of developing HF is unknown. Purpose We aimed to: 1) explore the relationship between CCI with conventional imaging biomarkers of LV systolic dysfunction and 2) assess whether CCI could identify those at increased risk of incident HF in people without pre-existing left ventricular dysfunction in the UK Biobank imaging study. Methods We explored the relationship between CCI and laboratory and imaging biomarkers of systolic function, including LVEF and LV strain. Scatter plots were constructed for CCI with LVEF and LV strain. Pearson’s coefficients (r) and coefficient of determination (r2) were calculated to assess for correlations. People with sex-specific thresholds of abnormally low LVEF derived from within the same cohort (<48% for men, and <51% for women) were then excluded. CCI was then dichotomised as being high or low based its median value (4.4 mmHg/ml/m2). Age-sex adjusted Cox proportional hazards ratios (HR) with 95% CIs were estimated for the primary outcome of incident HF (derived from linked national digital registries) in addition to modelling with restricted cubic splines. Results We included 38,215 people (median age 55 years, 48% men). There was moderate correlation between CCI with LVEF (r=0.53 [0.53-0.54], R2=0.29; p<0.001), LV global circumferential strain (r=-0.50 [-0.50- -0.49], R2=0.25; p<0.001) and radial strain (r=-0.49 [0.48-0.50], R2=0.24; p<0.001), although was only weekly correlated with LV global longitudinal strain (r=-0.19 [-0.20- -0.18], R2=0.03; p<0.001) (Figure 1A). Using sex-specific thresholds 33,739 (88.3%) had a normal LVEF. During 195,584 person-years of follow-up (median 5.5 years), a total of 221 (0.7%) participants developed HF. Age-sex adjusted low CCI at baseline was associated with an increased risk of incident HF (adjusted HR 1.33 [1.01-1.75]; p=0.043). The association between CCI and incident HF was curvilinear (Figure 1B). Conclusions CCI identifies people with subclinical left ventricular systolic dysfunction at risk of developing incident heart failure.

Levosimendan improves the early prognosis of patients with Non ST-segment elevation myocardial infarction and Killip class > II

Abstract Background Levosimendan is an inotropic agent known for its calcium-sensitizing myofilament effect and ATP-dependent potassium channel opening mechanism, which enhances myocardial contractility without increasing oxygen consumption. Despite its potential benefits, the impact of levosimendan on the prognosis of patients with myocardial infarction remains uncertain and requires further investigation through larger-scale studies. Purpose This study aimed to investigate the effect of levosimendan on the short-term prognosis of patients with Non-ST-segment elevation myocardial infarction (NSTEMI) and Killip> II. Methods The data for this study were derived from the Health and Medical Big Data Superplatform, comprising a retrospective cohort of patients admitted to and discharged from 72 secondary and tertiary hospitals in the City from 2010 to 2023. A total of 12472 patients with NSTEMI and Killip > II were included. Patients were divided into the levosimendan group and the non-leosimendan group based on whether levosimendan was used during hospitalization. Propensity score matching (PSM) was employed to balance covariates between the two groups. Multivariate Cox regression was used to evaluate the relationship between levosimendan and clinical outcomes. Covariates adjusted in PSM included age, sex, Killip class, early PCI, previous PCI, previous medical conditions (diabetes, hypertension, ischemic stroke, and chronic kidney disease), and medications during hospitalization (aspirin, clopidogrel, indobufen, ticagrelor, statins, cedilanid, recombinant human brain natriuretic peptide [rhBNP], milrinone, dopamine, dobutamine, and angiotensin converting enzyme inhibitor/angiotensin receptor blockers [ACEI/ARB]). The primary endpoint was major cardiovascular and cerebrovascular adverse events (MACCE), defined as the composite endpoint of cardiac death, myocardial infarction, and ischemic stroke within 3 months. Results The levosimendan group comprised 782 patients, while the non-leosimendan group included 11690 patients. After PSM, the covariates were balanced, resulting in 756 well-matched pairs. In PSM patients, the levosimendan group exhibited a significantly lower incidence of MACCE (aHR, 0.573; 95%CI, 0.466–0.704; p < 0.001) and cardiac death (aHR, 0.500; 95%CI, 0.399-0.626; p < 0.001). However, there was no significant difference in the incidence of myocardial infarction and ischemic stroke. Conclusions Levosimendan was associated with a lower incidence of MACCE within 3 months in patients with NSTEMI and Killip> II, mainly driven by lower incidence of cardiac death. However, these findings are based on observational data and require confirmation through adequately powered, randomized, controlled trials.

Electrical heart failure treatment in the Goldilocks zone: cardiac contractility modulation proves equally effective for heart failure control in HFrEF patients with mid-range QRS durations

Abstract Background Current guidelines recommend a four pillar therapy for heart failure with reduced ejection fraction (HFrEF). A subgroup of patients, namely those with a QRS duration (QRSd) ≥150 ms, may also qualify for cardiac resynchronization therapy. However, a 30% CRT non-responder rate persists, with patients with narrower QRSd (i.e., QRSd <150 ms) and non-left bundle branch block receiving less benefit. At present, cardiac contractility modulation (CCM) has only been established in patients with QRSd <120 ms. Given these limitations, new options for additional device therapy are urgently sought for those patients who face drug-refractory HFrEF and with intermediate QRSd of 120-149 ms. Purpose Primarily to evaluate the impact of CCM on HF-related hospitalizations and secondarily on left ventricular EF (LVEF) as well as quality of life (by Minnesota Living with Heart Failure Questionnaire (MLWHF) score and New York Heart Association (NYHA) class) in a real-world population of HFrEF patients with QRSd 120-149 ms, compared to QRSd <120 ms. Methods CCM-REG enrolled 503 HF patients receiving CCM with a follow-up of up to 2 yrs. HF-related hospitalization rates were available for 1 yr pre-implant. Safety was assessed by comparison of actual versus MAGGIC score predicted mortality. Results 455 patients were studied for these analyses. Among 111 subjects with QRSd 120-149 ms (mean QRSd 130±8 ms, age 68±10 yrs, 20% female, LVEF 29±9%, 82% NYHA class III), CCM diminished HF-related hospitalization rate by 72% (pre- vs. post-implant 0.90 vs. 0.25 events/per patient-yr over 2 yrs; p<0.001; Figure). LVEF improved by 7±8% (p=0.01 vs. baseline), MLWHFQ score by 10±23 pts (p=0.01 vs. baseline), and NYHA class by 0.5±0.7 classes (<0.001 vs. baseline). The effect size was similar to that in the QRSd <120 ms patients. Mortality within first year was 19% in QRSd 120-149 ms patients and thus not significantly different from the MAGGIC score prediction. Conclusions CCM significantly improved HF control in symptomatic HFrEF patients with moderately prolonged QRSd 120-149 ms. The effect was similar to patients with QRSd <120ms.Reduction in hospitalization rates