Improvement In Diastolic Function Research Articles

The effect of bachmann bundle pacing on diastolic function in patients with non-obstructive HCM

Abstract Background and Objective Patients with non-obstructive HCM (nHCM) have advanced diastolic dysfunction and atrial remodeling, leading to increased heart failure hospitalisations. The objective of this study was to evaluate the role of Bachmann bundle pacing (BBP) in diastolic filling compared to right atrial appendage pacing (RAAP). Methods Forty patients with symptomatic nHCM and normal LV function were prospectively enrolled from January 2021 to June 2023. Inclusion criteria included electrocardiographic evidence of inter-atrial delay, E/e’ > 15, and an indication for ICD implantation. BBP was attempted in twenty patients, others underwent RAAP. A Biotronik Selectra 3D 40-S sheath was used for BBP in patients in whom initial lead implantation was unsuccessful. BBP was defined based on P-wave morphology and fluoroscopic lead position. The RV lead was implanted in the RV apex in all patients and the AV delay was optimized based on diastolic filling period and E/e’. Devices were programmed in DDD mode. During follow up, diastolic function, functional capacity, atrial fibrillation, and heart failure hospitalisations were assessed in both groups. Results Among the forty patients (age 48.2+7.8 yrs, males 75%, ESC-SCD Risk 4.3+0.6%), the baseline P wave duration, E/A, E/e’ were 138.4+16.4 ms, 2.5+0.5, and 17.5+2.4, respectively. Six patients (15%) had a history of paroxysmal AF (3 each in BBP and RAAP groups). Of the 16 patients (80%) who underwent successful BBP, the Selectra 3D 40-S sheath was used in 8 patients (Figure 1, Panel A). During BBP, a bachmann bundle potential was recorded in 7 of 16 patients (43.8%) (Figure 1, Panel C). The pacing threshold (1.5+0.5@0.4ms vs. 0.9+0.3@0.4ms, p=0.026) was higher and the atrial sensing (1.8+0.4 vs. 3.3+0.6, p=0.002) was lower in the BBP group compared to the RAAP group at 4 weeks and 6 months of follow up. There was an acute rise in threshold (2.1@0.4 ms) in 1 BBP patient at 4 weeks of follow up. Patients in the BBP group had a reduction in P wave duration compared to the patients in the RAAP group (-22.5 + 5.4 vs. +5.6 + 3.2 ms, p<0.001). During follow up (11.4 + 3.4 months), there was a significant improvement in diastolic function (E/e’), functional capacity (NYHA Class) and reduction in NT-proBNP in the BBB group compared to the RAAP group (Figure 1). The percentage of atrial pacing was similar in both groups (BBP 73.2 + 7.8 vs. RAAP 78.5 + 9.1 %, p=0.219). The risk of atrial fibrillation/tachycardia (12.5% vs. 35.0%, p=0.022) and heart failure hospitalisations (6.3% vs. 20%, p=0.042) was lower in the BBP group compared with RAAP during follow up. Conclusions BBP is safe and effective in improving diastolic function, functional capacity and heart failure hospitalizations in patients with nHCM.BBP Pacing using Selectra 3D 40-S SheathChange in E/e', NYHA, and NT-pro BNP

#1755 Cardio-protective effect of soy proteins during long-term consumption of Cynomolgus Monkeys high-saline diet

Abstract Background and Aims High salt intake is accompanied by the development of cardiovascular disorders, not always associated with an increase in blood pressure (BP). Recently, it has been found that the introduction of soy protein into the diet can have some nephroprotective and cardioprotective effects in chronic kidney disease. Considering the cardioprotective effect of soy proteins in chronic kidney disease, the question arose about the possibility of using soy proteins to neutralize the damaging effect of a high-salt diet on the cardiovascular system. This work aims to study the effect of long-term use of a diet high in NaCl and soy protein on myocardial remodeling in monkeys. Method The study was performed on male Macaca fascicularis. The animals were divided into three groups (6 animals each), comparable in weight and age (6-8 years, body weight - 5.15-9.7 kg). The control group received a standard diet (2 g NaCl/kg feed). The second was a high salt diet (8 g NaCl/kg feed), and the third was a high salt diet and SUPRO760 soy protein (200 g/kg feed). Echocardiography (EchoCG), registration of BP and heart rate were performed at baseline, after 4 and 12 months. EchoCG was performed with a sector transducer with a frequency of 3–5 MHz on the Chison SonoTouch 60 ultrasound system (China). EchoCG was performed in B_mode (two-dimensional scanning), M_mode (one-dimensional scanning), as well as in pulse and tissue Doppler modes. Statistical analysis was performed using parametric statistics: mixed ANOVA in comparing data from 3 study groups (with post hoc analysis using Tukey criterion) and single factor variance analysis for related samples in studying the dynamics of one or another index in each group during the 12-month follow-up. Differences were considered significant at p < 0.05. Results In animals of all three groups for 12 months, blood pressure (BPsis-109±10.09, BPdias – 60 ± 7.42 mm Hg) and heart rate (77 ± 12.61 min-1) did not change significantly (p>0. 05). However, in macaques on a high-salt diet, deterioration in left ventricular (LV) systolic and diastolic function was noted by the end of the study. Macaques of this group had a decrease in the LV shortening fraction (27.9±2.69%) and an increase in the thickness of the posterior wall of the LV in systole (0.69±0.039 cm), LV mass (19.60±2.83 g), compared with animals additionally receiving soy proteins (34.9±6.57%; 0.57 0.0559 cm; 14.86±2.94 g, respectively; all p < 0.05). In addition, the monkeys receiving soy isolate did not differ from the control in these parameters. By the time the study was completed, the animals in this group had significantly increased the magnitude of systolic excursion of the mitral annulus plane, and signs of improvement in LV diastolic function appeared in the form of an increase in the maximum rate of excursion of the mitral valve fibrous annulus in early diastole, as well as a decrease in the E/e' ratio. The thickness of the interventricular septum also decreased (0.42±0.04 cm; in the high-salt group - 0.51±0.08 cm), which can be interpreted as a sign of positive myocardial remodeling. Conclusion Thus, high salt intake leads to adverse structural and functional disorders of the heart in cynomolgus monkeys, not associated with an increase in blood pressure. The inclusion of soy isolate in the diet reduces the negative effects of a high-salt diet on the cardiovascular system.

Therapeutic potential of hiPSC-derived cardiomyocytes for Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) results in progressive and incurable cardiomyopathy, leading to significant morbidity and mortality due to heart failure. There is currently no effective cure for DMD that can correct the genetic defects and compensate for the lack of dystrophin. Therefore, the therapeutic strategies that focus on the transplantation of induced pluripotent stem cells (iPSCs) derived cardiomyocytes are promising options, and remain to be investigated to which extent they can restrain the cardiomyocyte loss phenotype and improve cardiac function. There has been significant progress in the differentiation of cardiomyocytes (CMs) from hiPSCs (human iPSCs). Three hiPSC lines: AICS-0011, 029 iPS clone 4-PCBC, and PCBC16iPS were investigated based on previously published culture and differentiation methods. We will inject differentiated CMs into the heart of Mdx mice that are mutated or deficient for NOD-scid, IL2Rg to allow for xenotransplantation engraftment. Having confirmed the effcient differentiation of CMs from all three hiPSC lines, the next step will be to transplant CMs. The engraftment rate after transplantation will be quantified by IHC staining for human lamin A/C and the relative level of genomic human DNA from isolated hearts. Correction of dystrophin expression will be measured via IHC for dystrophin. Echocardiography will be performed to measure improvement in cardiac systolic or diastolic function. If therapeutic transplantation of hiPSC-CMs is possible, it could improve the survival of DMD patients. This project was supported by RMM091621DS008, NIH155993, and NIH160665. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

COMPARISON OF CARDIAC STRUCTURAL AND FUNCTIONAL CHANGES BETWEEN SURGERY AND MEDICATION TREATMENT IN PATIENTS WITH PRIMARY ALDOSTERONISM BASED ON ECHOCARDIOGRAPHY

Objective: Conducted a systematic meta-analysis on the changes in follow-up parameters of echocardiography in patients with primary aldosteronism after surgery and drug treatment, in order to explore their differences. Design and method: We conducted the PubMed, Embase, and Cochrane library databases for English full-text articles on the follow-up study of echocardiography parameters in PA patients before and after surgery and drug treatment published from its establishment until June 1, 2023,Perform meta-analysis on the included studies using RevMan software. Results: A total of 515 PA patients (>18 years old) were included in 4 studies, including the surgical group (n=303) and the medication group (n=212), 2 short-term follow-up studies (average follow-up time of 1 year), and 2 long-term follow-up studies (average follow-up time of 3.7 years). Surgery treatment had better performance in improving cardiac contractile function, The main manifestation is the reversal of left ventricular hypertrophy (LVMI: M=-2.6, p=0.047), while there is no significant improvement in cardiac diastolic function (E/A: M=+0.06, p=0.51); In long-term follow-up studies, surgery and medical treatment still showed significant benefits in reducing blood pressure (surgical group: -14 ± 6 mm Hg/-9 ± 10 mm Hg, p<0.001; drug group: -10 ± 12mmHg/-11 ± 9mmHg, p<0.001). Interestingly, the surgical group and drug group did not show better blood pressure control effects than short-term follow-up (p=0.56), Surgery (LVMI: M=-12.6, p=0.01)and medication (LVMI: M=-11.9, p=0.01])can significantly improve left ventricular hypertrophy in patients, with no significant difference (P=0.143). Although surgery (E/A: M=+0.14, p=0.125) and medication (E/A: M=+0.09, p=0.2) can numerically improve diastolic function, there is no statistically significant difference. Conclusions: Both medication and surgical treatment can reverse the damage to the heart structure and function in PA patients. In the short term, surgical treatment has a more significant reversal of cardiac function, especially in left ventricular hypertrophy, but in the long term, there is no significant difference between medication and surgical treatment.

Cholinergic Stimulation Exerts Cardioprotective Effects and Alleviates Renal Inflammatory Responses after Acute Myocardial Infarction in Spontaneous Hypertensive Rats (SHRs).

In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial infarction (AMI) in spontaneously hypertensive rats (SHRs). Adult male SHRs were randomized into three experimental groups: sham-operated; AMI + Veh (infarcted, treated with vehicle); and AMI + PY (infarcted, treated with the cholinesterase inhibitor, pyridostigmine bromide (PY)-40 mg/kg, once daily for seven days). Rats were euthanized 7 or 30 days post-surgery. The clinical parameters were assessed on the day before euthanasia. Subsequent to euthanasia, blood samples were collected and renal tissues were harvested for histological and gene expression analyses aimed to evaluate inflammation and injury. Seven days post-surgery, the AMI + PY group demonstrated improvements in left ventricular diastolic function and autonomic regulation, and a reduction in renal macrophage infiltration compared to the AMI + Veh group. Furthermore, there was a notable downregulation in pro-inflammatory gene expression and an upregulation in anti-inflammatory gene expression. Analysis 30 days post-surgery showed that PY treatment had a sustained positive effect on renal gene expression, correlated with a decrease in biomarkers, indicative of subclinical kidney injury. Short-term cholinergic stimulation with PY provides both cardiac and renal protection by mitigating the inflammatory response after AMI.

Influence of dapagliflozin on cardiovascular remodeling in hypertensive patients with accompanying type 2 diabetes

Aim. To compare the results of 12-week treatment of patients with stage II hypertension (HTN) with accompanying diabetes mellitus (DM) type 2 between the combination of metformin + dapagliflozin and metformin monotherapy by studying changes in the elastic properties of the common carotid arteries (CCA), echocardiographic indicators, 24-hour ambulatory blood pressure monitoring (ABPM) and laboratory parameters of lipid and carbohydrate metabolism. Materials and methods. 24 patients with stage II HTN with type 2 DM were involved in the study, the average age was 60.4 years, 50 % – men. Patients in the first group were randomized to receive metformin, and the second group – to receive a combination of metformin and dapagliflozin. At inclusion and after 3 months of treatment, basic anthropometric data, laboratory indicators of lipid and carbohydrate metabolism, ABPM, echocardiography, and indicators of CCA local stiffness were studied. Statistical analysis was performed, the probability of differences is at the level of p < 0.05. Results. In both observation groups, there was a comparable decrease in SCORE 2-Diabetes range, glucose and glycated hemoglobin, total cholesterol, LDL cholesterol, average daily systolic blood pressure (SBP), daily SBP load, day and night pulse BP, as well as an increase in speed systolic movement of the lateral fibrous ring of the mitral valve (S lat). Only in the metformin + dapagliflozin group a decrease in the adipose tissue level, the average daily diastolic blood pressure (DBP), the burden of DBP, the size of the left atrium and right ventricle, an increase in the movement speeds of the medial (e’med), lateral (e’lat) ring of the mitral and of the tricuspid (e’tk) valve in the period of early diastolic filling of the ventricles, velocities of systolic movement of the medial fibrous ring of the mitral (S med) and tricuspid (S tk) valves, a decrease in the ratio E/e’, and an improvement in the elastic properties of general carotid arteries were observed. Conclusions. In persons with HTN stage II with DM type 2 the addition of dapagliflozin to the treatment regimen was associated with better control of blood pressure, improvement of diastolic function and longitudinal contractility of the left ventricle, elastic properties of CCA.

Concurrent Resistance and Cardiorespiratory Training in Patients with Hypertrophic Cardiomyopathy: A Pilot Study.

Background: Exercise training in patients with HCM has evidenced benefits on functional capacity, cardiac function, and a reversion of adverse cardiac remodeling. The objective of this study was to assess the effect of a concurrent resistance and cardiorespiratory training program on functional capacity, biochemical parameters, and echocardiographic variables in a pilot group. Methods: Two HCM patients were evaluated before and after 12 weeks of individualized concurrent training with two sessions/week. Pre- and post-training data were compared for each patient. Evaluations included a cardiopulmonary exercise test (CPET), body composition, echocardiography, electrocardiography, and blood analysis. Results: Training promoted an increase in functional capacity (+4 mL·kg-1·min-1), ventilatory thresholds, and other CPET-derived variables associated with a better prognosis and long-term survival. Muscular mass was augmented (0.8 and 1.2 kg), along with a mean increase of 62% in upper and lower body strength. Echocardiographic features demonstrated the maintenance of cardiac function with signs of positive left ventricular remodeling and an improvement in diastolic function. Blood analyses, including cardiac troponins and NT-proBNP, displayed uneven changes in each patient, but the values fell into normal ranges in both cases. Conclusions: The available data suggest a positive effect of concurrent resistance and cardiorespiratory training on patients' functional capacity and cardiac function that may improve their functional class, quality of life, and long-term prognosis. The replication of this protocol in a larger cohort of patients is warranted to confirm these preliminary results.

Heart failure with preserved ejection fraction: A short review of diagnosis and management

Around 64 million persons in the world have heart failure (HF). HF patients with left ventricle ejection fraction (LVEF) of ≥50% are classified as having HF with preserved ejection fraction (HFpEF). It is estimated that about fifty percent of all HF is HFpEF. Our aim was to provide evidence of contemporary data regarding diagnosis and management of HFpEF. We conducted literature search through online search such as Google Scholar and PubMed Central (PMC), focusing on diagnosis and management of HFpEF. Several criteria exist for the diagnosis of HFpEF, including EF 50%, evidence of diastolic dysfunction, elevated brain natriuretic peptide. High (≥15) or intermediate (9–14) E/eʹ index indicates the likelihood of HFpEF. SGLT2I decrease E/eʹ, indicating improvement of LV diastolic function as mentioned in several studies. Treatment duration to achieve this effect spans from 3 months to 1 year. SGLT2I have positive effect on echocardiographic parameter HFpEF patients. In the researches included in the review, E/eʹ was mainly used as primary end point.

Selective SERCA2a activator as a candidate for chronic heart failure therapy

BackgroundThe sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) depression substantially contributes to diastolic dysfunction in heart failure (HF), suggesting that SERCA2a stimulation may be a mechanism-based HF therapy. Istaroxime is a drug endowed with both a SERCA2a stimulatory activity and a Na+/K+ pump inhibitory activity for acute HF treatment. Its main metabolite PST3093 shows a more favorable therapeutic profile as compared to the parent drug, but it is still unsuitable for chronic usage. Novel PST3093 derivatives have been recently developed for oral (chronic) HF treatment; compound 8 was selected among them and here characterized.MethodsEffects of compound 8 were evaluated in a context of SERCA2a depression, by using streptozotocin-treated rats, a well-known model of diastolic dysfunction. The impact of SERCA2a stimulation by compound 8 was assessed at the cellular level ad in vivo, following i.v. infusion (acute effects) or oral administration (chronic effects).ResultsAs expected from SERCA2a stimulation, compound 8 induced SR Ca2+ compartmentalization in STZ myocytes. In-vivo echocardiographic analysis during i.v. infusion and after repeated oral administration of compound 8, detected a significant improvement of diastolic function. Moreover, compound 8 did not affect electrical activity of healthy guinea-pig myocytes, in line with the absence of off-target effects. Finally, compound 8 was well tolerated in mice with no evidence of acute toxicity.ConclusionsThe pharmacological evaluation of compound 8 indicates that it may be a safe and selective drug for a mechanism-based treatment of chronic HF by restoring SERCA2a activity.Graphical

Unveiling the Therapeutic Potential of SGLT2 inhibitors and Oral Ketone Ester in Heart Failure with Preserved Ejection Fraction: A Comprehensive Exploration of Cardiac Function, Structure, and Metabolism in a Rat Model

BackgroundThis study investigated the potential efficacy of SGLT2 inhibitors empagliflozin and oral ketone supplementation as treatments for heart failure with preserved ejection fraction (HFpEF), which is often associated with obesity and type 2 diabetes mellitus. Methods20-week-old obese ZSF-1 rats were given different treatments for 12 weeks, including vehicle, empagliflozin, ketone ester (KE), or a combination of empagliflozin and KE. Cardiac magnetic resonance imaging (CMR) and hyperpolarized carbon-13 (13C) labeled pyruvate magnetic resonance spectroscopy imaging were used to evaluate cardiac function and metabolism, while histological and molecular markers of cardiac remodeling were assessed in the left ventricle. ResultsThe untreated HFpEF rats exhibited obesity, diabetes, cardiac hypertrophy, atrial enlargement, lung congestion, and increased cardiomyocyte size and cardiac expression of atrial natriuretic peptide (ANP) and fibrosis marker col1a1 and TIMP1. The treatment groups exhibited decreased body weight, increased circulating ketone levels, and reduced blood glucose levels. All treatment regimens significantly attenuated ventricular hypertrophy, atrial enlargement, and lung congestion. Furthermore, all treatments significantly reduced cardiomyocyte size and the expression of ANP and fibrosis marker. The combination of empagliflozin and KE showed the greatest improvement in diastolic function and cardiac ATP levels. Interestingly, hyperpolarized [1-13C] pyruvate detected a decrease in lactate/pyruvate ratio in the hearts treated with empagliflozin. ConclusionObese ZSF1 rats exhibit features of clinical HFpEF with predominant background of obesity and diabetes. A combination of empagliflozin and KE has greater benefits in treating HFpEF. Targeting cardiometabolic dysregulation may be a promising approach for HFpEF treatment.

Improvement in myocardial energetics and perfusion with Liraglutide in patients with type 2 diabetes- A randomised, single centre, open label, cross-over drug trial

Abstract Background Both the insulin secretion and insulin resistance in Type 2 diabetes (T2D) are amenable to pharmacological intervention. In a single center, open-label, randomized, cross-over design trial we sought to compare two distinct glycaemic control strategies of targeting beta-cell dysfunction and promoting insulin secretion using Glucagon-like peptide-1 receptor agonists (GLP-1RA) -liraglutide and targeting peripheral insulin resistance using a peroxisome proliferator activated receptor-gamma agonist (PPAR-g)-pioglitazone to see which results in greater improvements in myocardial perfusion, energetics and function in patients with T2D. Methods Fifty-two T2D patients were screened. Eligible patients with no known prior cardiovascular disease were randomized in a 1:1 ratio to be administered one of the study drugs for a 16-week treatment period followed by an 8-week washout and a further 16-week treatment period for the second drug. Thirty-three eligible participants completed both treatment periods. Participants have undergone 31phosphorus magnetic resonance spectroscopy (31P-MRS) at rest and dobutamine stress followed by the cardiac magnetic resonance (CMR) scans. The CMR protocol consisted of rest and dobutamine stress cine imaging, perfusion imaging (motion corrected, automated in-line perfusion mapping), velocity-encoded mitral in-flow imaging and late gadolinium enhanced imaging at 3T immediately before commencement and after completion of each treatment arm (four scans per participant). Results Clinical and biochemical characteristics, and CMR/31P-MRS results are provided in Tables 1&2 respectively. Liraglutide therapy resulted in a significant reductions in the body mass index and significant improvements in glycemic control. Both drugs reduced insulin resistance indicated by a reduction in the mean triglyceride index. There were no significant changes in NTproBNP or troponin levels with either drug. Therapy with either drug did not result in a significant change in the LV end-diastolic volume, ejection fraction or global longitudinal shortening. Pioglitazone led to a significant increment in mean LV mass and LV mass index, while no significant effect in myocardial mass or mass index were detected with liraglutide. Liraglutide therapy resulted in increased rest and dobutamine stress energetics, global stress myocardial blood flow and myocardial perfusion reserve index. While pioglitazone treatment showed no significant effect in these parameters, an isolated improvement in the rest diastolic function was detected in this arm. Conclusions In this randomised cross-over design trial we showed for the first time that four months treatment with glucagon like protein 1 receptor agonist liraglutide results in significant improvements in myocardial stress perfusion and energetics. Pioglitazone results in an isolated improvement in rest diastolic funct

Abstract 13962: Exploring the Therapeutic Potential of SGLT2 Inhibitors and Oral Ketone Ester in HFpEF: A Comprehensive Exploration of Cardiac Function, Structure, and Metabolism in a Rat Model

Introduction: This study aimed to assess the potential efficacy of the SGLT2 inhibitor empagliflozin and oral ketone ester supplementation as treatments for heart failure with preserved ejection fraction (HFpEF), which is commonly associated with obesity and type 2 diabetes mellitus. Methods: Twenty-week-old obese ZSF-1 rats were initially fed a high-fat diet (HFD) to establish and maintain the phenotype. Subsequently, the rats were randomly assigned to different treatment groups. These groups consisted of a control group receiving only the high-fat diet (HFD), as well as groups receiving empagliflozin, ketone ester (DeltaG®, KE), or a combination of both in addition to the HFD. Cardiac magnetic resonance imaging (CMR) and hyperpolarized carbon-13 (13C) labeled pyruvate magnetic resonance spectroscopy imaging were used to evaluate cardiac function and metabolism. Histological and molecular markers of cardiac remodeling were assessed in the left ventricle. Results: Untreated HFpEF rats exhibited obesity, diabetes, cardiac hypertrophy, atrial enlargement, lung congestion, increased cardiomyocyte size and fibrosis, as well as elevated expression of atrial natriuretic peptide (ANP), col1a1 (fibrosis marker), and TIMP1. The treatment groups displayed decreased body weight, increased circulating ketone levels, and reduced blood glucose levels. All treatment regimens significantly mitigated ventricular hypertrophy, atrial enlargement, and lung congestion. Furthermore, they reduced cardiomyocyte size, ANP expression, fibrosis marker expression, and increased cardiac ATP levels. CMR revealed that the combination of empagliflozin and KE resulted in improvement in diastolic function. Hyperpolarized [1-13C] pyruvate imaging revealed a decrease in lactate/pyruvate ratio in empagliflozin-treated hearts, indicating improved oxidative metabolism. Conclusions: The findings of this study suggest that targeting cardiometabolic dysregulation holds promise as an effective approach for the treatment of HFpEF. While both empagliflozin or KE alone demonstrated improvements in cardiac energetics and remodeling, the combination of empagliflozin and KE yielded the most notable benefits in enhancing cardiac diastolic function.

Abstract 12927: Impact of AAV- MYBPC3 Gene Transfer on Heart Structure and Function in Human and Mouse Models of Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a life-threatening inherited heart disease characterized by left ventricular hypertrophy and diastolic dysfunction. The most common cause of HCM is genetic variants in MYBPC3 , encoding cardiac myosin binding protein C (cMyBP-C), a sarcomeric protein with structural and regulatory roles. The majority of MYBPC3 gene variants are truncating leading to protein haploinsufficiency. Hypothesis: Transfer of a functional copy of MYBPC3 to heart muscle deficient in cMyBP-C will lead to sustained improvements in cardiac function. Aims: To determine whether BMN 293 (AAV-hMYBPC3) can restore cMyBP-C levels in the sarcomere and halt and/or reverse disease progression in non-clinical models of genetic HCM due to MYPBC3 deficiency. Methods: BMN 293 is an adeno-associated virus (AAV) vector that encodes wild-type human MYBPC3 under the control of a cardiomyocyte-selective promoter. We transduced human iPSC-derived cardiomyocytes and engineered heart tissues (EHTs) carrying a compound heterozygous truncating MYBPC3 mutation (MYBPC3 -/- ) with BMN 293 and assessed cMyBP-C levels and contractile parameters. We also systemically administered BMN 293 to MYBPC3 -/- mice and assessed cardiac distribution of human cMyBP-C by molecular and histological methods and determined its impact on left ventricular hypertrophy and function by echocardiography and other imaging techniques. Results: BMN 293 transduction of human iPSC MYBPC3 -/- cardiomyocytes and EHTs resulted in high levels of human MYBPC3 mRNA and cMyBP-C protein, correct incorporation of cMyBP-C into the sarcomere, and complete normalization of contractile kinetics. BMN 293 was well tolerated in MYBPC3 -/- mice and resulted in uniform restoration of cMyBP-C expression throughout the heart and significant correction of structural and functional cardiac abnormalities. Conclusions: A single IV infusion of BMN 293 to MYBPC3 -/- mice resulted in early and sustained reduction in left ventricular hypertrophy and durable improvements in diastolic function.

Clinical efficacy of a fixed-dose combination of amlodipine/indapamide/perindopril in patients with hypertension and multiple risk factors

Aim. To evaluate the antihypertensive and organ protective efficacy of the triple fixed-dose combination of amlodipine/indapamide/perindopril in patients with hypertension (HTN) who did not achieve target blood pressure (BP) on previous antihypertensive therapy (AHT).Material and methods. The study included 47 patients with HTN and multiple risk factors who did not achieve target blood pressure during previous AHT. They were prescribed triple fixed-dose combination of amlodipine/indapamide/perindopril with preliminary prescription of amlodipine, indapamide and perindopril in the free-dose combination. At baseline and after 3 months of AHT, 24-hour ambulatory blood pressure monitoring (ABPM), echocardiography and arterial stiffness were analyzed.Results. Initially, in patients included in the study, the main ABPM parameters were increased, while non dipper and reduced dipper (66% of patients) patterns prevailed. The results of echocardiography indicated left ventricular (LV) hypertrophy (LVH) by left ventricular mass index (LVMI), left ventricular posterior wall thickness (LVPWT), interventricular septum (IVS) and its diastolic dysfunction by E/A, while an increase in CAVI and biological vascular age reflected an increase in arterial stiffness. After 3 months of AHT, significant (p£0,05) ABPM changes and a predominance of the dipper-type 24-hour BP pattern were recorded in more than half of the patients (53%). A decrease in LVMI, LVPWT and IVS by 7%, 12% and 8%, respectively (p£0,05), while an E/A increase by 12% reflected LVH regression and LV diastolic function improvement. A decrease in arterial stiffness was evidenced by a decrease (p£0,05) in CAVI by an average of 10% and biological vascular age by 4 years.Conclusion. Triple fixed-dose therapy of amlodipine/indapamide/perindopril after 3-month treatment made it possible to achieve target blood pressure in 78% of patients, improved ABPM parameters and ensured pronounced cardioand vasoprotective effects, reflected in LVH regression, improvement of LV diastolic function and reduction of arterial stiffness.

The effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats treated with the ACE2 inhibitor MLN-4760

BackgroundAngiotensin converting enzyme 2 (ACE2) plays a crucial role in the infection cycle of SARS-CoV-2 responsible for formation of COVID-19 pandemic. In the cardiovascular system, the virus enters the cells by binding to the transmembrane form of ACE2 causing detrimental effects especially in individuals with developed hypertension or heart disease. Zofenopril, a H2S-releasing angiotensin-converting enzyme inhibitor (ACEI), has been shown to be effective in the treatment of patients with essential hypertension; however, in conditions of ACE2 inhibition its potential beneficial effect has not been investigated yet. Therefore, the aim of the study was to determine the effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats, an animal model of human essential hypertension and heart failure, under conditions of ACE2 inhibition induced by the administration of the specific inhibitor MLN-4760 (MLN).ResultsZofenopril reduced MLN-increased visceral fat to body weight ratio although no changes in systolic blood pressure were recorded. Zofenopril administration resulted in a favorable increase in left ventricle ejection fraction and improvement of diastolic function regardless of ACE2 inhibition, which was associated with increased H2S levels in plasma and heart tissue. Similarly, the acute hypotensive responses induced by acetylcholine, L-NAME (NOsynthase inhibitor) and captopril (ACEI) were comparable after zofenopril administration independently from ACE2 inhibition. Although simultaneous treatment with zofenopril and MLN led to increased thoracic aorta vasorelaxation, zofenopril increased the NO component equally regardless of MLN treatment, which was associated with increased NO-synthase activity in aorta and left ventricle. Moreover, unlike in control rats, the endogenous H2S participated in maintaining of aortic endothelial function in MLN-treated rats and the treatment with zofenopril had no impact on this effect.ConclusionsZofenopril treatment reduced MLN-induced adiposity and improved cardiac function regardless of ACE2 inhibition. Although the concomitant MLN and zofenopril treatment increased thoracic aorta vasorelaxation capacity, zofenopril increased the participation of H2S and NO in the maintenance of endothelial function independently from ACE2 inhibition. Our results confirmed that the beneficial effects of zofenopril were not affected by ACE2 inhibition, moreover, we assume that ACE2 inhibition itself can lead to the activation of cardiovascular compensatory mechanisms associated with Mas receptor, nitrous and sulfide signaling.

Effect of physical activity on left ventricular dimensions and function after myocardial infarction: a systematic review.

Coronary artery disease is the major pathophysiological driver of ventricular remodeling. A multimodal intervention is the key strategy to promote a positive left ventricular remodeling with improvement in volumes and ejection fraction, known as "reverse remodeling." The aim of this review was to highlight the effect of physical activity (PA) on echocardiographic and cardiac magnetic resonance parameters of left ventricle in patients with myocardial infarction. We performed a systematic review of the literature to summarize current evidence about the efficacy (in terms of improvement in chamber dimensions, ejection fraction, speckle tracking and diastolic function) of physical activity in patients with myocardial infarction, supported by echocardiographic or magnetic resonance data. Articles were searched in Pubmed, Cochrane Library and Biomed Central. Only papers published in English and in peer-reviewed journals up to November 2022 were selected. After an initial evaluation, 1029 records were screened; the literature search identified 20 relevant articles. From this data, some PA protocols appeared to favor left ventricular reverse remodeling. PA provides beneficial effects on left ventricular parameters analyzed by echocardiography and cardiac magnetic resonance.

Effects of sacubitril/valsartan in patients with cancer therapy-related heart failure

To evaluate the effect of Sacubitril/Valsartan (S/V) on the functional status, systolic and diastolic function of the left ventricle (LV), tolerability of therapy and to determine predictors of its effectiveness in patients with cancer therapy-related heart failure (СTRHF). Forty patients 58 [46; 65.5] years of age with HF associated with anthracycline-containing cancer therapy were enrolled. Clinical examination, echocardiography, and assessment of potassium and creatinine levels were performed at baseline and after 6 months of S/V therapy. NYHA functional class (FC) improvement was observed in 22 (64.7%) patients. Radiation therapy (RT) decreased (OR 0.091; 95% CI 0.01-0.83; p=0.03) while baseline low LV EF increased (OR 9.0; 95% CI 1.78-45.33; p=0.008) the odds of FC improvement. LV EF increased from 37.3 [30; 42.5] % to 45 [38; 48] % (p<0.0001) and exceeded 50% in 7 (20.6%) patients. The odds of LV EF recovery increased when S/V therapy was initiated ≤1 year after anthracycline therapy (OR 10.67; 95% CI 1.57-72.67; p=0.0016) and decreased in patients with the history of RT (OR 0.14; 95% CI 0.02-0.89; p=0.0037) and in patients over 58 years (OR 0.07; 95% CI 0.01-0.68; p=0.022). LV diastolic function improvement included E/e' descent from 13.6 [10; 18.3] to 8.9 [6.9; 13.7] (p=0.0005), and decrease in diastolic dysfunction grade in 18 (45%) patients (p=0.0001). No significant change in serum potassium (4.45 [4.2; 4.8] versus 4.5 [4.3; 4.8]; p=0.5) and creatinine (75.4 [67.6; 85.1] versus 75.5 [68.2; 98.3]; p=0.08) levels were observed. S/V therapy is associated with improvement of EF, systolic and diastolic LV function, demonstrates a favorable tolerability profile in patients with СTRHF. Lack of RT and low baseline LV EF increased the odds of LV EF improvement; lack of RT, early (≤1 year) start of treatment after discontinuation of anthracycline therapy, and age <58 years increased the odds of LV EF recovery.

Effect of Glucagon-like Peptide-1 Receptor Agonist on Cardiac Structure and Function in Patients with Heart Failure: A Systematic Review and Meta-analysis

Article Effect of Glucagon-like Peptide-1 Receptor Agonist on Cardiac Structure and Function in Patients with Heart Failure: A Systematic Review and Meta-analysis Xinyu Zhang 1, and Hongyuan Zhang 2, * 1 Division of Bioscience, University College London, London, UK 2 Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK * Correspondence: hongyuan.zhang-3@postgrad.manchester.ac.uk Received: 23 May 2023 Accepted: 8 August 2023 Abstract: Recent clinical trials have shown that glucagon-like peptide-1 receptor agonists (GLP-1RAs) yield positive effects on composite cardiovascular endpoints, rendering them potentially promising therapeutic agents for heart failure (HF). This study analysed the effect of GLP-1RAs on cardiac structure and function in HF patients. MethodsA comprehensive search was conducted across PubMed, Cochrane Library, Ovid Embase, Ovid Medline, and Web of Science databases, spanning from inception to August 1, 2022, to identify randomised controlled trials (RCTs) comparing alterations in cardiac structure and function in HF patients receiving GLP-1RAs or placebo. Cardiac structures were assessed through left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular mass (LVM). Systolic function was evaluated using left ventricular ejection fraction (LVEF), stroke volume (SV), and global longitudinal strain (GLS). Diastolic function was assessed via the early to late diastolic filling velocity ratio (E/A ratio) and the early transmitral filling velocity to early diastolic mitral annular velocity ratio (E/e ratio). The I2 statistic was used to test heterogeneity. Pooled relative risks were calculated using random-effects models. Potential publication bias was assessed using the Cochrane Risk of Bias 2 tool. ResultsA total of 1,417 patients from 16 randomised placebo-controlled trials were enrolled in this meta-analysis. Among all HF patients, GLP-1RAs demonstrated improvement in diastolic function as indicated by E/A (MD = -0.15; 95% CI: -0.21 to -0.09; P &lt; 0.00001; I2 = 43%) and E/e’ (MD = -0.82; 95% CI: -1.53 to -0.11; P = 0.02; I2= 62%). However, GLP-1RAs did not exhibit any improvement in cardiac structure and systolic function parameters for HF patients. ConclusionGLP-1RAs demonstrated potential for improving diastolic function in HF patients, but did not show any impact on systolic function and cardiac structure. Therefore, the application of GLP-1RAs should be based on the specific HF type and accompanying comorbidities.

Hemodynamics and diastolic function after native aortic valve preserving vs replacing surgery.

Background Alterations in left ventricular (LV) diastolic function following native tissue-preserving aortic valve (AV) procedures have not been systematically investigated. Furthermore, no comparisons have been made between these changes and those observed after prosthetic AV replacement. Methods From October 2017 to August 2020, 74 patients aged <65 years were referred to our institution for elective AV surgery. Preoperative and postoperative (i.e., discharge, 3-months and 1-year follow-up) transthoracic echocardiography was analyzed. Results Native tissue-preserving surgery was performed in 55 patients (AV repair: n=42, Ross procedure: n=13). The remaining 19 patients underwent prosthetic AV replacement. Preoperatively and at discharge, transvalvular hemodynamics and LV diastolic function were comparable in both groups. At 1-year follow-up, native valve patients showed significantly lower mean transvalvular gradients (7±5 vs. 9±3 mmHg,p=0.046) and peak velocity (1.74±0.51 vs. 2.26±0.096 m/s,p=0.004) and significantly better septal e' (9.1±2.7 vs. 7.7±2.5 cm/s,p=0.043) and lateral e' (14.7±3.1 vs. 11.7±3.7 cm/s,p=0.001). From preoperatively to 1 year postoperatively, septal and lateral e' and E/e' improved markedly after native valve preservation (septal e': +0.7 cm/s,p=0.075; lateral e': +2.3 cm/s,p<0.001; E/e': -1.5,p=0.001) but not after AV replacement (septal e': +0.2 cm/s,p=0.809; lateral e': +0.8 cm/s,p=0.574; E/e': -1.2,p=0.347). Significant negative linear correlations between postoperative transvalvular gradients and absolute changes in lateral e' and E/e' were detected during follow-up. Conclusion Preservation of native tissue in AV surgery results in superior transvalvular hemodynamics compared to prosthetic AV replacement. This may induce faster LV reverse remodeling and may explain more pronounced improvement in LV diastolic function.

Effect of empagliflozin on the left ventricular diastolic function in patients with type 2 diabetes mellitus and concomitant heart failure with preserved ejection fraction

Background. Heart failure with preserved ejection fraction is a common disease affecting more than half of people with heart failure. Among the extracardiac proinflammatory conditions, type 2 diabetes mellitus, which occurs in approximately 30–40 % of patients with heart failure, deserves special attention. The purpose of the study is to evaluate the effect of empagliflozin on the left ventricular diastolic function in patients with type 2 diabetes mellitus and concomitant heart failure with preserved ejection fraction. Materials and methods. One hundred and twenty patients met the study criteria and were randomized in a 1 : 1 ratio to the empagliflozin group (n = 60) or the control group (n = 60), which received other antidiabetic drugs. The follow-up period lasted 12 weeks. A transthoracic echocardiogram was performed and functional and structural changes of the heart in these diseases were identified. Results. The data showed a marked improvement in several cardiac parameters. One important result was a decrease in the left ventricular mass index, which indicates a reduction in the left ventricular size and hypertrophy. This reduction shows a favorable course of remodeling and a potential regression of cardiac remodeling under the influence of empagliflozin. In addition, the study demonstrated an improvement in the left ventricular diastolic function. In particular, deceleration time and the E/e’ ratio showed favorable changes. Deceleration time, which reflects the relaxation and compliance of the left ventricle, decreased significantly, indicating an improvement in diastolic function. The E/e’ ratio, a marker of the left ventricular filling pressure, also showed positive changes, indicating a decrease in cardiac tension and improved ventricular relaxation. Conclusions. The results of the study demonstrated that empagliflozin treatment has a posi­tive effect on various cardiovascular parameters in patients with the studied diseases, in particular on the left ventricular diastolic function. These findings contribute to our understanding of the therapeutic potential of empagliflozin in the management of cardiovascular diseases.