Improvement In Left Ventricular Diastolic Function Research Articles

Lipoxin A4 improves cardiac remodeling and function in diabetes-associated cardiac dysfunction

BackgroundDiabetic heart disease may eventually lead to heart failure, a leading cause of mortality in diabetic individuals. The lack of effective treatments for diabetes-induced heart failure may result from a failure to address the underlying pathological processes, including chronic, low-grade inflammation. Previous studies have reported that lipoxin A4 (LXA4), known to promote resolution of inflammation, attenuates diabetes-induced atherosclerosis, but its impact on diabetic hearts has not been sought. Thus, we aimed to determine whether LXA4 therapeutic treatment attenuates diabetes-induced cardiac pathology.MethodsSix-week-old male apolipoprotein E-deficient (ApoE−/−) mice were followed for 16 weeks after injection of streptozotocin (STZ, 55 mg/kg/day, i.p. for 5 days) to induce type-1 diabetes (T1DM). Treatment with LXA4 (5 μg/kg, i.p.) or vehicle (0.02% ethanol, i.p.) was administered twice weekly for the final 6 weeks. One week before endpoint, echocardiography was performed within a subset of mice from each group. At the end of the study, mice were euthanized with sodium pentobarbital (100 mg/kg i.p.) and hearts were collected for ex vivo analysis, including histological assessment, gene expression profiling by real-time PCR and protein level measurement by western blot.ResultsAs expected diabetic mice showed a significant elevation in plasma glycated hemoglobin (HbA1c) and glucose levels, along with reduced body weight. Vehicle-treated diabetic mice exhibited increased cardiac inflammation, macrophage content, and an elevated ratio of M1-like to M2-like macrophage markers. In addition, myocardial fibrosis, cardiomyocytes apoptosis and hypertrophy (at the genetic level) were evident, with echocardiography revealing early signs of left ventricular (LV) diastolic dysfunction. Treatment with LXA4 ameliorated diabetes-induced cardiac inflammation, pro-inflammatory macrophage polarization and cardiac remodeling (especially myocardial fibrosis and cardiomyocytes apoptosis), with ultimate improvement in cardiac function. Of note, this improvement was independent of glucose control.ConclusionsThese findings demonstrated that LXA4 treatment attenuated the extent of cardiac inflammation in diabetic hearts, resulting in limited cardiac remodeling and improved LV diastolic function. This supports further exploration of LXA4-based therapy for the management of diabetic heart disease. The recent development of stable LXA4 mimetics holds potential as a novel strategy to treat cardiac dysfunction in diabetes, paving the way for innovative and more effective therapeutic strategies.Graphical

Relationship between changes in renal function after acute phase of tafamidis administration and left ventricular diastolic function at mid-term follow-up in transthyretin cardiac amyloidosis

Abstract Background A large number of heart failure (HF) patients present with various degrees of renal dysfunction, known as cardio-renal syndrome. Renal impairment in HF patients is also associated with an independent risk factor for morbidity and mortality. Transthyretin (TTR) amyloidosis (ATTR) is characterized by disintegrated liver-derived TTR that accumulates as amyloid fibrils in the myocardium, leading to initially presenting as left ventricular (LV) hypertrophy and LV diastolic dysfunction. Although there is no proven therapy for patients with ATTR cardiomyopathy (ATTR-CM), tafamidis meglumine, a TTR stabilizer, has been associated with favorable outcomes. Although the kidneys are also an important organ where amyloid deposition occurs, the effect of tafamidis on renal function and its relationship to LV diastolic function is unclear. Purpose The purpose of this study was to investigate the relationship between changes in renal function after the acute phase of tafamidis administration and LV diastolic function at mid-term follow-up in patients with ATTR-CM. Methods We studied 56 patients with biopsy-proven ATTR-CM who were treated with tafamidis. All patients underwent blood examinations before and 45.6 ± 23.0 days after the acute phase of tafamidis administration. Echocardiography was performed before and 15.6 ± 9.8 months after the mid-term of tafamidis administration. The primary endpoint was defined as a composite of cardiovascular death or HF hospitalization for 5.0 years. Results Twelve patients had improved renal function as assessed by estimated glomerular filtration rate in the acute phase after tafamidis administration, while 44 patients deteriorated. In the group with improved renal function in the acute phase after tafamidis administration, pulsed-wave Doppler-derived early diastolic velocity from the septal mitral annulus (E’) and left atrial volume index (LAVI) tended to improve at mid-term follow-up compared to the non-improved group. (E’: 0.8 ± 1.7 cm/s vs. 0.2 ± 1.1 cm/s, p=0.127, LAVI: -8.7 ± 12.0 mL/m2 vs. 0.2 ± 16.8 mL/m2, p=0.093). Furthermore, Kaplan-Meier curve indicated that the occurrence of cardiovascular events for patients with improved renal function in the acute phase after tafamidis administration tended to be lower than those without (log-rank P=0.137). Conclusions The improvement of renal function in the acute phase after tafamidis administration was associated with the improvement of LV diastolic function at mid-term follow-up, leading to favorable outcome. Our findings may provide new insights for the management of patients with ATTR-CM.

PDE9A Inhibition Improves Coronary Microvascular Rarefaction and Left Ventricular Diastolic Dysfunction in the ZSF1 Rat Model of HFpEF.

Heart failure with preserved ejection fraction (HFpEF) commonly arises from comorbid diseases, such as hypertension, obesity, and diabetes mellitus. Selective inhibition of phosphodiesterase 9A (PDE9A) has emerged as a potential therapeutic approach for treating cardiometabolic diseases. Coronary microvascular disease (CMD) is one of the key mechanisms contributing to the development of left ventricular (LV) diastolic dysfunction in HFpEF. Our study aimed to investigate the mechanisms by which PDE9A inhibition could ameliorate CMD and improve LV diastolic function in HFpEF. The obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat model of HFpEF was employed in which it was found that a progressively developing coronary microvascular rarefaction is associated with LV diastolic dysfunction when compared to lean, nondiabetic hypertensive controls. Obese ZSF1 rats had an increased cardiac expression of PDE9A. Treatment of obese ZSF1 rats with the selective PDE9A inhibitor, PF04447943 (3 mg/kg/day, oral gavage for 2 weeks), improved coronary microvascular rarefaction and LV diastolic dysfunction, which was accompanied by reduced levels of oxidative and nitrosative stress markers, hydrogen peroxide, and 3-nitrotyrosine. Liquid chromatography-mass spectrometry (LC-MS) proteomic analysis identified peroxiredoxins (PRDX) as downregulated antioxidants in the heart of obese ZSF1 rats, whereas Western immunoblots showed that the protein level of PRDX5 was significantly increased by the PF04447943 treatment. Thus, in the ZSF1 rat model of human HFpEF, PDE9A inhibition improves coronary vascular rarefaction and LV diastolic dysfunction, demonstrating the usefulness of PDE9A inhibitors in ameliorating CMD and LV diastolic dysfunction through augmenting PRDX-dependent antioxidant mechanisms.

#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.

Urocortin 2 Gene Transfer in Mice Improves Diastolic Function in Heart Failure with Preserved Ejection Fraction

Patients with heart failure and preserved ejection fraction (HFpEF) comprise about 50% of patients with heart failure in the US (>3 million people). There are currently no treatments for HFpEF that prolong life, and few that reduce HF hospitalization rates. The Schlager BPH (Blood Pressure-High) mouse is a genetic model of hypertension, a major contributing factor in left ventricular (LV) diastolic dysfunction and HFpEF. This study test the hypothesis that intravenous (i.v.) delivery of a long-term expression vector encoding murine urocortin 2 (AAV8.m Ucn2) can improve LV diastolic function in mice with impaired LV diastolic function. Twelve male and 12 female BPH mice (21.3±0.5 g; 3.1±0.1 months-old) with an ejection fraction (EF) of 60±2% (echocardiography) were studied. Prior to Ucn2 gene transfer their unsedated systolic/diastolic blood pressures (tail cuff) were (183/146±2/7 mmHg, n=24), conforming the presence of severe hypertension. The BPH mice were separated into two groups (6M & 6F in each group). One group (BPH + Ucn2) received AAV8.m Ucn2 (2x1013 gc/kg, i.v) and the other group (BPH) received saline, i.v. Seven weeks after randomization, LV EF showed a group difference (BPH: 54±2%, n=12; BPH+Ucn2: 74±2%, n=12; p<.0001) that was same as with systolic/diastolic blood pressure (BPH: 183/154±4/4 mmHg, n=12; BPH +Ucn2: 142/117±4/4 mmHg; p<0.0001). In addition, physiological studies conducted in vivo showed accelerated cardiac relaxation in the Ucn2-treated mice (see Tau in Table), indicating superior LV relaxation after Ucn2 gene transfer. Conclusion: Ucn2 gene transfer improves LV diastolic and systolic function in mice with HFpEF, indicating that such a strategy may be applicable in clinical settings. [Formula: see text] Merit grant from the Department of Veterans Affairs (I01 BX003774). 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.

Effects of ipragliflozin on left ventricular diastolic function in patients with type 2 diabetes: A sub-analysis of the PROTECT trial

BackgroundWe hypothesized that the beneficial effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on diastolic function might depend on baseline left ventricular (LV) systolic function. MethodsTo investigate the effects of SGLT2 inhibitors on LV diastolic function in patients with type 2 diabetes mellitus (T2DM), we conducted a post-hoc sub-study of the PROTECT trial, stratifying the data according to LV ejection fraction (LVEF) at baseline. After excluding patients without echocardiographic data at baseline or 24 months into the PROTECT trial, 31 and 38 patients with T2DM from the full analysis dataset of the PROTECT trial who received ipragliflozin or no SGLT2 inhibitor (control), respectively, were included. The primary endpoint was a comparison of the changes in echocardiographic parameters and N-terminal pro-brain natriuretic peptide levels from baseline to 24 months between the two groups stratified according to baseline LVEF. ResultsDifferences in diastolic functional parameters (e' and E/e') were noted between the two groups. Among the subgroups defined according to median LVEF values, those with higher LVEF (≥60 %) who received ipragliflozin appeared to have a higher e' and lower E/e' than did those who received the standard of care with no SGLT2 inhibitor, indicating longitudinal improvements between baseline and follow up (p = 0.001 and 0.016, respectively). ConclusionsIpragliflozin generally improved LV diastolic function in patients with type 2 diabetes, the extent of this improvement might appear to vary with LV systolic 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.

Cross-sectional associations between questionnaire-measured physical activity and tissue doppler indices of left ventricular diastolic function

BackgroundThe prevalence of left ventricular (LV) diastolic dysfunction has been increasing over the past decade, and to date, effective pharmacotherapies that enhance LV diastolic function have not yet been identified. Though some data has demonstrated the beneficial effects of exercise training on LV diastolic function, little is known about the adaptations of diastolic function to daily physical activity (PA). Accordingly, our study aimed to investigate the impact of daily PA on tissue Doppler indices of LV diastolic function.MethodsA total of 432 participants were enrolled for clinically indicated echocardiography from July 2019 to July 2020 at Peking University People’s Hospital. Participants aged ≥ 18 years were included if they had stable PA in the past six months and normal LV systolic function. A questionnaire was used to collect demographic characteristics, medical history, and daily PA. According to PA Guidelines for Americans, we identified these participants into low-intensity PA (LPA) group and moderate-high-intensity PA (MHPA) group. Propensity score matching (PSM) was performed to match potential confounding factors between the two groups. The clinical characteristics and echocardiographic parameters between LPA group and MHPA group were compared using student’s t-test, Mann-Whitney U test, and chi-square test as appropriate.ResultsAfter matching potential confounding factors using PSM with a 1:3 matching ratio, our final analysis included 86 cases in the MHPA group and 214 cases in the LPA group. All demographic characteristics and comorbidities were statistically similar between the two groups. Compared to the LPA group, the MHPA group showed higher septal e’ (7.9 ± 2.9 cm/s versus 7.2 ± 2.6 cm/s, P = 0.047). Other echocardiographic parameters associated with LV diastolic function concerning lateral e’ and average E/e’, also trended towards improved LV diastolic function in the MHPA group, but failed to reach statistical significance.ConclusionsOur study demonstrated that moderate-high-intensity daily PA was associated with improved septal e’, suggesting that moderate-high-intensity PA could potentially ameliorate LV diastolic dysfunction.

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 renal denervation on diastolic function in patients with resistant hypertension and type 2 diabetes mellitus

Aim: To assess the change in the left ventricular (LV) diastolic function (DF) in patients with resistant hypertension (RHTN) and type 2 diabetes mellitus (T2DM) during 6-month follow-up after renal denervation (RDN) according to echocardiography in conjunction with changes in hemodynamic parameters.Material and Methods. A single center prospective interventional study with renal denervation included 30 patients with RHTN and T2DM. All patients underwent measurement of office and 24-hour blood pressure (BP), echocardiography according to the standard method with an assessment of LV DF.Results. At 6 months after RDN, a significant antihypertensive effect was noted (p &lt; 0.05), as well as an improvement in LV DF in the form of a decrease in E/e` by 1 c.u. was observed in 50% (15) patients. A significant decrease in the average E/e` was documented (–1.3 [95% CI –2.55; –0.08], р = 0.038). There were no changes in the indexed volumes of the left atrium (р = 0.940). The baseline values of E/e` had correlation with the level of mean pulse BP 24h (r = 0.51, р = 0.001) in the absence of significant relationships with other ABPM parameters. A decrease in systolic BP 24h by 3 mm Hg and an increase in nocturnal systolic BP fall by 1.6% were accompanied by a decrease in the average E/e` by 1 unit. According to the ROC-analysis, baseline level of nocturnal systolic BP fall 5.5% or less associated with a decrease in the E/e` ratio by more than 1 unit.Conclusion. Renal denervation in patients with RHTN and T2DM is accompanied by a favorable effect on LV diastolic function during 6-month follow-up, closely related to the hemodynamic effects of the procedure such as a decrease in systolic and pulse BP 24h, as well as improvement in the circadian rhythm of BP.

Three-vessel coronary infusion of cardiosphere-derived cells for the treatment of heart failure with preserved ejection fraction in a pre-clinical pig model.

Heart failure with preserved ejection fraction (HFpEF) is a major public health concern. Its outcome is poor and, as of today, barely any treatments have been able to decrease its morbidity or mortality. Cardiosphere-derived cells (CDCs) are heart cell products with anti-fibrotic, anti-inflammatory and angiogenic properties. Here, we tested the efficacy of CDCs in improving left ventricular (LV) structure and function in pigs with HFpEF. Fourteen chronically instrumented pigs received continuous angiotensin II infusion for 5weeks. LV function was investigated through hemodynamic measurements and echocardiography at baseline, after 3weeks of angiotensin II infusion before three-vessel intra-coronary CDC (n = 6) or placebo (n = 8) administration and 2weeks after treatment (i.e., at completion of the protocol). As expected, arterial pressure was significantly and similarly increased in both groups. This was accompanied by LV hypertrophy that was not affected by CDCs. LV systolic function remained similarly preserved during the whole protocol in both groups. In contrast, LV diastolic function was impaired (increases in Tau, LV end-diastolic pressure as well as E/A, E/E'septal and E/E'lateral ratios) but CDC treatment significantly improved all of these parameters. The beneficial effect of CDCs on LV diastolic function was not explained by reduced LV hypertrophy or increased arteriolar density; however, interstitial fibrosis was markedly reduced. Three-vessel intra-coronary administration of CDCs improves LV diastolic function and reduces LV fibrosis in this hypertensive model of HFpEF.

Recovery of Biventricular Function After Catheter Intervention or Surgery for Neonatal Coarctation of the Aorta

BackgroundCritical coarctation of the aorta (CoA) is a life-threatening condition in newborns that is associated with biventricular dysfunction. ObjectivesThe purpose of this study was to examine clinical outcome and echocardiographic changes in isthmus diameter and biventricular function in newborns with critical CoA treated with balloon dilation/stent placement or surgery. MethodsThis is a retrospective single-center cohort study of 26 consecutive neonates with isolated critical CoA, who underwent transcatheter intervention (balloon angioplasty/stent; n = 10) or surgical CoA-repair (n = 16) (2012-2021). Isthmus dimensions and biventricular function at baseline and at hospital discharge were examined by echocardiography, including strain analysis of systolic and diastolic function using 2-dimensional speckle tracking. ResultsCardiogenic shock at hospital admission was more frequent in the interventional vs the surgical cohort (50% vs 25% of neonates). Echocardiographic isthmus diameter increased with therapy by 0.9 ± 0.1 mm and 1.0 ± 0.1 mm, respectively. Severe systolic left ventricular (LV) dysfunction was more common in interventional patients pre-therapy (LV ejection fraction <50% in 90% vs 38% of surgical patients), resulting in strongly reduced longitudinal strain (LV: −12.3% vs −16.3%; right ventricle:−13.8% vs −16.1% in the interventional and surgical patients, respectively). Prior to hospital discharge, all 26 patients had full recovery of biventricular systolic function, including normalization of longitudinal, radial, and circumferential LV strain and longitudinal right ventricular free wall strain. Improvement of LV diastolic function by strain analysis was evident in both cohorts pre-hospital discharge. ConclusionsInitial treatment of isolated CoA by percutaneous transcatheter intervention or surgical repair results in recovery of biventricular systolic function, making transcatheter treatment particularly suitable as rescue therapy for neonates with critical CoA.

PS-B05-4: COMPARATIVE EFFECTS OF RENAL DENERVATION IN DIFFERENT STAGES OF HYPERTENSION ON CARDIAC, RENAL, AND ADIPOSE PATHOLOGY IN DAHL SALT-SENSITIVE RATS

Objective: Renal denervation (RDN) has emerged as a novel therapy for resistant hypertension. In Dahl salt-sensitive (DahlS) rats, RDN does not prevent the development of hypertension but attenuates the progression of hypertension. We have now investigated the comparative effects of RDN in early versus advanced stages of hypertension on cardiac, renal, and adipose tissue pathology in DahlS rats. Design and method: Male DahlS rats fed an 8% NaCl diet after 6 weeks of age were subjected to RDN or sham surgery at 7 (early stage) or 9 (advanced stage) weeks. In the RDN groups, all visible nerves along the vessels were cut and the vessels were painted with a solution of 10% phenol in absolute ethanol. In contrast, in the sham-operated groups, the kidneys were exposed but the vessels were not stripped or coated with phenol. At 12 weeks, left ventricular (LV), renal, and adipose tissue were excised for analysis. Results: Successful RDN was confirmed by determination of renal norepinephrine content in each rat subjected to RDN less than 10% of the mean values of those in the sham-operated groups. Although both stages of RDN modestly attenuated blood pressure elevation, they improved LV diastolic function and fibrosis and attenuated macrophage infiltration and expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) genes in the heart, to a similar extent. In addition, both stages of RDN similarly reduced macrophage infiltration in glomeruli, the glomerulosclerosis index, the tubulointerstitial injury score as well as expression of MCP-1 and TNF-α genes in the kidney. The early stage group showed reductions in both retroperitoneal fat mass and adipocyte cross-sectional area, whereas the advanced stage group did an increase in fat mass without any change in adipocyte size. Conclusions: Both early and advanced stages of RDN mildly attenuated hypertension as well as ameliorated cardiac and renal injury, to a similar extent, in salt-loaded DahlS rats. The anti-hypertensive effect of RDN is thus likely attributable primarily to improved renal pathology. These results also suggest a possible crosstalk among the kidney, cardiovascular system, and adipose tissue via neural mechanisms in salt-sensitive hypertension.

Effect of Ivabradine on Left Ventricular Diastolic Function of Patients With Preserved Ejection Fraction - Results of the IVA-PEF Study.

Background: The association between heart rate (HR) reductions caused by ivabradine and left ventricular (LV) diastolic function in heart failure with preserved ejection fraction (HFpEF) remains uncertain because of off-label use. Thus, the present study investigated the effect of HR reductions by ivabradine on LV diastolic function in HFpEF patients.Methods and Results: This study enrolled 16 HFpEF patients with HR ≥75 beats/min. After 3 months administration of ivabradine, no significant changes were observed in mitral inflow E and mitral e’ annular velocities, B-type natriuretic peptide, or left atrial volume index, but there were significant improvements in global longitudinal strain.Conclusions: Ivabradine did not improve LV diastolic function for HFpEF patients with HR ≥75 beats/min. Because this may be due to some study limitations, further studies should be conducted.

A phase 2a trial investigating ninerafaxstat – a novel cardiac mitotrope for the treatment of diabetic cardiomyopathy (IMPROVE-DiCE)

Abstract Background Type 2 diabetes (T2D) is a significant, independent contributor to the development of heart failure (HF), driven by energetic, metabolic, structural and functional myocardial changes. The T2D heart is characterised by over-reliance on fatty acid utilisation, shows reduced glucose oxidation and inhibition of pyruvate dehydrogenase (PDH). This results in a diminished myocardial energy reserve and blunted adenosine triphosphate (ATP) generation as well as cardiac steatosis, contributing to lipotoxicity, and diastolic dysfunction. Purpose We assessed the effects of ninerafaxstat – a novel cardiac mitotrope designed to shift myocardial substrate utilisation in favour of glucose and thus, restore myocardial energy homeostasis – on cardiac metabolism &amp; diastolic function in patients with T2D and obesity. Methods In this open-label, mechanistic phase 2a trial, we enrolled 21 patients with T2D &amp; obesity (HbA1c median 7.0% (IQR 6.6, 7.8), weight 97kg (90, 102)) and subsequently treated them with 200mg ninerafaxstat twice daily for 4 or 8 weeks; (Fig. 1). Cardiac metabolism and function were assessed pre- &amp; post-treatment using magnetic resonance imaging (MRI), 31P-, 1H- and, in a subset of n=9, hyperpolarized [1-13C]pyruvate MR spectroscopy. Results T2D patients at baseline presented with impaired myocardial energetics with a markedly reduced PCr/ATP (1.6 [1.4, 2.1]), myocardial steatosis (myocardial triglycerides 2.2% [1.5, 3.2]) left ventricular (LV) hypertrophy (LV mass 130g [98, 152]), and diastolic dysfunction (peak diastolic strain rate 0.86 1/s [0.82, 1.06]). Ninerafaxstat significantly improved myocardial energetics (PCr/ATP median by 32%, p&amp;lt;0.01), reduced myocardial triglyceride content (by 34%, p=0.03) and improved LV diastolic function (peak circumferential diastolic strain rate by 10%, peak LV filling rate by 11%, both p&amp;lt;0.05) (Fig. 2). PDH flux was increased in 7/9 subjects (mean 45%, p=0.08), consistent with improved glucose utilisation. Left ventricular volumes and mass, heart rate and blood pressure remained unchanged. Conclusions Treatment with ninerafaxstat significantly improves myocardial energetics, reduces myocardial steatosis and improves diastolic function in patients with T2D and obesity. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Imbria Pharmaaceuticals

Both short- and long-term treatment with the direct AMP kinase activator PXL770 improves cardiac function in ZSF-1 rats

AMP kinase activation is a target for the treatment of metabolic syndrome-related cardiac dysfunction PXL770 is a direct AMP kinase activator under clinical development for the treatment of metabolic diseases. Since potential cardiac effects of PXL770 have not been previously assessed we investigated whether PXL770 treatment exerts protective cardiac effects in rats with metabolic syndrome. ZSF-1 rats were treated with PXL770 (150 mg/kg orally BID for 90 days initiated at the age of 12 weeks, or for 7 days initiated at the age of 23 weeks) in order to determine left ventricular (LV) function and remodeling. After 90 days, untreated ZSF-1 rats showed signs of LV diastolic dysfunction, illustrated by the increases in LV end-diastolic pressure (LV EDP; 5.58 ± 0.57 and 8.28 ± 1.02 mmHg in lean and ZSF-1 rats, respectively) and in LV end-diastolic pressure volume-relation (LV EDPVR; 1.10 ± 0.23 and 5.44 ± 0.65 mmHg/RVU in lean and ZSF-1 rats, respectively) with preserved LV systolic function, illustrated by the slight decrease in LV fractional shortening (LV FS; 46 ± 1 and 42 ± 1% in lean and ZSF-1 rats, respectively; P < 0.05) and similar LV end-systolic pressure (LV ESP; 173 ± 10 and 197 ± 6 mmHg, respectively) or LV end-systolic pressure volume-relation (LV ESPVR; 32.7 ± 4.2 to 28.6 ± 1.4 mmHg/RVU, respectively), associated with a significant increase in LV tissue collagen density (2.62 ± 0.17 and 4.03 ± 0.13%, respectively) without an alteration in LV weight (1.27 ± 0.02 to 1.27 ± 0.02 g; respectively). Short- and long-term PXL770 improved LV diastolic function, illustrated by the reduced LV EDP in short- and long-term PXL treated ZSF-1 (5.98 ± 0.94 and 5.34 ± 0.93 mmHg, respectively) and reduced LV EDPVR (4.22 ± 0.30 and 3.35 ± 0.12 mmHg/RVU, respectively). Simultaneously LV FS was significantly increased (52 ± 1 and 50 ± 1%; respectively), as well as LV ESPVR (34.6 ± 1.4 and 33.0 ± 0.9 mmHg/RVU). The improvement of diastolic function was associated with a slight reduction in LV weight (1.19 ± 0.04 and 1.17 ± 0.02 g) and a significant reduction in collagen density long-term PXL770 (3.35 ± 0.12%; P < 0.05) but not short-term PXL770 (4.22 ± 0.30) ( Table 1 ). These results suggest that PXL770 exerts protective effects on cardiac function and structure in developing or established cardiomyopathy. Thus, direct AMP kinase activation appears promising for the treatment of cardiac abnormalities associated with metabolic diseases.

Nitric Oxide Therapy Attenuates Heart Failure with Preserved Ejection Fraction

IntroductionNitric oxide (NO) based therapeutics have proven to exert cardioprotective actions in the setting of heart failure with reduced ejection fraction (HFrEF). However, NO therapy has failed to exert beneficial effects in clinical studies of heart failure with preserved ejection fraction (HFpEF).We investigated (1) the effects of the NO donor, sodium nitrite, as a monotherapy, (2) hydralazine monotherapy, a known vasodilator and antioxidant, and (3) combination therapy with both drugs in a murine model of HFpEF. We assessed left ventricular (LV) function, oxidative/nitrosative stress, exercise tolerance, and cardiac fibrosis.Materials and MethodsMale, C57/BL6N (n=15 per group) were placed on a Western high fat diet (60% kCal from fat) and treated with L‐NG‐Nitro arginine methyl ester (L‐NAME, 0.5 g/L/day) in the drinking water beginning at 10 weeks of age. At 15 weeks of age, mice were randomly assigned to four separate groups for five additional weeks: HFpEF control, sodium nitrite in drinking water (75 mg/L), hydralazine (2 mg/kg/day, i.p., b.i.d.), or the combination of sodium nitrite and hydralazine.Plasma was collected to measure circulating 8‐isoprostane and 3‐nitrotyrosine levels, biomarkers of oxidative and nitrosative stress respectively. In addition, cardiac tissue was harvested at 20 weeks for Masson’s Trichrome staining and to measure cardiac nitrite levels. Echocardiography and exercise tolerance testing was performed at 10, 15, and 20 weeks of age.ResultsThere was a significant increase in circulating nitrite levels (p &lt; 0.05) in the sodium nitrite + hydralazine group compared to the control and either monotherapy groups. There was no significant difference in the cardiac tissue nitrite levels between the combination therapy and the control group. Plasma 8‐isoprostane and 3‐nitrotyrosine levels were significantly (p &lt; 0.05) reduced in the sodium nitrite + hydralazine group compared to the HFpEF control group, indicating a reduction in oxidative and nitrosative stress. Although there was no significant difference in the extent of interstitial cardiac fibrosis between groups, there was a significant decrease (p &lt; 0.05) in myocardial perivascular fibrosis in the sodium nitrite + hydralazine group compared to control. Left ventricular end‐diastolic pressure (LVEDP) was significantly reduced in all treatment groups, and LVEDP was reduced to the greatest extent in the nitrite + hydralazine group vs. HFpEF control. Furthermore, we observed a significant (p &lt; 0.01) improvement in LV diastolic function (i.e., E/e’) in the sodium nitrite and hydralazine group that was superior to either of the treatments alone. There was no significant difference in the exercise distance or duration among the various groups.ConclusionThese data demonstrate that the combination of a powerful antioxidant with NO donor therapy significantly enhances the beneficial effects NO therapy in the setting of severe HFpEF.

Both short-and long-term treatment with the direct AMP kinase activator PXL770 improves cardiac function in ZSF-1 rats

Abstract Introduction AMPK is a central energy sensor with cardioprotective effects, and its activation has emerged as a target for the treatment of metabolic syndrome-related cardiac dysfunction. PXL770 is the first direct AMPK activator under clinical development, currently investigated for the treatment of NASH. Since potential cardiac benefits of PXL770 have not been previously assessed we investigated whether short- and long-term PXL770 treatment exerts protective cardiac effects in rats with metabolic syndrome. Methods ZSF-1 rats were treated with PXL770 (150 mg/kg orally BID for 90 days initiated at the age of 12 weeks, or for 7 days initiated at the age of 23 weeks) in order to determine left ventricular (LV) function and remodeling. Results After 90 days, untreated ZSF-1 rats showed signs of LV diastolic dysfunction, illustrated by the increase in LV end-diastolic pressure (LV EDP; 5.58±0.57 and 8.28±1.02 mmHg in lean and ZSF-1 rats, respectively; p&amp;lt;0.05) and in LV end-diastolic pressure volume-relation (LV EDPVR; 1.10±0.23 and 5.44±0.65 mmHg/RVU in lean and ZSF-1 rats, respectively; p&amp;lt;0.05) with preserved LV systolic function, illustrated by the slight decrease in LV fractional shortening (LV FS; 46±1 and 42±1% in lean and ZSF-1 rats, respectively; p&amp;lt;0.05) and similar LV end-systolic pressure (LV ESP; 173±10 and 197±6 mmHg, respectively) or LV end-systolic pressure volume-relation (LV ESPVR; 32.7±4.2 to 28.6±1.4 mmHg/RVU, respectively). LV diastolic dysfunction was associated with a significant increase in LV tissue collagen density (2.62±0.17 and 4.03±0.13%, respectively) without an alteration in LV weight (1.27±0.02 to 1.22±0.03 g; respectively) Short- and long-term treatment with PXL770 improved LV diastolic function in treated ZSF-1, illustrated by the reduced LV EDP (5.34±0.93 and 5.98±0.94 mmHg, short- and long-term PXL770, respectively) and the reduced LV EDPVR (3.31±0.43 and 2.73±0.16 mmHg/RVU, respectively; p&amp;lt;0.05 vs untreated ZSF-1). Simultaneously LV FS was significantly increased (52±1 and 50±1%, respectively; p&amp;lt;0.05 vs untreated ZSF-1), as well as LV ESPVR (34.6±1.4 and 33.0±0.9 mmHg/RVU, respectively; p&amp;lt;0.05 vs untreated ZSF-1). The improvement of diastolic function was associated with a reduction in LV weight (1.19±0.04 and 1.17±0.02 g, respectively; long-term PXL770 p&amp;lt;0.0.5 vs untreated ZSF-1) and a significant reduction in collagen density after long-term PXL770 (3.35±0.12%; p&amp;lt;0.05) but not short-term PXL770 (4.22±0.30%). Conclusion These results suggest that PXL770 exerts protective effects on cardiac function and structure in developing or established cardiomyopathy. Thus, by directly activating AMPK, the PXL770 appears promising for the treatment of cardiac dysfunction associated with metabolic diseases. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Poxel SA

Effects of deferred versus immediate stenting on left ventricular function in patients with ST elevation myocardial infarction.

Background:Previous studies have shown conflicting results on the benefits of deferred stenting (DS) in infarct size and the incidence of microvascular obstruction in patients with ST elevation myocardial infarction (STEMI). However, effect of DS on left ventricular (LV) function was not known. We aimed to evaluate whether DS improve LV function and relevant clinical outcomes after STEMI, using follow-up data from the INNOVATION study (NCT02324348).Methods:In total, 114 patients were randomly assigned to DS group or immediate stenting (IS) group at a 1:1 ratio. LV functional remodeling indices and MACE (major adverse cardiac events: a composite of death, non-fatal MI, unplanned target vessel revascularization, or hospitalization due to heart failure) were compared between DS and IS groups.Results:Serial echocardiographic analyses were completed in 89 subjects (78%). There were no significant changes in LV volume in either group. While LV ejection fraction and wall motion score index (WMSI) improved in both groups during follow-up, the increments were not statistically different between the 2 groups (4.3 ± 8.2 vs 3.2 ± 7.1, P = .504 for ΔLV ejection fraction; –0.16 ± 0.25 vs –0.16 ± 0.25, P = .99 for ΔWMSI). However, E/e′’ was decreased and e′ was increased only in the DS group (–3.31 ± 5.60 vs –0.46 ± 3.10, P = .005 for ΔE/e′; 0.77 ± 1.71 vs –0.22 ± 1.64, P = .009 for Δe′). The incidence of major adverse cardiac events was numerically lower in the DS group than in the IS group without a statistical significance at 1-year follow-up.Conclusions:Routine DS improved LV diastolic function but not systolic function compared with IS in patients with STEMI.

Correlation between Body Mass Index and Left Ventricular Remodeling and Function in Children with Sickle Cell Disease

Background:Cardiovascular complications play an important role in morbidity and mortality of patients with sickle cell disease (SCD). Historically, patients with SCD were underweight, but due to changes in the diet and advances in therapies there is a trend of increasing BMI, with some patients developing metabolic syndrome (MS). We hypothesized that obesity, MS, and SCD are associated with left ventricular (LV) remodeling and dysfunction and the presence of these conditions may increase the risk of cardiac disease.Objective:We aimed to evaluate the association between BMI and LV remodeling and dysfunction in pediatric patients with SCD, as well as the association with laboratory markers and clinical outcomes.Methods:We performed a retrospective study that included patients 10 to 22 years old with SCD followed at St. Christopher's Hospital for Children. Data collected included BMI, markers of MS, hemolysis, and inflammation, clinical outcomes and 2D and Doppler echocardiographic parameters. Echocardiogram parameters included those of cardiac structure, geometry, systolic function, and diastolic function. Analysis of variance (ANOVA) tests were performed to examine the differences between biomarkers and various weight categories. Pearson correlations were calculated to evaluate associations of BMI percentile with biomarkers and LV remodeling variables. A chi square test was used to assess differences in geometry by weight categories. Differences in BMI percentile associated with MS status was explored with a T-Test. ANOVA was used to assess differences in mean LV remodeling and functional variables associated with the various weight categories.Results:Demographic and laboratory data was collected on all 139 patients who met inclusion criteria, 35 had both pediatric cardiology evaluation and complete echocardiography. Of the 139 patients, 17 (12%) were obese, with 5 of them meeting the criteria for MS as defined by the International Diabetes Federation. Blood pressure was found to be significantly higher in obese patients when compared to non-obese patients (p = 0.026). Hemoglobin was statistically different among weight groups (underweight, normal weight, overweight, obese), with higher mean values being seen in the overweight and obese groups (p = 0.006). No significant correlations were found between cardiac biomarkers, BMI percentile and MS. In 35 patients with echocardiographic data, BMI percentile was positively correlated with relative wall thickness and negatively correlated with peak early LV filling and peak early LV filling/septal annuli early peak (E/Ea) velocities. Relative wall thickness was also positively associated with age. Partial correlations of BMI percentile with these variables were therefore calculated and remained significant in the same directions: Relative wall thickness (r = 0.345, p = 0.046), peak early LV filling velocity (r = -0.473, p = 0.011) and E/Ea (r = -0.415, p = 0.015). E/Ea was also significantly associated with weight category, with higher values in the normal and underweight groups (p = 0.020). Weight category and geometry were not significantly related.Conclusions:Obese patients were found to have significantly higher blood pressures and higher BMI percentiles were associated with LV remodeling, contributing to the risk of cardiac disease. Conversely, higher BMI percentile was associated with lower diastolic function measures (improved LV diastolic function) and the trend of higher mean hemoglobin values. This study suggests a complex relationship between BMI, hemoglobin and cardiovascular risks in children with SCD. Further prospective studies with larger sample size are necessary to validate our findings and to develop preventive strategies for cardiovascular risks in SCD. DisclosuresNo relevant conflicts of interest to declare.