Left Ventricular Diastolic Stiffness Research Articles

Impact of ventricular interaction and ventricular afterload on biventricular diastolic dysfunction in heart failure with preserved ejection fraction

Abstract Background Pressure-volume (PV) loop analyses recently identified two different hemodynamic phenotypes in response to exercise in heart failure with preserved ejection fraction (HFpEF). In addition to a rightward shift (RS) along the end-diastolic PV relation, a cohort of HFpEF patients characterised by a straight upward shift (US) of the PV relation with markedly increased systolic and diastolic stiffness and impaired left ventricular (LV) stroke volume (SV) was identified. Whether this is an effect of RV-LV interdependence or an alternative mechanism remains elusive. Purpose To invasively study biventricular exercise physiology in patients with HFpEF to decode cardiac mechanisms underlying exercise intolerance. Methods HFpEF was diagnosed according to the 2016 ESC guidelines. Patients underwent cardiac magnetic resonance imaging prior to invasive hemodynamic characterisation including sequential biventricular PV loop analysis during preload reduction and handgrip exercise. HFpEF patients were grouped according to LV hemodynamic phenotypes into RS cohort (change in indexed end-diastolic volume, ∆EDVi >0ml/m²) and US cohort (∆EDVi ≤0 ml/m²). Results A total of 37 HFpEF patients (n=20 RS and n=17 US, median age 71 years [68, 78], 70% female) were included. Clinical presentation did not differ between cohorts regarding age (p=0.22), functional NYHA class (p=0.52) and NTproBNP (p=0.57). In PV loop analysis, diastolic stiffness (EDP/EDVi ratio) was higher in the US cohort as compared to the RS cohort in both the LV (0.31 vs. 0.23 mmHg/ml, p<0.01) and the RV (0.14 vs. 0.10 mmHg/ml, p=0.03). This difference was even more pronounced during handgrip exercise (LV: 0.45 vs. 0.29 mmHg/ml/m², p<0.01; RV: 0.18 vs. 0.12 mmHg/ml/m², p=0.02). Similarly, exertional systolic stiffness was increased in US cohort compared to the RS cohort in both the LV (V120i 21.1 vs. 30.6 ml/m², p=0.04) and RV (V40i 27.8 vs. 40.5 ml/m², p<0.01). LV and RV volumes were closely correlated at rest (EDVi r=0.77, p<0.01; end-systolic volume, ESVi r=0.54, p<0.01; SVi r=0.95 p<0.01). The US of the LV PV relations could not be explained by ventricular interaction since exercise-induced increases (∆) in RV-EDVi did not correlate with increases in LV diastolic stiffness (∆LV-EDP/EDVi, p=0.58). However, the change in LV afterload from baseline to peak exercise (∆LV-Ea) did correlate with ∆LV-EDP/EDVi (r=0.61, p<0.01). A similar correlation was also found for RV afterload and RV diastolic stiffness (r=0.50, p<0.01). Conclusion Biventricular hemodynamic profiles closely resemble one another. The pathological LV US of the PV relations in response to exercise could not be explained by ventricular interdependence but was rather related to excess of biventricular afterload. Therefore, these findings indicate HFpEF to be a biventricular disease, which should be incorporated in future considerations about pathomechansims and potential therapeutic targets.Schematic biventricular PV-Loops

Association Between Endothelial Dysfunction and Left Ventricular Diastolic Stiffness - Subanalysis of the Flow-Mediated Dilation Japan (FMD-J) Study.

Endothelial dysfunction and increased left ventricular (LV) stiffness are associated with the incidence of heart failure with preserved ejection fraction (HFpEF). This study evaluated the association between endothelial dysfunction and LV diastolic stiffness.Methods and Results: Endothelial dysfunction evaluated by flow-medicated vasodilation (FMD) and the reactive hyperemia index (RHI), which reflects endothelial dysfunction in the microvasculature, was measured in 112 subjects with hypertension in the Flow-Mediated Dilation Japan (FMD-J) study. Using transthoracic echocardiography, LV diastolic stiffness was evaluated by measuring diastolic wall strain (DWS) in the LV posterior wall. In this cross-sectional study, associations among FMD, RHI, and DWS were investigated using multiple regression analyses. The mean (±SD) age of the subjects 65±9 years, and 63% were men. DWS was significantly associated with RHI, but not FMD, on multivariate linear regression analysis (β=0.39; P<0.0001). This association was preserved in subjects without LV hypertrophy (β=0.46; P<0.0001). A DWS ≤median, suggesting increased LV diastolic stiffness, was significantly associated with RHI on multivariate logistic regression analysis (odds ratio 20.58; 95% confidence interval 4.83-87.63; P<0.0001). The receiver operating characteristic curve presented a cut-off value of 2.21 for RHI, with a sensitivity of 77% and a specificity of 71%, for DWS ≤median. RHI, rather than FMD, was associated with DWS. Endothelial dysfunction in the microvasculature may be associated with increased LV diastolic stiffness.

Ventricular stiffening and chamber contracture in heart failure with higher ejection fraction.

Ancillary analyses from clinical trials have suggested reduced efficacy for neurohormonal antagonists among patients with heart failure and preserved ejection fraction (HFpEF) and higher ranges of ejection fraction (EF). A total of 621 patients with HFpEF were grouped into those with low-normal left ventricular EF (LVEF) (HFpEF<65% , n = 319, 50% ≤ LVEF <65%) or HFpEF≥65% (n = 302, LVEF ≥65%), and compared with 149 age-matched controls undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing. A sensitivity analysis was performed in a second non-invasive community-based cohort of patients with HFpEF (n = 244) and healthy controls without cardiovascular disease (n = 617). Patients with HFpEF≥65% had smaller left ventricular (LV) end-diastolic volume than HFpEF<65% , but LV systolic function assessed by preload recruitable stroke work and stroke work/end-diastolic volume was similarly impaired. Patients with HFpEF≥65% displayed an end-diastolic pressure-volume relationship (EDPVR) that was shifted leftward, with increased LV diastolic stiffness constant β, in both invasive and community-based cohorts. Cardiac filling pressures and pulmonary artery pressures at rest and during exercise were similarly abnormal in all EF subgroups. While patients HFpEF≥57% displayed leftward shifted EDPVR, those with HFpEF<57% had a rightward shifted EDPVR more typical of heart failure with reduced EF. Most pathophysiologic differences in patients with HFpEF and higher EF are related to smaller heart size, increased LV diastolic stiffness, and leftward shift in the EDPVR. These findings may help to explain the absence of efficacy for neurohormonal antagonists in this group and raise a new hypothesis, that interventions to stimulate eccentric LV remodelling and enhance diastolic capacitance may be beneficial for patients with HFpEF and EF in the higher range.

Is HFpEF Caused by Coronary Microvascular Disease?

Heart failure is responsible for one of eight deaths in the United States. Despite advances in the treatment of heart failure, e.g., beta1‐adrenergic antagonists, angiotensin converting enzyme inhibitors, these therapies are successful only in one type of HF—heart failure with reduced ejection fraction (HFrEF). Another type of heart failure termed HFpEF (heart failure with preserved ejection fraction) presents a far more difficult condition, because there have been no successful clinical trials demonstrating an effective therapy. Moreover, epidemiological data show the prevalence of HFpEF is increasing while that of HFrEF is decreasing. In some studies of patients with non‐obstructive coronary disease, categorized by poor coronary reserve without obstructive coronary artery lesions, HFpEF is observed. Because such patients have coronary microvascular disease, we proposed that a murine model of coronary microvascular disease may also present with HFpEF. In mice null for Kv1.5 channels (KO), a model of inadequate coronary metabolic dilation, we have observed poor exercise tolerance, shortened lifespan, and ventricular fibrosis. We hypothesized that inadequate metabolic dilation in the KO mice leads to chronic coronary insufficiency, i.e., inadequate myocardial blood flow, which would lead to cardiac apoptosis resulting in diffuse fibrosis, stiffening, and culminating in HFpEF. Although many laboratories use standard echocardiographic measurements of diastolic function as verification of HFpEF, such measurements may be spurious in small animals, such as mice, because several indices of diastolic function are heart rate dependent. To overcome this hindrance, we directly evaluated left ventricular diastolic stiffness by measuring LV pressure‐volume (PV) loops, using the slope of the end‐diastolic pressure and volume points (in anesthetized mice using a PV solid‐state transducer). LV PV loops were measured in anesthetized, wild‐type control (WT) and the KO mice during changes in preload induced by slow volume infusion. The series of PV loops were superimposed, and a computer best fit the diastolic PV points to a line, where the slope of the PV line reflects LV diastolic elastance (stiffness). The average slope of the LV end‐diastolic PV lines were roughly doubled in the KO vs WT (P&lt;0.05), indicating increased stiffness. Moreover, LV end‐diastolic pressures were nearly tripled in the KO vs WT, 7.3±1.6 vs 2.8±1.7 mmHg, respectively. (P&lt;0.05). In conclusion, a model of inadequate coronary dilation in mice, which we believe parallels patients with coronary microvascular disease, leads to increased stiffening of the left ventricle and HFpEF.

Серцева недостатність зі збереженою фракцією викиду лівого шлуночка

Серцева недостатність зі збереженою фракцією викиду лівого шлуночка є частим явищем, що спостерігається в осіб похилого віку. Вона супроводжується артеріальною гіпертензією та гіпертрофією лівого шлуночка. До симптомів відносять ригідність стінок лівого шлуночка з компенсаторним збільшенням тиску наповнення і знижену здатність збільшувати ударний об’єм за законом Франка Старлінга. Прогнози практично такі ж невтішні, як і при серцевій недостатності зі зниженою фракцією викиду, що певною мірою відображає наявність супутніх захворювань. До встановлення діагнозу серцевої недостатності зі збереженою фракцією викиду важливо виключити кардіологічну природу захворювання. Через неспецифічність симптомів серцевої недостатності необхідно знайти об’єктивне підтвердження діастолічної дисфункції, що за відсутності даних, отриманих інвазивно, має бути підтверджена з використанням ехокардіографії, при якій будуть виявлені ознаки підвищеного тиску наповнення лівого шлуночка, порушення його розслаблення чи збільшення його діастолічної ригідності. Лікування серцевої недостатності зі збереженою фракцією викиду симптоматичне, із застосуванням тих же препаратів, що і при серцевій недостатності зі зниженою фракцією викиду.

Shortening the thick filament by partial deletion of titin's C-zone alters cardiac function by reducing the operating sarcomere length range

Titin's C-zone is an inextensible segment in titin, comprised of 11 super-repeats and located in the cMyBP-C-containing region of the thick filament. Previously we showed that deletion of titin's super-repeats C1 and C2 (TtnΔC1–2 model) results in shorter thick filaments and contractile dysfunction of the left ventricular (LV) chamber but that unexpectedly LV diastolic stiffness is normal. Here we studied the contraction-relaxation kinetics from the time-varying elastance of the LV and intact cardiomyocyte, cellular work loops of intact cardiomyocytes, Ca2+ transients, cross-bridge kinetics, and myofilament Ca2+ sensitivity. Intact cardiomyocytes of TtnΔC1–2 mice exhibit systolic dysfunction and impaired relaxation. The time-varying elastance at both LV and single-cell levels showed that activation kinetics are normal in TtnΔC1–2 mice, but that relaxation is slower. The slowed relaxation is, in part, attributable to an increased myofilament Ca2+ sensitivity and slower early Ca2+ reuptake. Cross-bridge dynamics showed that cross-bridge kinetics are normal but that the number of force-generating cross-bridges is reduced. In vivo sarcomere length (SL) measurements revealed that in TtnΔC1–2 mice the operating SL range of the LV is shifted towards shorter lengths. This normalizes the apparent cell and LV diastolic stiffness but further reduces systolic force as systole occurs further down on the ascending limb of the force-SL relation. We propose that the reduced working SLs reflect titin's role in regulating diastolic stiffness by altering the number of sarcomeres in series. Overall, our study reveals that thick filament length regulation by titin's C-zone is critical for normal cardiac function.

Abstract 10997: Long-Term Prognostic Value of Catheter-Derived Left Ventricular Diastolic Stiffness in Patients Undergoing Transcatheter Aortic Valve Replacement

Introduction: Despite successful transcatheter aortic valve replacement (TAVR), low flow rate (FR) severe aortic stenosis (AS) patients reportedly experienced poorer clinical outcomes than normal FR AS patients. Left ventricular (LV) diastolic function influences stroke volume, though limited data on TAVR outcomes in patients with severe LV diastolic dysfunction is available. Hypothesis: AS patients with severe LV diastolic dysfunction may develop adverse cardiac events, such as heart failure, even after TAVR. Methods: Consecutive patients with severe AS and preserved LV ejection fraction (&gt; 50%) who underwent hemodynamic assessment of LV function using cardiac catheterization before TAVR were enrolled. The average slope of the end-diastolic pressure-volume relationship was calculated to determine LV diastolic stiffness. Adverse cardiac events were defined as cardiac death or heart failure hospitalization. High LV stiffness (&gt; 190 mmHg/L) patients were compared to normal LV stiffness patients. Results: Of the 78 patients (age 83.2 ± 5.1 years; 21 men), 30 (38.5%) were classified to the high LV stiffness group. Low FR (&lt; 200 mL/s) severe AS was more likely in patients with high LV stiffness than in those with normal LV stiffness (66.7% vs 33.3%, P = 0.004). Adverse cardiac events increased in the high LV stiffness group (Figure, Log rank P = 0.054). Cox regression analysis revealed that LV stiffness was associated with increased adverse cardiac events, after adjusting for age, sex, aortic valve area, and renal function (HR, 1.008; 95%CI, 1.001-1.014; P = 0.026). Conclusion: Increased LV stiffness derived from cardiac catheterization was related to low FR and was also associated with poor clinical outcomes after TAVR.

Coffee Pulp, a By-Product of Coffee Production, Modulates Gut Microbiota and Improves Metabolic Syndrome in High-Carbohydrate, High-Fat Diet-Fed Rats.

Waste from food production can be re-purposed as raw material for usable products to decrease industrial waste. Coffee pulp is 29% of the dry weight of coffee cherries and contains caffeine, chlorogenic acid, trigonelline, diterpenes and fibre. We investigated the attenuation of signs of metabolic syndrome induced by high-carbohydrate, high-fat diet in rats by dietary supplementation with 5% freeze-dried coffee pulp for the final 8 weeks of a 16-week protocol. Coffee pulp decreased body weight, feed efficiency and abdominal fat; normalised systolic blood pressure, left ventricular diastolic stiffness, and plasma concentrations of triglycerides and non-esterified fatty acids; and improved glucose tolerance in rats fed high-carbohydrate, high-fat diet. Further, the gut microbiota was modulated with high-carbohydrate, high-fat diet and coffee pulp supplementation and 14 physiological parameters were correlated with the changes in bacterial community structures. This study suggested that coffee pulp, as a waste from the coffee industry, is useful as a functional food for improving obesity-associated metabolic, cardiovascular and liver structure and function, and gut microbiota.

Influence of Left Ventricular Function on the "Aortic Regurgitation Index" Proposed for the Hemodynamic Assessment of Postprocedural Aortic Regurgitation.

The aortic regurgitation (AR) index, proposed as an objective indicator of postprocedural AR, decreases in proportion to AR severity, besides reportedly providing additional prognostic information. Meanwhile, left ventricular (LV) function has also been considered an essential prognostic factor. This study aimed to clarify whether LV function affected the AR index using cardiac catheterization data.A retrospective study was performed in patients whose LV function was evaluated using a micromanometer-tipped catheter. Patients with grade 2 or higher AR were excluded to explore non-AR factors affecting the AR index value. The AR index was calculated as a ratio of the gradient between the aortic diastolic blood pressure (DBP) and the LV end-diastolic pressure (EDP) to the aortic systolic blood pressure (SBP): AR Index = [ (DBP - LVEDP) / SBP] × 100.A total of 64 patients [age, 62 (interquartile range: 48-70) years; LV ejection fraction, 19% (16%-26%) ] were examined. AR index values ranged from 18.3 to 68.6. Despite having no AR, two patients displayed an AR index < 25, indicating significant AR. Multiple-regression analysis revealed that LV diastolic stiffness (β = -0.750, P < 0.001), LV max dP/dt (β = -0.296, P = 0.006), and heart rate (β = 0.284, P = 0.011) were independent determinants of the AR index value.Patients with impaired LV diastolic function and preserved systolic function had low AR index values. The additional prognostic information of the AR index may be related to LV diastolic function.

Sacubitril/Valsartan Improves Diastolic Function But Not Skeletal Muscle Function in a Rat Model of HFpEF.

The angiotensin receptor/neprilysin inhibitor Sacubitril/Valsartan (Sac/Val) has been shown to be beneficial in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, the impact of Sac/Val in patients presenting with heart failure with preserved ejection fraction (HFpEF) is not yet clearly resolved. The present study aimed to reveal the influence of the drug on the functionality of the myocardium, the skeletal muscle, and the vasculature in a rat model of HFpEF. Female obese ZSF-1 rats received Sac/Val as a daily oral gavage for 12 weeks. Left ventricle (LV) function was assessed every four weeks using echocardiography. Prior to organ removal, invasive hemodynamic measurements were performed in both ventricles. Vascular function of the carotid artery and skeletal muscle function were monitored. Sac/Val treatment reduced E/é ratios, left ventricular end diastolic pressure (LVEDP) and myocardial stiffness as well as myocardial fibrosis and heart weight compared to the obese control group. Sac/Val slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function. Our results demonstrate striking effects of Sac/Val on the myocardial structure and function in a rat model of HFpEF. While vasodilation was slightly improved, functionality of the skeletal muscle remained unaffected.

Renal Sympathetic Denervation in Patients With Heart Failure With Preserved Ejection Fraction.

Arterial hypertension is the most common comorbidity in patients with heart failure with preserved ejection fraction (HFpEF) and mediates adverse hemodynamics through related aortic stiffness and increased pulsatile load. We aimed to investigate the clinical and hemodynamic implications of renal sympathetic denervation (RDN) in patients with HFpEF and uncontrolled arterial hypertension. Patients undergoing RDN between 2011 and 2018 in a single-center were retrospectively analyzed and classified as HFpEF (n=99) or no HF (n=65). Stroke volume index and aortic distensibility were measured through cardiac magnetic resonance imaging, and left ventricular (LV) systolic and diastolic properties were assessed echocardiographically. At baseline, patients with HFpEF had higher stroke volume index (median 40 [interquartile range, 33-48] versus 33 [26-40] mL/m2, P=0.002), pulse pressure (69 [63-77] versus 61 [55-67] mm Hg, P<0.001), but lower LV-VPES100mm Hg (18 [10-28] versus 24 [15-40] mL, P=0.007) and aortic distensibility (1.5 [1.1-2.6] versus 2.7 [1.1-3.5] 10-3 mm Hg-1, P=0.013) as compared to no-HF patients. Systolic blood pressure decreased comparable in patients with HFpEF and no-HF patients following RDN (-9 [-16 to -2], P<0.001). After RDN stroke volume index (-3 [-9 to +3] mL/m2, P=0.011) decreased and aortic distensibility (0.2 [-0.1 to +1.1] 10-3 mm Hg-1, P=0.007) and systolic stiffness (P<0.001) increased in HFpEF patients. LV diastolic stiffness and LV filling pressures as well as NT-proBNP (N-terminal pro-B-type natriuretic peptide) decreased after RDN in patients with HFpEF (P=0.032, P=0.043, and P<0.001, respectively). Patients with HFpEF undergoing RDN showed increased stroke volume index, vascular, and LV stiffness as compared to no-HF patients. Following RDN those hemodynamic alterations and reduced systolic and diastolic LV stiffness were partly normalized, implying RDN might be a potential therapeutic strategy for arterial hypertension and HFpEF.

The Impact of Hypertension on Left Ventricular Diastolic Dysfunction and Arterial Stiffness in the Elderly: A Cross-Sectional Study

Objectives: To study the prevalence of LVDD and arterial stiffness and the association with LVDD and/or arterial stiffness among residents with HTN, as well as determine whether aging was independently correlated with LVDD and arterial stiffness. This was a cross-sectional study, using results from the Shanghai Heart Health study, a national project in China. Methods: Using data from 2086 participants, we explored the associations of HTN and LVDD with or without arterial stiffness using brachial–ankle pulse wave velocity (baPWV). Correlations of LVDD with or without arterial stiffness were analyzed in adjusted multivariable logistic models. Results: The proportion of subjects with LVDD was 37.5%, arterial stiffness was 47.5%, and HTN was 58.4%. LVDD in participants with arterial stiffness occurred in 55.2% and HTN in 65.9%. Pairwise comparisons showed that systolic blood pressure was significantly different and more strongly associated with HTN (68%) (P

Sodium-glucose cotransporter2 inhibitors represent a paradigm shift in the prevention of heart failure in type2 diabetes patients.

Recent major clinical trials of the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have shown that they reduce three‐point major adverse cardiovascular events, cardiovascular death, hospitalization for heart failure (HF) and a composite renal outcome. These beneficial effects of SGLT2 inhibitors are also evident in type 2 diabetes patients with a previous history of atherosclerotic cardiovascular disease or advanced renal disease. HF is a major determinant of the prognosis of diabetes patients. Although HF with low ejection fraction can be effectively treated with antihypertensive drugs, these treatments do not reduce mortality in HF patients with preserved ejection fraction (HFpEF). HFpEF is clinically characterized by left ventricular diastolic dysfunction, perivascular fibrosis and stiffness of cardiomyocytes, defined as “cardiomyopathy”. Therefore, HFpEF is considered to be an entirely separate entity to HF with low ejection fraction. Recent studies have suggested that HFpEF might be treatable using SGLT2 inhibitors, which ameliorate visceral adiposity, insulin resistance, hyperglycemia, hyperlipidemia, volume overload, hypertension and cardiac inflammation. In the final part of the present review, we discuss the biochemical and molecular mechanisms of the effects of SGLT2 inhibitors in type 2 diabetes patients with HFpEF. These involve amelioration of the low nitric oxide production and oxidative stress, a reduction in cardiac inflammatory cytokine signaling, inhibition of Ca2+ overload, and an improvement in cardiac energy metabolism as a result of ketone body production. Investigations of the beneficial effects of SGLT2 inhibitors on cardiorenal outcomes, including hospitalization for HF, are now being carried out in preclinical and clinical studies.

High-intensity interval training for heart failure with preserved ejection fraction: A protocol for systematic review and meta-analysis.

Background:The benefits of high-intensity interval training (HIIT) are well-known, there is insufficient evidence about the effects of HIIT on heart failure with preserved ejection fraction (HFpEF).Method:Multiple databases include MEDLINE, PubMed, EMBASE, CINAHL, Web of Science, PEDro, Cochrane Library, and Google Scholar are used to search for randomized controlled trials investigating the effects of HIIT on HFpEF. All related articles published with the English language with no time limitation will be included. Two reviews independently conducted the selection, data extraction, and quality assessment. The primary outcome is exercise capacity. The secondary outcomes include quality of life (QoL), blood pressure (BP), ventricular function, and left ventricular diastolic function, symptom improvement, endothelial function, and arterial stiffness. Data analysis is performed with Review Manager Software (Version 5.3).Result:This systematic review and meta-analysis aim to evaluate the efficacy of HIIT on HFpEF, its outcome will provide reliable evidence for future studies.Conclusion:The findings of this study will be published in a related peer-reviewed journal.Registration number:INPLASY202050097

Ibudilast, a Phosphodiesterase Inhibitor and Toll-Like Receptor-4 Antagonist, Improves Hemorrhagic Shock and Reperfusion-Induced Left Ventricular Dysfunction by Reducing Myocardial Tumor Necrosis Factor α

ObjectivesRapid loss of blood volume causes ischemic injury to myocardial cells and impairs cardiac function. Subsequent reperfusion, although necessary to revitalize stunned tissues, can induce production of reactive oxygen species and inflammation, causing further tissue damages and weakening cardiac function. Ibudilast, a Toll-like receptor-4 (TLR4) antagonist and an inhibitor of phosphodiesterase-4, possesses antioxidative and anti-inflammatory capacities. In this study, we aim to examine the protective efficacy of ibudilast against hemorrhagic shock and reperfusion (HSR)-induced myocardial injury and cardiac dysfunction. MethodsStudies were conducted on male Sprague-Dawley rats in 3 groups: sham-operated, HSR with, and HSR without pretreatment of ibudilast. Hemorrhagic shock was induced by withdrawing blood from the femoral artery until the mean aortic pressure dropped to around 40 mm Hg; reperfusion was conducted by replenishing blood after 120 minutes of hemorrhagic shock, and the observation continued for another 240 minutes. The left ventricular (LV) contractility, diastolic suction capacity, and ventricular stiffness were evaluated using simultaneous LV pressure, and volume was recorded during a temporary inferior vena cava constriction at the end of reperfusion. Ibudilast (10 mg/kg) was administered intraperitoneally 3 days and 20 minutes prior to HSR. Serum creatine kinase myocardial band (CK-MB) was examined at the end of both HSR, and serum CK-MB, myocardial TLR4 protein expression, and malondialdehyde (MDA) and tumor necrosis factor (TNF)-α levels at the end of reperfusion. ResultsHSR induced an increase in serum CK-MB. Subsequent reperfusion further increased serum CK-MB, upregulated myocardial TLR4 protein expression, and increased tissue levels MDA and TNF-α vs the sham (P < .05). HSR reduced LV contractility, prolonged LV relaxation time, and increased LV diastolic stiffness. Ibudilast pretreatment attenuated HSR-induced TLR4 protein expression, reduced myocardial MDA and TNF-α levels, and protected against cardiac dysfunction. ConclusionsIbudilast pretreatment reduced myocardial TLR4 expression, decreased MDA and TNF-α levels, and protected against HSR-induced decrease in LV contractility, prolonged LV relaxation time, and increased diastolic stiffness.

Physiological and Metabolic Effects of Yellow Mangosteen (Garcinia dulcis) Rind in Rats with Diet-Induced Metabolic Syndrome.

Metabolic syndrome is a cluster of disorders that increase the risk of cardiovascular disease and diabetes. This study has investigated the responses to rind of yellow mangosteen (Garcinia dulcis), usually discarded as waste, in a rat model of human metabolic syndrome. The rind contains higher concentrations of phytochemicals (such as garcinol, morelloflavone and citric acid) than the pulp. Male Wistar rats aged 8–9 weeks were fed either corn starch diet or high-carbohydrate, high-fat diet for 16 weeks, which were supplemented with 5% freeze-dried G. dulcis fruit rind powder during the last 8 weeks. We characterised metabolic, cardiovascular, liver and gut microbiota parameters. High-carbohydrate, high-fat diet-fed rats developed abdominal obesity, hypertension, increased left ventricular diastolic stiffness, decreased glucose tolerance, fatty liver and reduced Bacteroidia with increased Clostridia in the colonic microbiota. G. dulcis fruit rind powder attenuated these changes, improved cardiovascular and liver structure and function, and attenuated changes in colonic microbiota. G. dulcis fruit rind powder may be effective in metabolic syndrome by appetite suppression, inhibition of inflammatory processes and increased fat metabolism, possibly related to changes in the colonic microbiota. Hence, we propose the use of G. dulcis fruit rind as a functional food to ameliorate symptoms of metabolic syndrome.

Statins with different lipophilic indices exert distinct effects on skeletal, cardiac and vascular smooth muscle

AimsData concerning the influence of statin lipophilicity on the myotoxic and pleiotropic effects of statins is conflicting, and mechanistic head-to-head comparison studies evaluating this parameter are limited. In order to address the disparity, this mechanistic investigation aimed to assess the effects of two short-acting statins with different lipophilic indices on skeletal, cardiac and vascular smooth muscle physiology. Materials and methodsYoung female Wistar rats were randomised to simvastatin (80 mg kg−1 day−1), pravastatin (160 mg kg−1 day−1) or control treatment groups. Changes in functional muscle performance were assessed, as well as mRNA levels of genes relating to atrophy, hypertrophy, mitochondrial function and/or oxidative stress. Key findingsThere were no significant differences in the mRNA profiles of isolated skeletal muscles amongst the treatment groups. In terms of skeleletal muscle performance, simvastatin reduced functionality but treatment with pravastatin significantly improved force production. Rodents given simvastatin demonstrated comparable myocardial integrity to the control group. Conversely, pravastatin reduced left ventricular action potential duration, diastolic stiffness and Mhc-β expression. Pravastatin improved endothelium-dependent relaxation, particularly in muscular arteries, but this effect was absent in the simvastatin-treated rats. The responsiveness of isolated blood vessels to noradrenaline also differed between the statin groups. The findings of this study support that the effects of statins on skeletal, cardiac and vascular smooth muscle vary with their lipophilic indices. SignificanceThe results of this work have important implications for elucidating the mechanisms responsible for the myotoxic and pleiotropic effects of statins.

Predictive value of left ventricular diastolic chamber stiffness in patients with severe aortic stenosis undergoing aortic valve replacement.

Despite improvements in cardiac haemodynamics and symptoms, long-term mortality remains increased in some patients after aortic valve replacement (AVR). Limited data exist on the prognostic role of left ventricular (LV) chamber stiffening in these patients. We performed a retrospective analysis in 1893 patients with severe aortic stenosis (AS) referred for AVR. LV end-diastolic pressure-volume relations (EDPVR, P = αV^β) were reconstructed from echocardiographic measurements of end-diastolic volumes and estimates of end-diastolic pressure (EDP). The impact of EDPVR-derived LV chamber stiffness (CS30, at 30 mmHg EDP) on all-cause mortality after AVR was evaluated. Mean age was 76 ± 10 years, 39% were females, and ejection fraction (EF) was 61 ± 12%. The mean LV chamber stiffness (CS30) was 2.2 ± 1.3 mmHg/mL. A total of 877 (46%) patients had high LV stiffness (CS30 >2 mmHg/mL). In these patients, the EDPVR curves were steeper and shifted leftwards, indicating higher stiffness at all pressure levels. These patients were slightly older, more often female, and had more prevalent comorbidities compared to patients with low stiffness. At follow-up [median 4.2 (interquartile range 2.8-6.3) years; 675 deaths], a higher CS30 was associated with lower survival (hazard ratio: 2.7 for severe vs. mild LV stiffening; P < 0.0001), both in patients with normal or reduced EF. At multivariate analysis, CS30 remained an independent predictor, even after adjusting for age, sex, comorbidities, EF, LV remodelling, and diastolic dysfunction. Higher preoperative LV chamber stiffening in patients with severe AS is associated with poorer outcome despite successful AVR.

Left ventricular mechanics in the acute phase of Takotsubo cardiomyopathy: distinctive ballooning patterns translate into different diastolic properties.

Although apical and midventricular Takotsubo cardiomyopathies (TTCs) share common triggers and pathophysiological features, little is known about the potential differences in left ventricular (LV) mechanistic properties between these TTC phenotypes. We sought to investigate whether LV systolic and/or diastolic function, as assessed invasively by left heart catheterization (LHC), differ according to ballooning patterns in the acute phase of TTC. One hundred and fourteen TTC patients were retrospectively identified between January 2009 and December 2015 at the University Hospital of Strasbourg, France. A comprehensive list of LV quantitative parameters was derived from LHC analysis for each patient. We examined 2 groups of patients according to ballooning patterns in the acute phase of TTC: patients with apical ballooning ("Apical group"; n = 76) and those with midventricular ballooning ("Midventricular group"; n = 38). LV minimal diastolic pressure (8.72 ± 6.72 vs. 5.02 ± 6.08mmHg; p = 0.004), LV end diastolic pressure (23.11 ± 8.32 vs. 18.84 ± 8.06mmHg; p = 0.01), and LV diastolic stiffness (LV stiffness 1: 0.29 ± 0.23 vs. 18.84 ± 8.06mmHg/mL; p = 0.04-LV stiffness 2: 0.16 ± 0.08 vs. 0.12 ± 0.05mmHg/mL; p = 0.005) were significantly higher in patients with apical TTC than in the midventricular group. Concomitantly, these findings were associated with significantly higher BNP levels in the apical group (923.91 ± 1164.53 vs. 418.71 ± 557.75pg/mL; p = 0.004) than in the midventricular group. In the acute phase of stress cardiomyopathy, the classic apical form of TTC is associated with poorer diastolic function compared to the midventricular ballooning variant, as assessed through direct invasive hemodynamic measurements using LHC.

Low-Dose Curcumin Nanoparticles Normalise Blood Pressure in Male Wistar Rats with Diet-Induced Metabolic Syndrome.

Nanoparticle formulations improve bioavailability and so may allow low-dose formulations of food-derived compounds such as curcumin to attenuate chronic systemic disease despite intrinsically low oral bioavailability. The current study induced metabolic syndrome in male Wistar rats aged eight–nine weeks using a high-carbohydrate, high-fat diet (H) with corn starch diet (C) as control. Using a reversal protocol, rats were given curcumin as either nanoparticles encapsulated in poly(lactic–co–glycolic acid) (5 mg/kg/day, HCNP) or as an unformulated low dose or high-dose suspension in water (low-dose, 5 mg/kg/day, HC5; high-dose, 100 mg/kg/day, HC100) or blank nanoparticles (HBNP) for the final eight weeks of the 16 week study. We analysed cardiovascular parameters including systolic blood pressure and left ventricular diastolic stiffness along with histopathology, liver parameters including plasma liver enzymes, histopathology and metabolic parameters, including glucose tolerance, blood lipid profile and body composition, and plasma curcumin concentrations. HC100 and HCNP but not HBNP normalised systolic blood pressure (C = 120 ± 4; H = 143 ± 5; HBNP = 141 ± 3; HC5 = 143 ± 4; HC100 = 126 ± 4; HCNP = 128 ± 4 mmHg), left ventricular diastolic stiffness and liver fat deposition. No other improvements were induced in HC100 or HCNP or other intervention groups (HC5 and HBNP). We conclude that 5 mg/kg/day curcumin nanoparticles in H rats showed similar improvements in cardiovascular function as 100 mg/kg/day unformulated curcumin correlating with similar plasma curcumin concentrations.