Left Ventricular Stiffness Research Articles

Aggravation of functional mitral regurgitation on left ventricle stiffness in type 2 diabetes mellitus patients evaluated by CMR tissue tracking

BackgroundFunctional mitral regurgitation (FMR) is one of the most common heart valve diseases in diabetes and may increase left ventricular (LV) preload and aggravate myocardial stiffness. This study aimed to investigate the aggravation of FMR on the deterioration of LV strain in type 2 diabetes mellitus (T2DM) patients and explore the independent indicators of LV peak strain (PS).Materials and methodsIn total, 157 T2DM patients (59 patients with and 98 without FMR) and 52 age- and sex-matched healthy control volunteers were included and underwent cardiac magnetic resonance examination. T2DM with FMR patients were divided into T2DM patients with mild (n = 21), moderate (n = 19) and severe (n = 19) regurgitation. LV function and global strain parameters were compared among groups. Multivariate analysis was used to identify the independent indicators of LV PS.ResultsThe T2DM with FMR had lower LV strain parameters in radial, circumferential and longitudinal direction than both the normal and the T2DM without FMR (all P < 0.05). The mild had mainly decreased peak diastolic strain rate (PDSR) compared to the normal. The moderate had decreased peak systolic strain rate (PSSR) compared to the normal and PDSR compared to the mild and the normal. The severe FMR group had decreased PDSR and PSSR compared to the mild and the normal (all P < 0.05). Multiple linear regression showed that the regurgitation degree was independent associated with radial (β = − 0.272), circumferential (β = − 0.412) and longitudinal (β = − 0.347) PS; the months with diabetes was independently associated with radial (β = − 0.299) and longitudinal (β = − 0.347) PS in T2DM with FMR.ConclusionFMR may aggravate the deterioration of LV stiffness in T2DM patients, resulting in decline of LV strain and function. The regurgitation degree and months with diabetes were independently correlated with LV global PS in T2DM with FMR.

Left ventricular mass versus pulse wave velocity as predictors of coronary artery disease in hypertensive patients: data from a 6-year-follow-up study.

In treated hypertensive patients, there is a substantial residual cardiovascular (CV) risk that cannot be assessed by the available prediction models. This risk can be associated with subclinical organ damage, such as increased left ventricular mass (LVM) and arterial stiffness. However, it remains unknown which of these two CV markers better predicts coronary artery disease (CAD). A prospective cohort study was used to answer the above question. The study sample consisted of 1033 patients with hypertension (mean age 55.6 years, 538 males) free of CAD at baseline, who were followed for a mean period of 6 years. At baseline, all subjects underwent a complete echocardiographic study and pulse wave velocity (PWV) measurement. Hypertensive individuals who developed CAD (2.8%) compared to those without CAD at follow-up, had a higher baseline LVM index (by 16.7 g/m2, p < 0.001), higher prevalence of left ventricular hypertrophy (LVH) (21% greater, p = 0.027) and greater prevalence of high PWV levels at baseline (21% greater, p = 0.019). Multivariate Cox regression analysis revealed that baseline age >65 years (HR = 2.067, p = 0.001), male gender (HR = 3.664, p = 0.001), baseline chronic kidney disease (HR = 2.020, p = 0.026), baseline diabetes mellitus (HR = 1.952, p = 0.015) and baseline LVH (HR = 2.124 p = 0.001) turned out to be independent predictors of CAD, whereas high PWV levels were not. LVH proved to be an independent prognosticator of CAD in contrast to arterial stiffness that was not related to CAD after accounting for established confounders. Therefore, LVM can reliably help physicians to identify high-risk hypertensives in whom an intensified therapeutic management is warranted.

Sodium-glucose co-transporter 2 inhibitors in heart failure with preserved ejection fraction: reasons for optimism.

Sodium-glucose co-transporter 2 inhibitors in heart failure with preserved ejection fraction: reasons for optimism.

Coarctation of aorta is associated with left ventricular stiffness, left atrial dysfunction and pulmonary hypertension

Brachial systolic blood pressure (BP) is the most commonly used metric for monitoring hypertension. However, recent studies suggest that brachial systolic BP underestimates left ventricle (LV) systolic load in patients with coarctation of aorta (COA). Since brachial systolic BP is used as a surrogate of arterial afterload in clinical practice, it is important to determine how well it correlates with LV remodeling and stiffness in patients with COA as compared to patients with idiopathic hypertension. This is cross-sectional study of COA patients with hypertension (COA group) and adults with idiopathic hypertension (control group). Both groups were matched 1:1 based on age, sex, BMI and systolic BP. We hypothesized that the COA group will have higher LV systolic and diastolic stiffness, and more advanced left atrial remodeling and pulmonary hypertension. We assessed LV systolic stiffness using end-systolic elastance, and diastolic stiffness using LV stiffness constant and chamber capacitance (LV-end-diastolic volume at an end-diastolic pressure of 20mm Hg) RESULTS: There were 112 patients in each group. Although both groups had similar systolic BP, the COA group had a higher end-systolic elastance (2.37 ± 0.74 vs 2.11 ± 0.54 mm Hg/mL, P= .008), higher LV stiffness constant (6.91 ± 0.81 vs 5.93 ± 0.79, P= .006) and lower LV-end-diastolic volume at an end-diastolic pressure of 20mm Hg (58 ± 9 vs 67 ± 11 mL/m2, P< .001). Additionally, the COA group had more advanced left atrial remodeling and higher pulmonary artery pressures which is corroborating evidence of high LV filling pressure. COA patients have more LV stiffness and abnormal hemodynamics compared to non-COA patients with similar systolic BP, suggesting that systolic BP may underestimate LV systolic load in this population. Further studies are required to determine whether the observed LV stiffness and dysfunction translates to more cardiovascular events during follow-up, and whether adopting a stricter systolic BP target in clinical practice or changing threshold for COA intervention will lead to less LV stiffness and better clinical outcomes.

Age-related alterations in cardiac and arterial structure and function in hypertensive women and men.

The study was to compare age‐related alterations in cardiac and arterial structure and function by sex and to explore the impacts of achieved systolic blood pressure (SBP; <130 mm Hg vs. <140 mm Hg) level on age‐related alterations in cardiac and arterial structure and function in hypertensive women and men. Community hypertensive individuals without cardiovascular disease who had echocardiographic examination were included. Age‐related alterations in cardiac and arterial structure and function were compared by sex, and interplay between age and sex was analyzed according to achieved SBP level. The mean age of the cohort was 66.5 years, and women accounted for 62% (n = 602) of the cohort (n = 971). Compared to men, women had worse left ventricular (LV) diastolic function and greater LV and arterial stiffness. After adjusting for covariates, the magnitude of the associations between age with septal E/e′ ratio, septal S′ velocity, effective arterial elastance (Ea) and LV end‐diastolic elastance (Eed) were greater in women. Sex differences in the magnitude of association between age with these four indices varied according to achieved SBP level. When achieved SBP <130 mm Hg, the magnitude of the associations between age with septal E/e′ ratio, septal S′ velocity, Ea and Eed did not differ by sex. Since age and sex are non‐modifiable, achieving SBP target, especially at a lower level, might be beneficial to attenuate sex differences in age‐related alterations in cardiac and arterial structure and function.

Paired Pressure-Volume Loop Analysis and Biaxial Mechanical Testing Characterize Differences in Left Ventricular Tissue Stiffness of Volume Overload and Angiotensin-Induced Pressure Overload Hearts.

Pressure overload (PO) and volume overload (VO) of the heart result in distinctive changes to geometry, due to compensatory structural remodeling. This remodeling potentially leads to changes in tissue mechanical properties. Understanding such changes is important, as tissue modulus has an impact on cardiac performance, disease progression, and influences on cell phenotype. Pressure-volume (PV) loop analysis, a clinically relevant method for measuring left ventricular (LV) chamber stiffness, was performed in vivo on control rat hearts and rats subjected to either chronic PO through Angiotensin-II infusion (4-weeks) or VO (8-weeks). Immediately following PV loops, biaxial testing was performed on LV free wall tissue to directly measure tissue mechanical properties. The β coefficient, an index of chamber stiffness calculated from the PV loop analysis, increased 98% in PO (n = 4) and decreased 38% in VO (n = 5) compared to control (n = 6). Material constants of LV walls obtained from ex vivo biaxial testing (n = 9-10) were not changed in Angiotensin-II induced PO and decreased by about half in VO compared to control (47% in the circumferential and 57% the longitudinal direction). PV loop analysis showed the expected increase in chamber stiffness of PO and expected decrease in chamber stiffness of VO. Biaxial testing showed a decreased modulus of the myocardium of the VO model, but no changes in the PO model, this suggests the increased chamber stiffness in PO, as shown in the PV loop analysis, may be secondary to changes in tissue mass and/or geometry but not an increase in passive tissue mechanical properties.

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

ObjectiveCardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy.MethodsSixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg−1•day−1; ZOSV); Group 3: valsartan (31 mg•kg−1•day−1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg−1•day−1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage.ResultsSac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD.ConclusionsThese studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.

NOVEL ANTHROPOMETRIC INDICES WERE BETTER ASSOCIATED WITH HYPERTENSIVE TARGET ORGAN DAMAGES IN THE COMMUNITY-DWELLING ELDERLY CHINESE: THE NORTHERN SHANGHAI STUDY

Objective: Body mass index (BMI), the most commonly used body composition assessing indice, has recently been challenged by two novel anthropometric indices, a body shape index (ABSI) and body roundness index (BRI), in arterial stiffness predicting capacity[1,2]. The purpose of this study was to detect and compare the different predictive capacities of the four anthropometric indices (ABSI, BRI, waist-hip ratio (WHR) and BMI) in predicting hypertensive target organ damages (HTODs). Design and method: Overall, 3077 community-dwelling elderly Chinese (age &gt; 65 years, 1329 men and 1748 women) in northern Shanghai were enrolled prospectively from June 2014 to August 2019. ABSI and BRI were calculated with validated formula. HTODs were defined as three levels: (1) left ventricular hypertrophy (LVH), (2) arterial stiffness (AS) and lower limb atherosclerosis (LLA), (3) micro-albuminuria (MAU). Multivariate linear and logistic regression were performed to detect the relations between anthropometric indices and HTODs. Results: Spearman correlation analysis revealed that all anthropometric indices were correlated with HTODs indices (all P &lt; 0.001). In multivariate logistic regression models, compared to the lowest quartiles, participants with the highest quartiles of ABSI, BRI and WHR all exhibited a significantly higher risk of LVH, AS and MAU independent of confounders and BMI (all P for trend &lt; 0.01). Results of receiver operator characteristic (ROC) analysis performed within the female subgroup demonstrated that BRI and WHR were the better anthropometric indices in predicting HTODs compared to BMI. However, similar trend disappeared in the male subgroup. Further comparison analysis about the predictive priorities in the female subgroup were tested with stepwise logistic regression, after all anthropometric indices were put into models, only BRI stayed and was significantly associated higher prevalence of LVH (OR = 1.42, 95%CI 1.30∼1.55) and LLA (OR = 1.48, 95%CI 1.23∼1.77) together with WHR stayed to predict higher risks of AS (OR = 1.30, 95%CI 1.18∼1.43) and MAU (OR = 1.48, 95%CI 1.28∼1.72, all P &lt; 0.01). Conclusions: Novel anthropometric indices, especially BRI and WHR, compared to the conventional indice BMI, have the superior capacities in predicting HTODs in the elderly female Chinese population.

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.

Finite-element based optimization of left ventricular passive stiffness in normal volunteers and patients after myocardial infarction: Utility of an inverse deformation gradient calculation of regional diastolic strain

IntroductionLeft ventricular (LV) diastolic dysfunction (DD) is common after myocardial infarction (MI). Whereas current clinical assessment of DD relies on indirect markers including LV filling, finite element (FE) -based computational modeling directly measures regional diastolic stiffness. We hypothesized that an inverse deformation gradient (DG) method calculation of diastolic strain (IDGDS) allows the FE model-based calculation of regional diastolic stiffness (material parameters; MP) in post-MI patients with DD. MethodsCardiac magnetic resonance (CMR) with tags (CSPAMM) and late gadolinium enhancement (LGE) was performed in 10 patients with post-MI DD and 10 healthy volunteers. The 3-dimensional (3D) LV DG from end-diastole (ED) to early diastolic filling (EDF; DGED→EDF) was calculated from CSPAMM. Diastolic strain was calculated from DGEDF→ED by inverting the DGED→EDF. FE models were created with MI and non-MI (remote; RM) regions determined by LGE. Guccione MPs C, and exponential fiber, bf, and transverse, bt , terms were optimized with IDGDS strain. Results3D circumferential and longitudinal diastolic strain (Ecc;Ell) calculated using IDGDS in CSPAMM obtained in volunteers and MI patients were EccH = 0.27 ± 0.01, EllH = 0.24 ± 0.03 and EccMI = 0.21 ± 0.02, and EllMI = 0.15 ± 0.02, respectively. MPs in the volunteer group were CH = 0.013 [0.001, 0.235] kPa, bfH = 20.280 ± 4.994, and btH = 7.460 ± 2.171 and CRM = 0.0105 [0.010, 0.011] kPa,bfRM = 50.786 ± 13.511 (p = 0.0846), and btRM = 17.355 ± 2.743 (p = 0.0208) in the remote myocardium of post-MI patients. ConclusionDiastolic strain, calculated from CSPAMM with IDGDS, enables calculation of FE model-based regional diastolic material parameters. Transverse stiffness of the remote myocardium, btRM, may be a valuable new metric for determination of DD in patients after MI.

High microvascular resistance and reduced left atrial strain in patients with coronary microvascular dysfunction: The micro-strain study

BackgroundIt is already known that high coronary microvascular resistance (Rμ) is linked to altered left ventricular stiffness and might be an early indicator of heart failure with preserved ejection fraction (HFpEF). Left atrial dysfunction, on the other hand, varies according to the grade of left ventricular diastolic dysfunction. This is the first study to use the latest development for invasive assessment of Rμ and to combine it with echocardiographic assessment of left atrial strain during reservoir phase (LASr) by speckle tracking in relation to left ventricular (LV) diastolic function. Methods and resultsAn invasive angiogram was performed in 97 patients because of suspected ANOCA. All patients underwent comprehensive echocardiography, yet image quality was poor in 15 patients leaving 82 patients to include in the final analysis. In order to compare Rμ with LASr values, patients were divided into 4 groups based upon normal values of Rμ as defined by Fournier et al. The mean LASr was plotted against the four resistance groups. The LASr was 48.6% in the lowest resistance group, and 40.1%, 36.3% and 30.1% in the low intermediate, high intermediate and high resistance group respectively. These differences were significant compared to the lowest resistance group (p < 0.05). Although higher Rμ groups showed more diastolic dysfunction, LASr was already decreased irrespective of the severity of diastolic dysfunction. ConclusionThis study shows a relationship between increased Rμ and reduced LASr, that seems to precede conventional measures of left ventricular diastolic dysfunction. This suggests that microvascular dysfunction might be an early indicator for the development of impaired LA function.

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.

Effects of Left Ventricular Hypertrophy and Myocardial Stiffness on Myocardial Strain Under Preserved Ejection Fraction.

Despite numerous experimental observations regarding heart failure with preserved ejection fraction (HFpEF), which is characterized mainly by left ventricular hypertrophy and a left ventricular ejection fraction over 50%, myocardial dynamics under HFpEF have not yet been fully clarified, particularly regarding the relationship between myocardial strain distribution and myocardial work. To address this issue, we numerically investigated radial distribution of myocardial strain during a cardiac cycle with fixed internal volume at the end of the systolic and diastolic phases under different mechanical conditions, such as those involving myocardial thickness and elasticity of myocardial fibers. The myocardium was a modeled as a visco-hyperelastic continuous material. This model was taken into account that active contractile stress along the myocardial fiber direction depends on membrane potential change. Our numerical results showed that both radial and circumferential strains decreased as wall thickness increased, which reflected cardiac hypertrophy, but that myocardial work became larger than that observed with thin ventricular walls. Further, the change in left ventricular diastolic internal pressure caused circumferential strain, while fiber stiffness contributed to radial strain. Since peak circumferential strain was well estimated by the maximum difference between total internal and myocardial volumes, measuring the epicardial contraction rate should be helpful in understanding patients with HFpEF.

Rind from Purple Mangosteen (Garcinia mangostana) Attenuates Diet-Induced Physiological and Metabolic Changes in Obese Rats.

The pulp of the purple mangosteen, Garcinia mangostana, is a popular tropical fruit but the rind containing xanthones such as α-mangostin together with procyanidins and anthocyanidins is usually discarded as waste. However, this rind has been used in South-East Asia for diarrhoea, dysentery, skin infections and wounds. As xanthones have reported anti-inflammatory and antioxidant responses, this study has determined the bioactive compounds and evaluated the effects of G. mangostana rind on physiological, metabolic, liver and cardiovascular parameters in rats with diet-induced metabolic syndrome. Rats fed a diet with increased simple sugars and saturated fats developed obesity, hypertension, increased left ventricular stiffness, dyslipidaemia and fatty liver. Administration of G. mangostana rind as 5% of the food to rats with diet-induced metabolic syndrome gave a dose of 168 mg/kg/day α-mangostin, 355 mg/kg/day procyanidins, 3.9 mg/kg/day anthocyanins and 11.8 mg/kg/day hydroxycitric acid for 8 weeks which reduced body weight and attenuated physiological and metabolic changes in rats including decreased abdominal fat deposition, decreased abdominal circumference and whole-body fat mass, improved liver structure and function and improved cardiovascular parameters such as systolic blood pressure, left ventricular stiffness and endothelial function. These responses were associated with decreased infiltration of inflammatory cells, decreased deposition of collagen in both heart and liver and decreased mean adipocyte size in retroperitoneal adipose tissues. We conclude that, in rats with diet-induced metabolic syndrome, chronic intake of G. mangostana rind decreased infiltration of inflammatory cells which decreased physiological, metabolic, liver and cardiovascular symptoms.

Association of prediabetes with impaired left atrial contractility in patients with never-treated hypertension.

Prediabetes defined by HbA1c 5.7-6.4 has been shown to be associated with left ventricular (LV) hypertrophy and diastolic dysfunction in hypertensive patients. We hypothesized HbA1c prediabetes may be related to the alterations of LA contractility or volume in nondiabetic hypertension. Nondiabetic individuals on sinus rhythm were enrolled; 107 patients with never-treated hypertension, 134 patients with treated hypertension, and 71 normotensive subjects. Participants were classified as normal glucose tolerance (NGT, HbA1c<5.7), prediabetes (HbA1c 5.7-6.4) according to the ADA criteria. They underwent echocardiography to measure left atrial (LA) phasic volumes and functions, as well as mitral E/e' and mitral e'. In nondiabetic patients with never-treated hypertension, prediabetes saw lower LA total emptying fraction (53.7 ± 8.2 vs. 48.3 ± 9.9*) and mitral e' (7.38 ± 2.18 vs. 6.17 ± 1.50*) than NGT, implicating that the association of prediabetes with reduced LA contractility and LV stiffness. On the other hand, in nondiabetic patients with treated hypertension, prediabetes saw higher maximum LA volume/BSA (29.7 ± 7.1 vs. 32.9 ± 6.2* ml/mm2) and mitral E/e' (10.72 ± 3.08 vs. 12.37 ± 3.35*) than NGT, suggesting the relationship of prediabetes with increased LA preload. Prediabetes may be involved in the progression of LA structural and functional alterations in nondiabetic hypertensive patients.

Collagen Cross-Linking Is Associated With Cardiac Remodeling in Hypertrophic Obstructive Cardiomyopathy.

BackgroundCollagen cross‐linking is covalent bonds among collagen fibers from catalysis of lysyl oxidase (LOX) and advanced glycation end products (AGEs). We aimed to evaluate the formation of enzymatic and nonenzymatic collagen cross‐linking and its clinical significance in patients with hypertrophic obstructive cardiomyopathy.Methods and ResultsForty‐four patients with hypertrophic obstructive cardiomyopathy who underwent surgical myectomy were consecutively enrolled. Cardiovascular magnetic resonance parameters of left atrial/left ventricular function were measured, including peak filling rate (PFR) and early peak emptying rate (PER‐E). Total collagen was the sum of soluble and insoluble collagen, which were assessed by collagen assay. The myocardial LOX and AGEs expression were measured by molecular and biochemical methods. Compared with patients without atrial fibrillation, insoluble collagen (P=0.018), insoluble collagen fraction (P=0.017), and AGEs (P=0.039) were higher in patients with atrial fibrillation, whereas LOX expression was similar (P=0.494). The insoluble collagen fraction was correlated with PFR index (PFR normalized by left ventricular filling volume) (r=−0.44, P=0.005), left atrial diameters (r=0.36, P=0.021) and PER‐E index (PER‐E normalized by left ventricular filling volume) (r=−0.49, P=0.001).Myocardial LOX was positively correlated with total collagen (r=0.37, P=0.025) and insoluble collagen fraction (r=0.53, P < 0.001), but inversely correlated with PFR index (r=−0.43, P=0.006) and PER‐E index (r=−0.35, P=0.027). In multiple regression analysis, myocardial LOX was independently associated with PFR, while insoluble collagen fraction showed independent correlation with PER‐E after adjustment for clinical confounders.ConclusionsCollagen cross‐linking plays an important role on heart remodeling in hypertrophic obstructive cardiomyopathy. Myocardial LOX expression is independently correlated with left ventricular stiffness, while accumulation of AGEs cross‐links might be associated with the occurrence of atrial fibrillation in patients with hypertrophic obstructive cardiomyopathy.

Linagliptin prevents left ventricular stiffening by reducing titin cleavage and hypophosphorylation.

The metabolic syndrome (MetS) is an escalating problem worldwide, causing left ventricular stiffening, an early characteristic of diastolic dysfunction for which no treatment exists. As diastolic dysfunction and stiffening in MetS patients are associated with increased circulating dipeptidyl peptidase‐4 (DPP‐4) levels, we investigated whether the clinically approved DPP‐4 inhibitor linagliptin reduces left ventricular stiffness in MetS‐induced cardiac disease. Sixteen‐week‐old obese ZSF1 rats, displaying the MetS and left ventricular stiffness, received linagliptin‐supplemented or placebo diet for four weeks. Linagliptin significantly reduced obesity, hyperlipidaemia, and hyperglycaemia and improved left ventricular relaxation. This improved relaxation was related to decreased cardiac fibrosis and cardiomyocyte passive stiffness (F passive). The reduced F passive was the result of titin isoform switching from the stiff N2B to the more flexible N2BA and increased phosphorylation of total titin and specifically its N2Bus region (S4080 and S3391). Importantly, DPP‐4 directly cleaved titin in vitro, resulting in an increased F passive, which was prevented by simultaneous administration of linagliptin. In conclusion, linagliptin improves left ventricular stiffness in obese ZSF1 rats by preventing direct DPP4‐mediated titin cleavage, as well as by modulating both titin isoform levels and phosphorylation. Reducing left ventricular stiffness by administering linagliptin might prevent MetS‐induced early diastolic dysfunction in human.

Increased left ventricular stiffness assessed by diastolic wall strain causes symptoms in patients with premature ventricular contraction

Abstract Background Premature ventricular contraction (PVC) is one of common arrhythmias and only some patients complain of PVC-related symptoms, however the mechanisms which cause the symptoms remain unclear in patients with PVCs. Purpose We investigated whether the left ventricular (LV) stiffness assessed by diastolic wall strain (DWS) relate symptoms or not in patients with PVC. Methods We studied 109 patients (48 males, age 60±19) with frequent monomorphic PVCs who underwent 12-leads electrocardiogram (ECG), signal-averaged electrocardiogram (SAECG), 24h-Holter ECG recording, and transthoracic echocardiography (TTE). Patients with structural heart disease or other arrhythmias such as atrial fibrillation were excluded. Clinical factors, blood samples for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and filtered QRS duration (f-QRS) and root mean square voltage of the terminal 40ms of the QRS complex (RMS40) obtained by SAECG were evaluated. We assessed PVC-SV (stroke volume during PVC), PVC-CI (CI between the previous sinus beat and VPC), and left ventricular (LV) stiffness assessed by diastolic wall strain (DWS). DWS was calculated from the M-mode echocardiographic measurement of the LV posterior wall thickness at end-systole (PWs) and end-diastole (PWd) during sinus rhythm, and DWS was defined as (PWs − PWd)/PWs. Results 31patients (28%) had PVC-related symptoms (18 palpitation and 13 pulse deficit). Patients with PVC-related symptoms showed shorter PVC coupling interval index (52±10 vs. 58±11%, p=0.0140), reduced PVC-SV (21±12 vs. 29±17ml, p=0.0103) and decreased DWS (0.38±0.06 vs. 0.42±0.06, p=0.0011). Meanwhile, the level of BNP and ANP, f-QRS, RMS40, QRS morphology of PVC and the total number of PVC per day were not associated with PVC-related symptoms. On multivariate analysis, decreased DWS was only independently associated with PVC-related symptoms (p=0.0357, OR 2.3629 for each 0.1 decrease in DWS 95% CI 1.0583–5.5815). Conclusion The reduced diastolic wall strain relates with PVC-related symptoms. The increased left ventricular stiffness might cause symptoms in patients with PVC. Funding Acknowledgement Type of funding source: None

Left ventricular stiffness assessed by diastolic wall strain predicts asymptomatic atrial high rate episodes in patients with pacemaker implantation

Abstract Background Asymptomatic atrial fibrillation has been reported to be associated with an increased risk of embolism. Purpose We investigated whether the left ventricular (LV) stiffness assessed by diastolic wall strain (DWS) predicts atrial high rate episodes (AHREs) in patients with pacemaker implantation (PMI). Methods One hundred forty seven patients (76 males, 75.2±8.9 years, 62 with sick sinus syndrome; SSS and 85 with atrioventricular block) who did not show atrial tachyarrhythmia before PMI were studied. DWS and other measurements were assessed using transthoracic echocardiography before DDD-pacemaker implantation. DWS was calculated from the M-mode echocardiographic measurement of the LV posterior wall thickness at end-systole (PWs) and end-diastole (PWd), and DWS was defined as (PWs-PWd)/PWs. Results AHREs (&amp;gt;5 min and &amp;gt;180 beats/min) were detected in 50/147 patients during follow-up periods (38.3±13.8 months). Patients with AHREs showed reduced DWS (0.29±0.07 vs. 0.39±0.06, p&amp;lt;0.0001), larger left atrial volume index, elevated E/e' ratio, thicker LV PWd, higher prevalence of SSS, and left bundle branch block pattern during ventricular pacing. On multivariate analysis, DWS was only independently associated with AHREs (p&amp;lt;0.0001, HR 1.987 for each 0.1 decrease in DWS, 95% CI 1.553–2.650). Patients with reduced DWS (&amp;lt;0.33) had a higher risk of incidences of AHREs (Figure 1). Conclusions LV stiffness assessed by DWS predicts AHREs in patients with PMI. Figure 1 Funding Acknowledgement Type of funding source: None

Stratified Treatment of Heart Failure with preserved Ejection Fraction: rationale and design of the STADIA-HFpEF trial.

AimsHigh myocardial stiffness in heart failure with preserved ejection fraction (HFpEF) is attributed to comorbidity‐induced structural and functional remodelling through inflammation and oxidative stress affecting coronary microvascular endothelial cells and cardiomyocytes, which augments interstitial fibrosis and cardiomyocyte stiffness. In murine and human HFpEF myocardium, sodium glucose co‐transporter 2 (SGLT2) inhibition ameliorates cardiac microvascular endothelial cell and cardiomyocyte oxidative stress, while enhancing myocardial protein kinase G activity and lowering titin‐based cardiomyocyte stiffness. Failure of previous HFpEF outcome trials refocuses attention to improving pathophysiological insight and trial design with better phenotyping of patients and matching of therapeutic targets to prevailing pathogenetic mechanisms. SGLT2 inhibition could represent a viable therapeutic option especially in HFpEF patients in whom high diastolic left ventricular (LV) stiffness is predominantly caused by elevated cardiomyocyte stiffness and associated endothelial dysfunction, whereas HFpEF patients with extensive myocardial fibrosis might be less responsive. This study aims to investigate a stratified treatment approach, using dapagliflozin in heart failure patients with preserved ejection fraction without evidence of significant myocardial fibrosis.Methods and resultsThe Stratified Treatment to Ameliorate DIAstolic left ventricular stiffness in early Heart Failure with preserved Ejection Fraction (STADIA‐HFpEF) is a Phase II, randomized, 2 × 2 crossover trial, evaluating the efficacy of 13 weeks of treatment with dapagliflozin 10 mg od in 26 patients with HFpEF, with normal cardiac magnetic resonance imaging‐derived extracellular volume. The co‐primary endpoint is echocardiographically derived change in E/e'/LV end‐diastolic volume index and change in mean LV e'.ConclusionsThe STADIA‐HFpEF trial will be the first study to evaluate the direct effects of dapagliflozin on amelioration of LV stiffness, using histological phenotyping to discern early HFpEF.