Evaluation of the relationship between left atrial stiffness, left ventricular stiffness, and left atrioventricular coupling index in type 2 diabetes patients: a speckle tracking echocardiography study.

Background: Cardiovascular complications are a leading cause of mortality and disability in individuals with diabetes mellitus (DM). Moreover, DM can directly impact the structure and function of cardiac muscle. We conducted a study to evaluate cardiac stiffness in DM patients in both the left atrium (LA) and left ventricle (LV), as well as to assess the impact of DM on the synchronization of the LA and LV, particularly within the Vietnamese population, utilizing speckle tracking echocardiography (STE). Methods: We studied 111 research subjects divided into two groups comprising 52 patients with DM and 59 healthy individuals. All the subjects provided relevant clinical information, and echocardiography was performed to assess the indices of LA stiffness, LV stiffness, and left atrioventricular coupling index (LACI). Results: Our study indicated that DM patients exhibited greater LA and LV stiffness than control patients. The LACI (%) in the DM group was also greater than that in the control group (17.12% ± 6.72% vs. 12.28% ± 3.96%, respectively; p < 0.001). The LACI was positively correlated with the LA and LV stiffness indices. Decreased levels of LV GLS, adjusted for age, sex, blood pressure, and BMI, have emerged as identified risk factors for DM. Conclusions: LA stiffness, LV stiffness, and the LACI are greater in DM patients than in normal individuals.

Comparative analysis of ventricular stiffness across species.

Investigating ventricular diastolic properties is crucial for understanding the physiological cardiac functions in organisms and unraveling the pathological mechanisms of cardiovascular disorders. Ventricular stiffness, a fundamental parameter that defines ventricular diastolic functions in chordates, is typically analyzed using the end-diastolic pressure-volume relationship (EDPVR). However, comparing ventricular stiffness accurately across chambers of varying maximum volume capacities has been a long-standing challenge. As one of the solutions to this problem, we propose calculating a relative ventricular stiffness index by applying an exponential approximation formula to the EDPVR plot data of the relationship between ventricular pressure and values of normalized ventricular volume by the ventricular weight. This article reviews the potential, utility, and limitations of using normalized EDPVR analysis in recent studies. Herein, we measured and ranked ventricular stiffness in differently sized and shaped chambers using ex vivo ventricular pressure-volume analysis data from four animals: Wistar rats, red-eared slider turtles, masu salmon, and cherry salmon. Furthermore, we have discussed the mechanical effects of intracellular and extracellular viscoelastic components, Titin (Connectin) filaments, collagens, physiological sarcomere length, and other factors that govern ventricular stiffness. Our review provides insights into the comparison of ventricular stiffness in different-sized ventricles between heterologous and homologous species, including non-model organisms.

Evaluation of left ventricular stiffness with echocardiography.

Half of patients with heart failure are presented with preserved ejection fraction (HFpEF). The pathophysiology of these patients is complex, but increased left ventricular (LV) stiffness has been proven to play a key role. However, the application of this parameter is limited due to the requirement for invasive catheterization for its measurement. With advances in ultrasound technology, significant progress has been made in the noninvasive assessment of LV chamber or myocardial stiffness using echocardiography. Therefore, this review aims to summarize the pathophysiological mechanisms, correlations with invasive LV stiffness constants, applications in different populations, as well as the limitations of echocardiography-derived indices for the assessment of both LV chamber and myocardial stiffness. Indices of LV chamber stiffness, such as the ratio of E/e' divided by left ventricular end-diastolic volume (E/e'/LVEDV), the ratio of E/SRe (early diastolic strain rates)/LVEDV, and diastolic pressure-volume quotient (DPVQ), are derived from the relationship between echocardiographic parameters of LV filling pressure (LVFP) and LV size. However, these methods are surrogate and lumped measurements, relying on E/e' or E/SRe for evaluating LVFP. The limitations of E/e' or E/SRe in the assessment of LVFP may contribute to the moderate correlation between E/e'/LVEDV or E/SRe/LVEDV and LV stiffness constants. Even the most validated measurement (DPVQ) is considered unreliable in individual patients. In comparison to E/e'/LVEDV and E/SRe/LVEDV, indices like time-velocity integral (TVI) measurements of pulmonary venous and transmitral flows may demonstrate better performance in assessing LV chamber stiffness, as evidenced by their higher correlation with LV stiffness constants. However, only one study has been conducted on the exploration and application of TVI in the literature, and the accuracy of assessing LV chamber stiffness remains to be confirmed. Regarding echocardiographic indices for LV myocardial stiffness evaluation, parameters such as epicardial movement index (EMI)/ diastolic wall strain (DWS), intrinsic velocity propagation of myocardial stretch (iVP), and shear wave imaging (SWI) have been proposed. While the alteration of DWS and its predictive value for adverse outcomes in various populations have been widely validated, it has been found that DWS may be better considered as an overall marker of cardiac function performance rather than pure myocardial stiffness. Although the effectiveness of iVP and SWI in assessing left ventricular myocardial stiffness has been demonstrated in animal models and clinical studies, both indices have their limitations. Overall, it seems that currently no echocardiography-derived indices can reliably and accurately assess LV stiffness, despite the development of several parameters. Therefore, a comprehensive evaluation of LV stiffness using all available parameters may be more accurate and enable earlier detection of alterations in LV stiffness.

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

BACKGROUND: 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 (ß=0.39; P<0.0001). This association was preserved in subjects without LV hypertrophy (ß=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. CONCLUSIONS: RHI, rather than FMD, was associated with DWS. Endothelial dysfunction in the microvasculature may be associated with increased LV diastolic stiffness.

Can we explore AF-pacemakers' relationship using clinical and echocardiographic parameters in patients with permanent pacemaker? (Echocardiography and subclinical AF in permanent pacemaker).

Patients on implanted permanent pacemakers frequently develop atrial fibrillation (AF). We aimed to determine the Echocardiographic and clinical parameters predicting AF in patients with a dual-chamber (DDD) pacemaker. This retrospective study included 208 patients with permanent pacemaker, classified according to development of AF during follow up into 2 groups: AF (77, 37%) and non AF (131, 63%), baseline: clinical, ECG(P-wave dispersion) and echo {diastolic wall strain (DWS),left arial volume index (LAVI), left ventricular stiffness index(LVSI)} data were assessed. AF group were older with more P wave dispersion, lesser DWS, greater LVSI& LAVI, LVSI at a cut off > 0.13 and DWS at a cut off < 0.34 were predictors of AF in patients with DDD pacemakers. LVSI and DWS could be used as simple good predictors for AF in patients with DDD pacemakers, for timely initiation of anticoagulants according to CHA2DS2VASc score to decrease ischemic stroke burden.

Prognostic value of an echocardiographic index reflecting right ventricular operating stiffness in patients with heart failure.

PURPOSE: We recently reported a noninvasive method for the assessment of right ventricular (RV) operating stiffness that is obtained by dividing the atrial-systolic descent of the pulmonary artery-RV pressure gradient (PRPGDAC) derived from the pulmonary regurgitant velocity by the tricuspid annular plane movement during atrial contraction (TAPMAC). Here, we investigated whether this parameter of RV operating stiffness, PRPGDAC/TAPMAC, is useful for predicting the prognosis of patients with heart failure (HF). METHODS: We retrospectively included 127 hospitalized patients with HF who underwent an echocardiographic examination immediately pre-discharge. The PRPGDAC/TAPMAC was measured in addition to standard echocardiographic parameters. Patients were followed until 2 years post-discharge. The endpoint was the composite of cardiac death, readmission for acute decompensation, and increased diuretic dose due to worsening HF. RESULTS: 58 patients (46%) experienced the endpoint during follow-up. Univariable and multivariable Cox regression analyses demonstrated that the PRPGDAC/TAPMAC was associated with the endpoint. In a Kaplan-Meier analysis, the event rate of the greater PRPGDAC/TAPMAC group was significantly higher than that of the lesser PRPGDAC/TAPMAC group. In a sequential Cox analysis for predicting the endpoint's occurrence, the addition of PRPGDAC/TAPMAC to the model including age, sex, NYHA functional classification, brain natriuretic peptide level, and several echocardiographic parameters including tricuspid annular plane systolic excursion significantly improved the predictive power for prognosis. CONCLUSION: A completely noninvasive index of RV operating stiffness, PRPGDAC/TAPMAC, was useful for predicting prognoses in patients with HF, and it showed an incremental prognostic value over RV systolic function.

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

BACKGROUND: Cardiac implantable electronic device-detected atrial high-rate episodes (AHREs) have been reported to be associated with thromboembolic risks. The present study aimed to investigate the association of echocardiographic and clinical parameters with the occurrence of AHREs in patients with a dual-chamber pacemaker (PMI). METHODS: One hundred forty-seven patients (76 males, 75.2 ± 8.9 years) who did not show atrial tachyarrhythmia before the implantation of the PMI were studied. Diastolic wall strain (DWS) and other measurements were assessed during sinus rhythm using transthoracic echocardiography before the PMI. DWS was calculated from the M-mode echocardiographic measurement of the left ventricular (LV) posterior wall thickness at end-systole (PWs) and end-diastole (PWd), and DWS was defined as (PWs-PWd) / PWs. RESULTS: AHREs (defined as AHREs duration >6 min and atrial rate >180 bpm) were detected in 50 / 147 patients during follow up (38.3 ± 13.8 months). Patients in the AHREs group had reduced DWS (0.29 ± 0.07 vs. 0.39 ± 0.06, p < 0.0001), larger left atrial volume index, thicker LV posterior diameter, higher rate of patients taking ß-blocker / diuretics, and higher prevalence of sinus node dysfunction. On multivariable analysis, only DWS was independently associated with AHREs. Patients with reduced DWS (<0.33) had a higher risk of incidences of AHREs. CONCLUSION: LV stiffness assessed by DWS was associated with AHREs in patients with a PMI.

Biomechanics of diastolic dysfunction: a one-dimensional computational modeling approach.

Diastolic dysfunction (DD) is a major component of heart failure with preserved ejection fraction (HFpEF). Accordingly, a profound understanding of the underlying biomechanical mechanisms involved in DD is needed to elucidate all aspects of HFpEF. In this study, we have developed a computational model of DD by leveraging the power of an advanced one-dimensional arterial network coupled to a four-chambered zero-dimensional cardiac model. The two main pathologies investigated were linked to the active relaxation of the myocardium and the passive stiffness of the left ventricular wall. These pathologies were quantified through two parameters for the biphasic delay of active relaxation, which simulate the early and late-phase relaxation delay, and one parameter for passive stiffness, which simulates the increased nonlinear stiffness of the ventricular wall. A parameter sensitivity analysis was conducted on each of the three parameters to investigate their effect in isolation. The three parameters were then concurrently adjusted to produce the three main phenotypes of DD. It was found that the impaired relaxation phenotype can be replicated by mainly manipulating the active relaxation, the pseudo-normal phenotype was replicated by manipulating both the active relaxation and passive stiffness, and, finally, the restricted phenotype was replicated by mainly changing the passive stiffness. This article presents a simple model producing a holistic and comprehensive replication of the main DD phenotypes and presents novel biomechanical insights on how key parameters defining the relaxation and stiffness properties of the myocardium affect the development and manifestation of DD.NEW & NOTEWORTHY This study uses a complete and validated computational model of the cardiovascular system to simulate the two main pathologies involved in diastolic dysfunction (DD), i.e., abnormal active relaxation and increased ventricular diastolic stiffness. The three phenotypes of DD were successfully replicated according to literature data. We elucidate the biomechanical effect of the relaxation pathologies involved and how these pathologies interact to create the various phenotypes of DD.

Myocardial Native T1 Predicts Load-Independent Left Ventricular Chamber Stiffness In Patients With HFpEF.

OBJECTIVES: This study sought to evaluate the potential of cardiac magnetic resonance T1 mapping to detect load-independent left ventricular (LV) chamber stiffness by histological confirmation. BACKGROUND: Accurate noninvasive diagnosis of LV diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF) remains challenging. METHODS: Nineteen HFpEF patients (14 female, 65 ± 16 years of age) without primary cardiomyopathy were prospectively enrolled. Cine, late gadolinium enhancement cardiac magnetic resonance, and triple-slice T1 mapping using a modified Look-Locker inversion recovery sequence were performed at 3-T. Extracellular volume (ECV) was quantified from pre- and post-contrast T1 values of the blood and myocardium with hematocrit correction. LV stiffness constant (beta) was assessed by calculating the slope of the end-diastolic pressure-volume relationship curve during vena cava occlusion. Biopsy samples were used for quantification of collagen volume fraction (CVF) and myocardial cell size. RESULTS: Six patients showed focal scar on late gadolinium enhancement. There was no significant difference in histological CVF between patients with and without focal myocardial scarring (p = 0.2). Septal ECV rather than native T1 was a better surrogate marker for detecting histological CVF (r = 0.54; p = 0.02, and r = 0.44; p = 0.06, respectively). Global native T1 and ECV, but not native T1 and ECV in the septal myocardium, correlated well with the beta of passive LV stiffness, and had similar ability for predicting LV stiffness to histological CVF (r = 0.54, 0.50, 0.53, all p < 0.05, respectively). When the beta ≥0.054 was considered as moderately increased LV stiffness, global native T1 ≥1,362 ms provided 88% sensitivity and 64% specificity with the C-statistic of 0.81 (95% confidence interval: 0.56 to 0.95). CONCLUSIONS: Myocardial native T1 provides comparable ability in predicting LV stiffness to ECV and histological CVF and may be useful for monitoring patients with HFpEF who have renal dysfunction, allergy to gadolinium, or wheezing that can simulate asthma. Our feasibility study shows the potential of native T1 to allow for insight of heterogeneous pathophysiology and better risk stratification of HFpEF.

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

AIMS: 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. METHODS AND RESULTS: 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^ß) 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. CONCLUSION: Higher preoperative LV chamber stiffening in patients with severe AS is associated with poorer outcome despite successful AVR.

Simple and noninvasive method to estimate right ventricular operating stiffness based on echocardiographic pulmonary regurgitant velocity and tricuspid annular plane movement measurements during atrial contraction.

It was recently shown that invasively determined right ventricular (RV) stiffness was more closely related to the prognosis of patients with pulmonary hypertension than RV systolic function. So far, a completely noninvasive method to access RV stiffness has not been reported. We aimed to clarify the clinical usefulness of our new echocardiographic index of RV operating stiffness using atrial-systolic descent of the pulmonary artery-RV pressure gradient derived from pulmonary regurgitant velocity (PRPGDAC) and tricuspid annular plane movement during atrial contraction (TAPMAC). We studied 81 consecutive patients with various cardiac diseases who underwent echocardiography and cardiac catheterization. We measured PRPGDAC and TAPMAC using continuous-wave Doppler and M-mode echocardiography, respectively, and calculated PRPGDAC/TAPMAC. RV end-diastolic pressure (RVEDP) and RV pressure increase during atrial contraction (ΔRVPAC) were invasively measured, and RV volume change during atrial contraction (ΔVAC) was calculated from echocardiographic late-diastolic transtricuspid flow time-velocity integral and tricuspid annular area; thus ΔRVPAC/ΔVAC was used as the standard index for RV operating stiffness. PRPGDAC/TAPMAC well correlated with ΔRVPAC/ΔVAC (r = 0.84, p < 0.001) and RVEDP (r = 0.80, p < 0.001), and the area under the receiver operating characteristic curve to discriminate RVEDP > 12 mmHg was 0.94. Multivariate regression analysis revealed that PRPGDAC/TAPMAC was the single independent determinant of ΔRVPAC/ΔVAC (ß = 0.86, p < 0.001). PRPGDAC/TAPMAC is useful to estimate RV operating stiffness and a good practical indicator of RVEDP.

Ventricular Stiffness and Ventricular-Arterial Coupling in Heart Failure: What Is It, How to Assess, and Why?

The heart and blood vessels are constantly interfering with each other in a closed system. For a few decades, the concept of ventricular-arterial coupling has been considered as a key pathogenesis of heart failure especially in heart failure with preserved ejection fraction.

Adiposity, body composition and ventricular-arterial stiffness in the elderly: the Atherosclerosis Risk in Communities Study.

AIM: Weight gain appears to accelerate age-related ventricular-arterial stiffening, which has been implicated in the development of heart failure (HF), but it is unclear whether body fat accumulation underpins this association. We evaluated the relationship of adiposity, using measures of body composition, with ventricular-arterial stiffness among the elderly in the community. METHODS AND RESULTS: Adiposity was accessed through body mass index (BMI), waist circumference, and body fat percentage. We studied the association of these measures with carotid-femoral pulse wave velocity (cfPWV), arterial elastance index (EaI), left ventricular (LV) end-systolic elastance index (EesI) and LV end-diastolic elastance index (EedI) in 5520 community-based, elderly Atherosclerosis Risk in Communities (ARIC) Study participants, who underwent echocardiography between 2011 and 2013. BMI and waist circumference were directly associated with EaI, EedI and EesI even after adjusting for age, sex, race, hypertension, diabetes mellitus, heart rate, prevalent coronary heart disease and HF. After further adjustment for BMI, body fat percentage demonstrated significant independent linear relationships with EaI [standardized beta coefficient (ß)=0.17, P<0.001], EesI (ß=0.08, P=0.003) and EedI (ß=0.20, P<0.001), and significant non-linear relationships with cfPWV (P=0.033). CONCLUSION: In this biracial community-based cohort, increased adiposity was associated with increased ventricular-arterial stiffness among the elderly and suggests a potential mechanism by which obesity might contribute to the development of HF.

Renal Denervation Reduces Pulmonary Vascular Remodeling and Right Ventricular Diastolic Stiffness in Experimental Pulmonary Hypertension.

Neurohormonal overactivation plays an important role in pulmonary hypertension (PH). In this context, renal denervation, which aims to inhibit the neurohormonal systems, may be a promising adjunct therapy in PH. In this proof-of-concept study, we have demonstrated in 2 experimental models of PH that renal denervation delayed disease progression, reduced pulmonary vascular remodeling, lowered right ventricular afterload, and decreased right ventricular diastolic stiffness, most likely by suppression of the renin-angiotensin-aldosterone system.

Natural history of severe aortic stenosis: Diastolic wall strain as a novel prognostic marker.

BACKGROUND AND AIM: Diastolic wall strain (DWS) has been proposed as a simple noninvasive measure of left ventricular (LV) stiffness. This study investigated DWS as a possible predictor of mortality in severe aortic stenosis (AS). METHODS: 138 patients with severe AS (indexed aortic valve area [AVA]<0.6 cm2 /m2 ) and normal ejection fraction (>55%) were included. 52 patients (38%) had aortic valve interventions or poor image quality (n=5) and were excluded leaving 86 in the study group (84±8 years, 70% female, 69% African American). DWS was defined as (LVPWs-LVPWd)/LVPWs where LVPWs=left ventricular posterior wall thickness in systole and LVPWd=left ventricular wall thickness in diastole. RESULTS: Follow-up extended 2.0±1.9 years (median 1.6 years). Mean DWS for the group was 0.21±0.11 (normal=0.4±0.07). In patients who died, DWS was significantly lower than in survivors (0.18±0.09 vs 0.24±0.11, P=.02). By contrast, traditional measures of diastolic dysfunction did not predict death. Regression analysis showed DWS predicted death even after adjusting for age, sex, race, indexed AVA, symptoms (angina, shortness of breath, dizziness, syncope), and clinical factors (creatinine, smoking, diabetes, hypertension, hyperlipidemia) (HR 2.5 [95% CI 1.02-5.90], P<.05). The best cutoff value for DWS of 0.25 had a sensitivity of 42% and specificity of 83% for predicting death. CONCLUSIONS: DWS is an independent predictor of all-cause mortality in patients with severe AS, even after accounting for traditional clinical and echocardiographic parameters.

Left ventricular stiffness predicts outcome in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation.

OBJECTIVES: Assessment of the prognostic role of left ventricular stiffness (LVS) in patients with aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). METHODS: We performed a complete two-dimensional transthoracic echocardiographic study before and after TAVI in patients with severe AS at high surgical risk. In order to assess LVS, we measured LV end-diastolic pressure (EDP) invasively during TAVI and LV end-diastolic volume (EDV) by means of echocardiography. We defined LVS as the EDV indexed by body surface area at an EDP of 20 mm Hg (EDVI20 ). Our aim was to assess the impact of LVS on one-year all-cause mortality after TAVI. RESULTS: One hundred sixty-six patients undergoing TAVI (64% female; mean age 82.7 ± 5.1 years) were enrolled. Seven patients died within the first 30 days after TAVI and 21 within 1 year. Overall follow-up duration was 580 ± 478 days. At multivariate analysis, independent predictors of 1-year all-cause mortality were moderate-to-severe paravalvular leak (PVL; HR 4.7, 95% confidence interval [CI] 1.9-11, P=.0003), female gender (HR 3.5, 95% CI 1.0-12, P=.045), and EDVI20 (HR 0.94, 95% CI 0.90-0.98, P=.015). In particular, patients with higher LVS (EDVI20 ≤48 mL/m2 ) had a 1-year mortality of 26.9% vs 7.4% in patients with lower LVS (EDVI20 >48 mL/m2 ; HR 4.2, 95% CI 1.6-10.6, P=.0007). Patients with higher LVS who developed moderate-to-severe PVL had the worst outcome (incremental chi-square test, P=.014). CONCLUSION: In patients with AS, an increased LVS has a negative prognostic impact. Development of significant PVL in patients with higher LVS had an incremental adverse effect.

Impact of chronic changes in arterial compliance and resistance on left ventricular ageing in humans.

AIMS: Left ventricular systolic elastance (Ees) and diastolic elastance (Eed) correlate with arterial elastance (Ea), but it is unknown how chronic changes in arterial compliance and resistance, which determine Ea, might differentially affect cardiac properties with ageing. We sought to characterize chronic changes in pulsatile and resistive arterial load and correlate them with longitudinal changes in LV structure and function in a prospective, community-based study. METHODS AND RESULTS: Comprehensive echocardiography was performed in 722 subjects participating in a randomly selected community-based study at two examinations separated by 4 years, allowing for assessment of LV Ees, Eed, and end-diastolic volume (EDV), Ea, total arterial compliance, and systemic vascular resistance at both examinations. Chronic changes in resistance and heart rate were the dominant contributors to change in Ea. Changes in arterial compliance had little impact on changes in Ea, but were strongly associated with changes in Ees. The combination of increased resistance and decreased compliance was associated with the largest increase in LV diastolic stiffness, an effect that was mediated by a decrease in LVEDV. In contrast, subjects with both improved arterial compliance and decreased resistance displayed an increase in LVEDV over time, with no increase in LV Eed. CONCLUSION: Increases in pulsatile arterial load with ageing contribute more to LV systolic stiffening, while combined pulsatile and resistive loading changes are associated with positive and negative chamber remodelling and diastolic stiffness. Therapies designed to improve arterial resistance and particularly to enhance aortic compliance may hold promise to prevent or reverse cardiac ageing and its sequelae.

Ablation of plasma membrane Ca(2+)-ATPase isoform 4 prevents development of hypertrophy in a model of hypertrophic cardiomyopathy.

The mechanisms linking the expression of sarcomeric mutant proteins to the development of pathological hypertrophy in hypertrophic cardiomyopathy (HCM) remain poorly understood. We investigated the role of the plasma membrane Ca(2+)-ATPase PMCA4 in the HCM phenotype using a transgenic model that expresses mutant (Glu180Gly) α-tropomyosin (Tm180) in heart. Immunoblot analysis revealed that cardiac PMCA4 expression was upregulated early in Tm180 disease pathogenesis. This was accompanied by an increase in levels of the L-type Ca(2+)-channel, which is implicated in pathological hypertrophy. When Tm180 mice were crossed with a PMCA4-null line, loss of PMCA4 caused the abrogation of hypertrophy in Tm180/PMCA4-null double mutant mice. RT-PCR analysis of Tm180/PMCA4-null hearts revealed blunting of the fetal program and reversion of pro-fibrotic Col1a1 and Col3a1 gene expression to wild-type levels. This was accompanied by evidence of reduced L-type Ca(2+)-channel expression, and diminished calcineurin activity. Expression of the metabolic substrate transporters glucose transporter 4 and carnitine palmitoyltransferase 1b was preserved and Tm180-related changes in mRNA levels of various contractile stress-related proteins including the cardiac ankyrin protein CARP and the N2B isoform of titin were reversed in Tm180/PMCA4-null hearts. cGMP levels were increased and phosphorylation of vasodilator-stimulated phosphoprotein was elevated in Tm180/PMCA4-null hearts. These changes were associated with a sharp reduction in left ventricular end-diastolic pressure in Tm180/PMCA4-null hearts, which occurred despite persistence of Tm180-related impairment of relaxation dynamics. These results reveal a novel and specific role for PMCA4 in the Tm180 hypertrophic phenotype, with the "protective" effects of PMCA4 deficiency encompassing multiple determinants of HCM-related hypertrophy.

Impact of general and central adiposity on ventricular-arterial aging in women and men.

OBJECTIVES: The aim of this study was to assess the effects of central and general obesity measures on long-term longitudinal changes in ventricular-arterial mechanics. BACKGROUND: Obesity, female sex, and ventricular-arterial stiffening are associated with the development of heart failure with preserved ejection fraction. Fat distribution and chronic changes in body composition may affect longitudinal changes in LV properties, independent of arterial load. METHODS: In 1,402 subjects from a randomly selected, community-based population, comprehensive echo-Doppler echocardiography was performed at two examinations separated by 4 years. From this population, 788 subjects had paired data adequate for determining left ventricular end-systolic elastance (Ees), end-diastolic elastance (Eed), and effective arterial elastance (Ea). RESULTS: Over 4 years, Ea was decreased by 3% in tandem with improved blood pressure control, whereas Ees and Eed were increased by 14% and 8% (all, p < 0.001). Greater weight loss over 4 years was associated with progressively greater decreases in Ea in men and women. After adjustment for Ea change, weight gain was correlated with increases in Eed in both women and men. Central obesity was associated with greater age-related increases in Ees in women but not in men, independent of arterial load, but central obesity did not predict changes in Eed or Ea. CONCLUSIONS: In these subjects, weight gain was associated with increases in LV diastolic stiffness, even after adjustment for changes in arterial afterload, whereas weight loss was associated with reductions in arterial stiffness. Age-related LV systolic stiffening was increased in women, but not in men, with central obesity. Strategies for promoting weight loss and reducing central adiposity may be effective in preventing heart failure with preserved ejection fraction, particularly in women.

Effects of spironolactone in spontaneously hypertensive adult rats subjected to high salt intake

OBJECTIVE: To evaluate the effect of spironolactone on ventricular stiffness in spontaneously hypertensive adult rats subjected to high salt intake. INTRODUCTION: High salt intake leads to cardiac hypertrophy, collagen accumulation and diastolic dysfunction. These effects are partially mediated by cardiac activation of the renin-angiotensin-aldosterone system. METHODS: Male spontaneously hypertensive rats (SHRs, 32 weeks) received drinking water (SHR), a 1 percent NaCl solution (SHR-Salt), or a 1 percent NaCl solution with a daily subcutaneous injection of spironolactone (80 mg.kg-1) (SHRSalt- S). Age-matched normotensive Wistar rats were used as a control. Eight weeks later, the animals were anesthetized and catheterized to evaluate left ventricular and arterial blood pressure. After cardiac arrest, a doublelumen catheter was inserted into the left ventricle through the aorta to obtain in situ left ventricular pressurevolume curves. RESULTS: The blood pressures of all the SHR groups were similar to each other but were different from the normotensive controls (Wistar = 109±2; SHR = 118±2; SHR-Salt = 117±2; SHR-Salt-S = 116±2 mmHg; P<0.05). The cardiac hypertrophy observed in the SHR was enhanced by salt overload and abated by spironolactone (Wistar = 2.90±0.06; SHR = 3.44±0.07; SHR-Salt = 3.68±0.07; SHR-Salt-S = 3.46±0.05 mg/g; P<0.05). Myocardial relaxation, as evaluated by left ventricular dP/dt, was impaired by salt overload and improved by spironolactone (Wistar = -3698±92; SHR = -3729±125; SHR-Salt = -3342±80; SHR-Salt-S = -3647±104 mmHg/s; P<0.05). Ventricular stiffness was not altered by salt overload, but spironolactone treatment reduced the ventricular stiffness to levels observed in the normotensive controls (Wistar = 1.40±0.04; SHR = 1.60±0.05; SHR-Salt = 1.67±0.12; SHR-Salt- S = 1.45±0.03 mmHg/ml; P<0.05). CONCLUSION: Spironolactone reduces left ventricular hypertrophy secondary to high salt intake and ventricular stiffness in adult SHRs.