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BACKGROUND: The existing algorithm for defining exercise-induced diastolic dysfunction incorporates resting e' velocity as a surrogate of myocardial relaxation. The additive prognostic value of incorporating post-exercise e' velocity in definition of exercise-induced diastolic dysfunction is poorly studied. AIM: To define the additive prognostic value of post-exercise e' septal velocity in the assessment of exercise-induced diastolic dysfunction compared to the traditional approach. METHODS: This retrospective study included 1409 patients undergoing exercise treadmill echocardiography with available full set of diastolic variables. Doppler measures of diastolic function included resting septal e' velocity, post-exercise septal e' velocity, post-exercise E/e' ratio, and post-exercise tricuspid regurgitant jet velocity. Approaches incorporating resting septal e' velocity and post-exercise septal e' velocity were compared in defining exercise-induced diastolic dysfunction, and for association with adverse cardiovascular outcomes. RESULTS: The mean age of study subjects was 56.3 ± 16.5 years and 791 (56%) patients were women. A total of 524 patients had disagreement between resting and post exercise septal e' velocities, and these values showed only weak agreement (kappa statistics: .28, P = .02). All categories of the traditional exercise-induced DD approach incorporating resting septal e' velocity witnessed reclassification when exercise septal e' velocity was used. When both approaches were compared, increased event rates were only evident when both approaches agreed on exercise-induced diastolic dysfunction (HR: 1.92, P < .001, 95% CI: 1.37-2.69). This association persisted after multivariable adjustment and propensity score matching for covariates. CONCLUSION: Incorporation of post-exercise e' velocity into the set of variables defining exercise-induced diastolic dysfunction can improve the prognostic utility of diastolic function assessment.

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BACKGROUND: Recent echocardiography studies in inherited long QT syndrome (LQTS) have shown left ventricular (LV) myocardial relaxation disturbances to follow markedly prolonged and dispersed mechanical contraction. AIM: We used speckle-tracking echocardiography to assess disturbances in LV myocardial relaxation sequence during exercise and their relationship to symptoms. METHODS: Forty seven LQTS patients (45 ± 15 years, 25 female and 20 symptomatic, LVEF: 65 ± 6%) and 35 controls underwent exercise echocardiogram using Bruce protocol. ECG and echo parameters were recorded at rest, peak exercise (p.e.) and recovery. RESULTS: Between patients and controls there were no differences in age, gender, HR or LVEF. At p.e, patients had longer time to LV longitudinal ESR (tESR) at all three LV segments; basal (p < 0.0001), mid- cavity (p = 0.03) and apical (p = 0.03) whereas at rest such difference was noted only at base (p = 0.0007). Patients showed reversed apico-basal relaxation sequence (ΔtESRbase-apex) with early relaxation onset occurring later at base than at apex, both at rest (49 ± 43 vs. -29 ± 19 ms, p < 0.0001) and at p.e. (46 ± 38 vs. -40 ± 22 ms, p < 0.0001), particularly in symptomatic patients (69 ± 44 vs. 32 ± 26, p < 0.0007). ΔtESRbase-apex correlated with longer QTc interval, lower ESR and attenuated LV stroke volume. CONCLUSION: LQTS patients show reversed longitudinal relaxation sequence, which worsens with exercise, particularly in those with previous cardiac events.

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BACKGROUND: Left ventricular (LV) diastolic dysfunction is recognized as playing a major role in the pathophysiology of heart failure; however, clinical tools for identifying diastolic dysfunction before echocardiography remain imprecise. OBJECTIVES: This study sought to develop machine-learning models that quantitatively estimate myocardial relaxation using clinical and electrocardiography (ECG) variables as a first step in the detection of LV diastolic dysfunction. METHODS: A multicenter prospective study was conducted at 4 institutions in North America enrolling a total of 1,202 subjects. Patients from 3 institutions (n = 814) formed an internal cohort and were randomly divided into training and internal test sets (80:20). Machine-learning models were developed using signal-processed ECG, traditional ECG, and clinical features and were tested using the test set. Data from the fourth institution was reserved as an external test set (n = 388) to evaluate the model generalizability. RESULTS: Despite diversity in subjects, the machine-learning model predicted the quantitative values of the LV relaxation velocities (e') measured by echocardiography in both internal and external test sets (mean absolute error: 1.46 and 1.93 cm/s; adjusted R2 = 0.57 and 0.46, respectively). Analysis of the area under the receiver operating characteristic curve (AUC) revealed that the estimated e' discriminated the guideline-recommended thresholds for abnormal myocardial relaxation and diastolic and systolic dysfunction (LV ejection fraction) the internal (area under the curve [AUC]: 0.83, 0.76, and 0.75) and external test sets (0.84, 0.80, and 0.81), respectively. Moreover, the estimated e' allowed prediction of LV diastolic dysfunction based on multiple age- and sex-adjusted reference limits (AUC: 0.88 and 0.94 in the internal and external sets, respectively). CONCLUSIONS: A quantitative prediction of myocardial relaxation can be performed using easily obtained clinical and ECG features. This cost-effective strategy may be a valuable first clinical step for assessing the presence of LV dysfunction and may potentially aid in the early diagnosis and management of heart failure patients.

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Aims: The relative impact of left ventricular (LV) diastolic dysfunction (LVDD) and impaired left atrial (LA) function on cardiovascular haemodynamics in heart failure with preserved ejection fraction (HFpEF) is largely unknown. We performed virtual patient simulations to elucidate the relative effects of these factors on haemodynamics at rest and during exercise. Methods and results: The CircAdapt cardiovascular system model was used to simulate cardiac haemodynamics in wide ranges of impaired LV relaxation function, increased LV passive stiffness, and impaired LA function. Simulations showed that LV ejection fraction (LVEF) was preserved (>50%), despite these changes in LV and LA function. Impairment of LV relaxation function decreased E/A ratio and mildly increased LV filling pressure at rest. Increased LV passive stiffness resulted in increased E/A ratio, LA dilation and markedly elevated LV filling pressure. Impairment of LA function increased E/A ratio and LV filling pressure, explaining inconsistent grading of LVDD using echocardiographic indices. Exercise simulations showed that increased LV passive stiffness exerts a stronger exercise-limiting effect than impaired LV relaxation function does, especially with impaired LA function. Conclusion: The CircAdapt model enabled realistic simulation of virtual HFpEF patients, covering a wide spectrum of LVDD and related limitations of cardiac exercise performance, all with preserved resting LVEF. Simulations suggest that increased LV passive stiffness, more than impaired relaxation function, reduces exercise tolerance, especially when LA function is impaired. In future studies, the CircAdapt model can serve as a valuable platform for patient-specific simulations to identify the disease substrate(s) underlying the individual HFpEF patient's cardiovascular phenotype.

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INTRODUCTION: Diastolic dysfunction is highly prevalent and a key pathophysiological contributor to several cardiovascular diseases, especially heart failure with preserved ejection fraction. In addition, some evidence suggests diastolic dysfunction is a risk factor for major adverse cardiovascular events. This study aimed to systematically review the evidence and to quantify the association between diastolic dysfunction and risk of cardiovascular events and death. METHODS: MEDLINE was systematically searched from 1974 up to October 2017. We included cohort studies that assessed diastolic function in adults in the community, providing a definition of diastolic dysfunction regarding the occurrence of any cardiovascular event or mortality. For the quantitative analysis, relative risk estimates comparing individuals with versus without diastolic dysfunction were combined using a random effects model. RESULTS: Nineteen studies were identified for inclusion in the systematic review, assessing a total of 63 802 participants. Nine studies were included in the meta-analysis. Diagnostic criteria and classification of diastolic dysfunction differed substantially between studies. The median prevalence of diastolic dysfunction in studies including individuals with and without diastolic dysfunction was 35.1% (range 5.3-65.2%). Comparing diastolic dysfunction with normal diastolic function, the summary relative risk estimate for cardiovascular events or mortality was 3.53 (95% CI: 2.75-4.53; I2=85.5%; nine studies). CONCLUSIONS: Although the definitions found in the literature differ, the diagnosis of diastolic dysfunction is associated with a 3.53-fold increased risk of cardiovascular events or death. This finding highlights the importance of developing easily applicable and consensual diagnostic criteria, as well as fostering research on effective treatment strategies when diastolic dysfunction is identified in the subclinical stage.

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KEY POINTS: Prior studies have shown variation in the functional properties of cardiomyocytes isolated from different regions of the left ventricular myocardium. We found that these region-dependent variations vanish below a tissue volume of ∼7 mm3 in the adult rat myocardium, revealing a fixed level of intrinsic relaxation rate heterogeneity that is independent of tissue volume. Within these microscopically varying cell populations, fast-relaxing cells were shown to have elevated phosphorylated troponin I compared to slow-relaxing cells. Relaxation rate was also correlated with cardiomyocyte length, in that slow-relaxing cells were longer than fast-relaxing cells. These results show a new relationship between cardiomyocyte morphology and myofilament relaxation, and suggest that functional diversity among individual myocytes at the microscale may contribute to bulk relaxation of the myocardium. ABSTRACT: The mean contractility and calcium handling properties of cardiomyocytes isolated from different regions of the ventricular myocardium are known to vary significantly. We designed experiments to quantify the variance in contractile properties among cells within the same myocardial region. Longitudinal strips of myocardial tissue were excised from the epicardial left ventricular free walls of adult Sprague-Dawley rats and then treated with collagenase to isolate individual myocytes. Cardiomyocytes were characterized by measuring sarcomere length changes and calcium transients during electrical pacing. Variance of the time from peak sarcomere shortening to 50% re-lengthening (RT50 ) was assessed in each cell population. Isolating cells from progressively shorter strips allowed an estimate of the myocardial volume below which regional variation vanished and only microscale heterogeneity remained (∼7 mm3 ). The SD of RT50 within this myocardial volume was 28% of the mean. In a series of follow-up experiments, RT50 was shown to correlate significantly with resting myocyte length, suggesting a connection between cell morphology and intrinsic relaxation behaviour. To explore the mechanistic basis of varying RT50 , a novel single-cell aspirator was employed to collect small batches of cardiomyocytes grouped according to their relaxation rates (fast or slow). Western blot analysis of the two groups revealed significantly elevated troponin I phosphorylation in fast-relaxing cells. Our observations suggest that cell-to-cell heterogeneity of active contractile properties is substantial, with implications for how we understand myocardial relaxation and design drug therapies intended to alter relaxation rate.

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BACKGROUND: Left ventricular diastolic dysfunction is associated with mortality outcomes in severe sepsis and septic shock. There are ongoing issues with diagnosing diastolic dysfunction in this cohort, partly owing to the poor applicability of traditional parameters in the hyperdynamic circulation. In this feasibility study, we sought to assess the utility of a novel parameter (septal e'/s') to identify diastolic dysfunction in patients with severe sepsis and septic shock who had normal systolic function against the 2016 American Society Echocardiography and European Association of Cardiovascular Imaging (ASE/EACI) guidelines on diastolic dysfunction. METHODS: In this prospective observational pilot study, patients identified as having severe sepsis and septic shock underwent transthoracic echocardiography on day 1 and day 3 of their intensive care unit admission. In patients with normal systolic function, septal e'/s' was calculated using the peak modal velocity of the s' compared with the e' from the septal annulus tissue Doppler imaging and compared with their diastolic grade according to the 2016 ASE/EACI guidelines on diastolic dysfunction. RESULTS: On day 1 of admission, 44 of 62 patients with severe sepsis and septic shock had normal systolic function. There was a strong association of those with diastolic dysfunction having a reduced septal e'/s' compared with patients with normal diastolic function (AUC 0.91). A similar relationship was seen with patients who had indeterminate diastolic dysfunction. On day 3, 37 patients had normal systolic function. Again, there was a strong association of those with diastolic dysfunction and a reduced septal e'/s' (AUC 0.95). CONCLUSIONS: A reduction in septal e'/s' may indicate diastolic dysfunction in patients with severe sepsis and septic shock who have normal systolic function. As opposed to limited traditional measures of diastolic dysfunction, it is applicable in those with hyperdynamic systolic function.

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AIMS: The aim of this article was to determine whether lateral and septal early diastolic mitral annular velocities (LW-e' and IS-e', respectively) accuracy to reflect left ventricular (LV) relaxation is truly compromised by a limitation of mitral annular motion due to mitral annulus calcification (MAC) and to search for e' surrogates to circumvent this limitation. METHODS AND RESULTS: LW-e', IS-e', and peak early diastolic velocities at the basal-lateral and basal-septal LV segments 2 cm distal to the annulus (LW-e'2 and IS-e'2, respectively) were measured using tissue Doppler imaging (TDI) in 206 consecutive patients referred for echocardiography. Significant MAC (assessed by two-dimensional echocardiography) was present in 57 (28%) subjects. There was a significant reduction in LW-Δe' (LW-e' minus LW-e'2) in subjects with posterior MAC (0.15 ± 1.35 vs. 1.30 ± 1.24 cm/s, P < 0.0001) and a small but not significant reduction in IS-Δe' (IS-e' minus IS-e'2) in subjects with anterior MAC (-0.15 ± 1.04 vs. 0.42 ± 1.56 cm/s, P = 0.07), compared with age-matched no MAC subjects. Potential confusion factors were analysed on multiple regression. The basal segments in which e'2 were measured were free of calcification regardless of MAC. In search for e'2-based surrogates for e', the regression equation [Formula: see text] (R(2) = 0.86, P < 0.0001) was obtained from the first 100 consecutive subjects and validated in the next 49 no MAC subjects (intraclass correlation coefficient 0.96, P < 0.0001). In the septal side, no difference was found between IS-e' and IS-e'2 in the 149 subjects with no MAC (8.5 ± 3.1 vs. 8.5 ± 2.9 cm/s, P = 0.55). CONCLUSION: MAC significantly affected LW-e' (and not significantly IS-e') accuracy to reflect LV relaxation. [Formula: see text] and IS-e'2 as surrogates for LW-e' and IS-e', respectively, may correct this inaccuracy.

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BACKGROUND: Left ventricular (LV) diastolic dysfunction is often observed in healthy older subjects without structural heart disease, although its exact mechanisms have not been established. A decrease in the aorto-septal angle (ASA), an alteration of LV shape due to aortic elongation, is also frequently seen in elderly subjects. The objective of this study was to evaluate whether it can contribute to LV diastolic dysfunction in healthy subjects. METHODS: Echocardiography was performed in 77 healthy subjects (42 men, mean age 43.2 ± 13.8 years) to measure the ASA, early diastolic transmitral flow velocity (E), isovolumic relaxation time (IRT), and early diastolic mitral annular velocity (e'). The LV peak early diastolic longitudinal strain rate (GSRE ) was measured using a two-dimensional speckle tracking imaging technique. RESULTS: ASA was significantly correlated with E (r = 0.54, p < 0.001), IRT (r = -0.41, p < 0.001), e' (r = 0.57, p < 0.001), and GSRE (r = 0.63, p < 0.001) and shown by stepwise multivariate analysis to be the strongest independent determinant of E, IRT, and GSRE , and one of the independent determinants of e'. CONCLUSIONS: The alteration of LV shape associated with reduced ASA may be one of the causes of LV diastolic dysfunction independently of age in otherwise healthy subjects.

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Although familial hypertrophic cardiomyopathy (FHC) is characterized as cardiac disease in the absence of overt stressors, disease penetrance, and pathological progression largely depend on modifying factors. Accordingly, pressure overload by transverse aortic constriction (TAC) was induced in 2-month-old, male mice with and without a FHC (R403Q) mutation in α-myosin heavy chain. A significantly greater number of FHC mice (n = 8) than wild-type (WT) mice (n = 5) died during the 9-week study period. TAC induced a significant increase in cardiac mass whether measured at 2 or 9 weeks post-TAC in both WT and FHC mice, albeit to a different extent. However, the temporal and morphological trajectory of ventricular remodeling was impacted by the FHC transgene. Both WT and FHC hearts responded to TAC with an early (2 weeks post-TAC) and significant augmentation of the relative wall thickness (RWT) indicative of concentric hypertrophy. By 9 weeks post-TAC, RWT decreased in WT hearts (eccentric hypertrophy) but remained elevated in FHC hearts. WT hearts following TAC demonstrated enhanced cardiac function as measured by the end-systolic pressure-volume relationship, pre-load recruitable stroke work (PRSW), and myocardial relaxation indicative of compensatory hypertrophy. Similarly, TAC induced differential histological and cellular remodeling; TAC reduced expression of the sarcoplasmic reticulum Ca(2+)-ATPase (2a) (SERCA2a; 2 and 9 weeks) and phospholamban (PLN; 2 weeks) but increased PLN phosphorylation (2 weeks) and ß-myosin heavy chain (ß-MyHC; 9 weeks) in WT hearts. FHC-TAC hearts showed increased ß-MyHC (2 and 9 weeks) and a late (9 weeks) decrease in PLN expression concomitant with a significant increase in PLN phosphorylation. We conclude that FHC hearts respond to TAC induced pressure overload with increased premature death, severe concentric hypertrophy, and a differential ability to undergo morphological, functional, or cellular remodeling compared to WT hearts.