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Background: Adjuvant breast cancer therapy containing anthracyclines with or without anti-human epidermal growth factor receptor-2 antibodies and radiotherapy is associated with cancer treatment-related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the β-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury., Methods: In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations., Results: A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group ( P =0.021) and attenuated decline in global longitudinal strain ( P =0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed., Conclusions: Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01434134.

Background: Concentrations of B-type natriuretic peptide (BNP) reflect myocardial distension and stress, and are associated with poor prognosis in patients with cardiovascular disease. Accordingly, we hypothesized that concentrations of BNP would be associated with indices of adverse left ventricular (LV) remodeling and early stages of LV systolic and diastolic dysfunction in healthy participants from the general population., Methods: We measured BNP in 1757 women and 1677 men free from known coronary heart disease participating in the prospective observational Akershus Cardiac Examination 1950 Study. All study participants underwent extensive cardiovascular phenotyping at baseline, including detailed echocardiography with assessment of indexed LV mass (LVMI), diastolic [tissue Doppler e', E/e' ratio, indexed left atrial volume (LAVI), maximal tricuspid regurgitation velocity (TRVmax), and E/A ratio], and systolic [global longitudinal strain (GLS) and LV ejection fraction (LVEF)] function., Results: Study participants with the highest BNP concentrations had higher GLS, LVMI, e', E/e' ratio, LAVI, TRVmax, and E/A ratio. In adjusted analyses, both GLS and LVEF exhibited significant nonlinear associations with BNP, with reduced LV systolic function observed in both the low and high concentration range of BNP., Conclusions: In healthy participants recruited from the general population, concentrations of BNP exhibit nonlinear associations with LV systolic function, and both low and high concentrations are associated with reduced LV systolic function. This supports the notion that natriuretic peptides are beneficial and elicit cardioprotective effects, and may have important implications for the interpretation of BNP measurements in the general population., (© American Association for Clinical Chemistry 2020.)

Background: Concentrations of cardiac troponin I (cTnI) and T (cTnT) are associated with clinical cardiac outcomes, but do not correlate closely in subjects recruited from the general population. Accordingly, we hypothesized that cTnI and cTnT concentrations would be influenced by different cardiovascular (CV) and non-CV risk factors and reflect different CV phenotypes., Methods: We measured cTnI and cTnT with last generation assays in 1236 women and 1157 men with no known CV disease participating in the prospective observational Akershus Cardiac Examination 1950 Study. All study participants underwent extensive CV phenotyping at baseline, including detailed echocardiography., Results: Concentrations of cTnI were measurable in 60.3% and cTnT in 72.5% of study participants (P < 0.001), and correlated moderately (r = 0.53; P < 0.001). cTnI was more strongly associated with male sex (P = 0.018), higher education (P < 0.001), history of hypertension (P < 0.001), and age (P < 0.001), whereas cTnT was more strongly associated with eGFR (P = 0.015). Both cTnI and cTnT were inversely associated with global longitudinal strain and positively associated with LV mass index (LVMI) in analyses adjusted for CV risk factors. The association between cTnI and LVMI was stronger than the association between cTnT and LVMI (P = 0.035). Concentrations of cTnI improved diagnostic accuracy for LV hypertrophy when added to established CV risk factors, but concentrations of cTnT did not improve these models further., Conclusions: In a large community-based cohort examined with extensive echocardiography, concentrations of cTnI and cTnT are associated with subclinical LV hypertrophy and dysfunction. Concentrations of cTnI appear superior to cTnT in predicting subclinical LV hypertrophy., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Chronic exercise induces adaptive changes of left ventricular (LV) ejection and filling capacities which may be detected by novel speckle-tracking echocardiography (STE) and tissue Doppler imaging (TDI)-based techniques. A total of 103 consecutive male elite Norwegian soccer players and 46 age-matched healthy controls underwent echocardiography at rest. STE was used to assess LV torsional mechanics and LV systolic longitudinal strain (LS). Diastolic function was evaluated by trans-mitral blood flow, mitral annular velocities by TDI, and LV inflow propagation velocity by color M-mode. Despite similar global LS, players displayed lower basal wall and higher apical wall LS values vs controls, resulting in an incremental base-to-apex gradient of LS. Color M-mode and TDI-derived data were similar in both groups. Peak systolic twist rate (TWR) was significantly lower in players (86.4±2.8 vs controls 101.9±5.2 deg/s, P<.01). Diastolic untwisting rate (UTWR) was higher in players (-124.5±4.2 vs -106.9±6.7 deg/s) and peaked earlier during the cardiac cycle (112.7±0.8 vs 117.4±2.4% of systole duration, both P<.05). Untwisting/twisting ratio (-1.48±0.05 vs -1.11±0.08; P<.001) and untwisting performance (=UTR/TW; -9.25±0.34 vs -7.38±0.40 s -1 , P<.01) were increased in players. Augmented diastolic wall strain (DWS), a novel measure of LV compliance in players, was associated with improved myocardial mechanical efficiency. The described myocardial biomechanics may underlie augmented exertional cardiac function in athletes and may have a potential role to characterize athlete's heart by itself or to distinguish it from hypertensive or hypertrophic cardiomyopathy., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Osteogenesis imperfecta (OI), also known as brittle bone disease or Lobstein syndrome, is a congenital bone disorder characterized by brittle bones that are prone to fracture. People with OI are born with defective connective tissue in most cases secondary to a deficiency of type-I collagen, which represents approximately 75% of total collagen in the adult myocardium. The purpose of our study was to assess the prevalence of cardiomyopathy, electrocardiogram (ECG) abnormalities, and cardiovascular symptoms among patients with OI., Methods: We studied 99 adults with OI from the national OI registry in Norway. Patients were divided into type I, III, and IV, and 52 control subjects. History and physical examination, ECG, and echocardiographic parameters of left ventricular (LV) and right ventricular (RV) systolic and diastolic function were obtained., Results: ECG abnormalities and cardiac symptoms were more common among patients with OI. RV and LV systolic peak velocity were significantly lower and diastolic mitral tricuspid valve wave and early diastolic tissue Doppler velocity ratio increased in the OI group compared with the control subjects; 5.7 ± 1.2 vs 6.3 ± 1.2 cm/s (P < 0.05) and 8 ± 1.8 vs 9.5 ± 1.4 cm/s (P < 0.05) and 9.8 ± 2.6 vs 7.4 ± 2.0 (P < 0.05) and 8.6 ± 3.3 vs 6.1 ± 1.4, respectively. In multivariate analysis OI was found to be an independent risk factor for RV systolic and diastolic dysfunction., Conclusions: Cardiac symptoms and ECG changes are common among patients with OI. Our study findings suggest RV and LV systolic and diastolic function to be impaired in patients with OI compared with normal individuals. In multivariate analysis, however, OI was an independent predictor only of reduced RV systolic and diastolic function., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Purpose: The main purpose of the this human study was by speckle tracking imaging to characterize the regional and temporal distribution of normal left ventricular (LV) deformation and the LV geometry during isovolumetric contraction (IVC) and the ejection phase., Methods: Twelve healthy young men [22 (2·3) years] were included. Longitudinal and circumferential strain and local twist angle were measured at four LV short-axis levels: basal, papillary, subpapillary and apical level during IVC and ejection phases. In addition, LV length from apex to the atrio-ventricular level, two diameters at LV basal short-axis level and atrio-ventricular plane displacement (AVPD) were measured to characterize LV shape during IVC., Results: During IVC, longitudinal and circumferential shortening was demonstrated at all four short-axis levels from base to apex, while the LV made a basal counterclockwise and apical clockwise rotation representing untwist. In addition, there was a reduction in LV length and changes in short-axis diameters at basal level and AVPD from end-diastole to end-IVC, reflecting that the LV changed from an oval to a more spherical shape. At end-systole, longitudinal and circumferential shortening and local twist angle were significantly increased towards apex (P<0·05)., Conclusion: This study demonstrated that the IVC in healthy humans is characterized by regional longitudinal and circumferential shortening and LV untwist, which occurs parallel to geometric changes of the LV into a spherical shape. During ejection, increased regional gradients of LV deformation towards apex in LV longitudinal and circumferential shortening and local and net twist angle were demonstrated., (© 2012 The Authors Clinical Physiology and Functional Imaging © 2012 Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Background: In normal left ventricles (LV), counterclockwise rotation (CCR) and net twist angle (NTA) have shown important roles during ejection. We investigated the effect of reduced preload by lower body negative pressure (LBNP) on CCR and NTA., Methods and Results: Twelve healthy men were examined at rest, LBNP -20 and -40 mmHg. By two-dimensional speckle-tracking imaging, we measured rotation at four short-axis levels: basal, papillary, sub-papillary and apical. LV NTA was calculated as apex-to-base difference in rotation. Additionally, regional end-diastolic (EDA) and end-systolic area (ESA) were measured and regional area fraction (RAF) calculated [(EDA-ESA)/EDA] × 100). From rest to LBNP -40 mmHg, rotation at basal and papillary levels was unchanged. At sub-papillary level, rotation increased from 3·2 ± 3·6 to 5·8 ± 4·7° (P<0·05), while apical rotation increased from 9·3 ± 3·4 to 12·8 ± 4·7° (P<0·05). Correspondingly, LV NTA increased for each load reduction by 1·6 ± 1·8° (P<0·05) and 4·2 ± 2·3° (P<0·05). RAF increased at sub-papillary and apical levels from 57·6 ± 3·7 to 64·7 ± 8·8% and from 63·4 ± 8·8 to 74·8 ± 10·1%, respectively (P<0·05). From rest to LBNP -40 mmHg, changes in rotation and RAF correlated significantly at sub-papillary and apical levels (r = 0·94, P<0·01, and r = 0·63, P<0·05, respectively)., Conclusions: Preload reduction in normal LV elicits increased systolic CCR and regional area fraction at sub-papillary and apical levels as well as net twist angle. These findings might be of physiological importance to minimize reduction in stroke volume and maintain arterial blood pressure., (© 2011 The Authors. Clinical Physiology and Functional Imaging © 2011 Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

This study investigates mechanisms of left ventricular (LV) intracavitary flow during early, rapid filling. In eight coronary artery disease patients with normal LV ejection fraction we recorded simultaneous LV apical and outflow tract pressures and intraventricular flow velocities by color M-mode Doppler echocardiography. In five anesthetized dogs we also recorded left atrial pressure and LV volume by sonomicrometry. In patients, as the early diastolic mitral-to-apical filling wave arrived at the apex, we observed an apex-outflow tract pressure gradient of 3.5 +/- 0.3 mmHg (mean +/- SE). This pressure gradient correlated with peak early apex-to-outflow tract flow velocity (r = 0.75, P < 0.05). The gradient was reproduced in the dog model and decreased from 3.1 +/- 0.3 to 1.7 +/- 0.5 mmHg (P < 0.05) with caval constriction and increased to 4.2 +/- 0.5 mmHg (P < 0.001) with volume loading. The pressure gradient correlated with peak early transmitral flow (expressed as time derivative of LV volume; r = 0.95) and stroke volume (r = 0.97). In conclusion, arrival of the early LV filling wave at the apex was associated with a substantial pressure gradient between apex and outflow tract. The pressure gradient was sensitive to changes in preload and correlated strongly with peak early transmitral flow. The significance of this gradient for intraventricular flow propagation in the normal and the diseased heart remains to be determined.

We investigated the repeatability of two recently reported colour M-mode Doppler measures of left ventricular diastolic function. 'Delay of peak velocity' is the time interval from peak velocity of early filling at the mitral tip level to peak velocity in the apical region. The 'velocity of flow propagation' is the speed of the mitral to apical spread of the early diastolic filling. Two examiners independently and blindly made measurements by both methods on 32 digital recordings twice, using custom software. Inter- and intra-observer repeatability were given in terms of limits of agreement, where 1 denotes perfect agreement. Limits of intra-observer agreement were 0.72-1.43 for measurements of 'delay of peak velocity', and 0.39-2.28 for 'velocity of flow propagation'. Limits of inter-observer agreement were 0.68-1.42 and 0.19-2.04 respectively. The correlation between the methods was weak (r = 0.45), suggesting that they may detect different properties of early diastole. We suggest that the reliability of the methods may be improved by replicate measurements performed blindly. There are reasons to express the velocity of flow propagation on a logarithmic scale.