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Rationale: There is a lack of information on the long-term prognosis of patients with acute pulmonary embolism (PE). Objectives: To assess the long-term risk for adverse events after PE. Methods: Consecutive patients diagnosed with PE between January 2001 and July 2007, and patients in whom PE was ruled out from a previous study were followed until July 2008 for the occurrence of adverse clinical events: mortality, symptomatic recurrent venous thromboembolism, cancer, arterial cardiovascular events and chronic thromboembolic pulmonary hypertension. Hazard ratios (HR) for all endpoints and a combined endpoint were calculated and adjusted for potential confounders. Measurements and Main Results: Three hundred eight patients with unprovoked, 558 with provoked, and 334 without PE were studied with a median follow-up period of 3.3 years. Patients with unprovoked PE had a lower overall risk for mortality than patients with provoked PE (HR, 0.59; 95% confidence interval [CI], 0.43-0.82), but a higher risk for nonmalignancy-related mortality (HR, 1.8; 95% CI, 1.3-2.5), recurrent venous thromboembolism (HR, 2.1; 95% CI, 1.3-3.1), cancer (HR, 4.4; 95% CI, 2.0-10), cardiovascular events (HR, 2.6; 95% CI, 1.5-3.8) and chronic thromboembolic pulmonary hypertension (1.5 vs. 0%). The risk for the combined endpoint did not differ between both groups (HR, 0.98; 95% CI, 0.82-1.1). Patients without PE had similar risks for malignancy and cardiovascular events than patients with provoked PE, but lower risks for the remaining outcomes. The fraction of both patients with provoked and unprovoked PE without events after 1 year was only 70% and decreased to fewer than 60% after 2 years and fewer than 50% after 4 years, whereas this latter was 84% for the control patients. Conclusions: The clinical course of acute PE is complicated by high rates of serious adverse events, which occur in half of the patients within 4 years. [ABSTRACT FROM AUTHOR]

Traditionally, echocardiography is used for volumetric measurements to aid in assessment of cardiac function. Multiple echocardiographic-based assessment techniques have been developed, such as Doppler ultrasound and deformation imaging (e.g., peak global longitudinal strain (GLS)), which have shown to be clinically relevant. Volumetric changes across the cardiac cycle can be related to deformation, resulting in the Ventricular Strain-Volume/Area Loop. These Loops allow assessment of the dynamic relationship between longitudinal strain change and volumetric change across both systole and diastole. This integrated approach to both systolic and diastolic function assessment may offer additional information in conjunction with traditional, static, measures of cardiac function or structure. The aim of this review is to summarize our current understanding of the Ventricular Strain-Volume/Area Loop, describe how acute and chronic exposure to hemodynamic stimuli alter Loop characteristics, and, finally, to outline the potential clinical value of these Loops in patients with cardiovascular disease. In summary, several studies observed Loop changes in different hemodynamic loading conditions and various (patho)physiological conditions. The diagnostic and prognostic value, and physiological interpretation remain largely unclear and have been addressed only to a limited extent., (© 2024. The Author(s).)

Objectives: Pulmonary hypertension is one of the leading causes of death in systemic sclerosis. Early detection and treatment of pulmonary hypertension in systemic sclerosis is crucial. Nailfold capillaroscopy microscopy, vascular autoantibodies AT1R and ETAR, and several candidate-biomarkers have the potential to serve as noninvasive tools to identify systemic sclerosis patients at risk for developing pulmonary hypertension. Here, we explore the classifying potential of nailfold capillaroscopy microscopy characteristics and serum levels of selected candidate-biomarkers in a sample of systemic sclerosis patients with and without different forms of pulmonary hypertension., Methods: A total of 81 consecutive systemic sclerosis patients were included, 40 with systemic sclerosis pulmonary hypertension and 41 with no pulmonary hypertension. In each group, quantitative and qualitative nailfold capillaroscopy microscopy characteristics, vascular autoantibodies AT1R and ETAR, and serum levels of 24 soluble serum factors were determined. For evaluation of the nailfold capillaroscopy microscopy characteristics, linear regression analysis accounting for age, sex, and diffusing capacity of the lungs for carbon monoxide percentage predicted was used. Autoantibodies and soluble serum factor levels were compared using two-sample t test with equal variances., Results: No statistically significant differences were observed in quantitative or qualitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibody ETAR and AT1R titer between systemic sclerosis-pulmonary hypertension and systemic sclerosis-no pulmonary hypertension. In contrast, several serum levels of soluble factors differed between groups: Endostatin, sVCAM, and VEGFD were increased, and CXCL4, sVEGFR2, and PDGF-AB/BB were decreased in systemic sclerosis-pulmonary hypertension. Random forest classification identified Endostatin and CXCL4 as the most predictive classifiers to distinguish systemic sclerosispulmonary hypertension from systemic sclerosis-no pulmonary hypertension., Conclusion: This study shows the potential for several soluble serum factors to distinguish systemic sclerosis-pulmonary hypertension from systemic sclerosis-no pulmonary hypertension. We found no classifying potential for qualitative or quantitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibodies., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.P.J.van.D. reports Grants or contracts from Janssen Pharmaceutical Company in the past 36 months, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen Pharmaceutical Company and Bayer. M.C.V. reports Research grants from Boehringer Ingelheim, Janssen, Ferrer and Galapagos in the past 36 months, Consulting fees from Boehringer Ingelheim and Janssen, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, Bristol-Myers Squibb, GSK, Janssen, MSD, Novartis and Roche, Participation on a Data Safety Monitoring Board or Advisory Board from Corbus pharmaceuticals, Leadership or fiduciary role in other board, society, committee or advocacy group at the Eustar extended board (unpaid). For the other authors competing interests are not applicable. The Editor/Editorial Board Member of JSRD is an author of this paper; therefore, the peer-review process was managed by alternative members of the Board and the submitting Editor/Board member had no involvement in the decision-making process., (© The Author(s) 2023.)

Background: Right atrial (RA) imaging has emerged as a promising tool for the evaluation of patients with pulmonary hypertension (PH), albeit without systematic validation., Methods: PubMed, Web of Science and the Cochrane library were searched for studies investigating the prognostic value of RA imaging assessment in patients with PH from 2000 to June 2021 (PROSPERO Identifier: CRD42020212850). An inverse variance-weighted meta-analysis of univariable hazard ratios (HRs) was performed using a random effects model., Results: Thirty-five studies were included (3,476 patients with PH; 74% female, 86% pulmonary arterial hypertension). Risk of bias was low/moderate (Quality of Prognosis Studies checklist). RA area (HR 1.06; 95% confidence interval [CI] 1.04-1.08), RA indexed area (HR 1.09; 95% CI 1.04-1.14), RA peak longitudinal strain (PLS; HR 0.94; 95% CI 0.91-0.97) and RA total emptying fraction (HR 0.96; 95% CI 0.94-0.98) were significantly associated with combined end-points including death, clinical worsening and/or lung transplantation; RA volume and volume index showed marginal significant associations. RA area (HR 1.06; 95% CI 1.04-1.07), RA indexed area (HR 1.12; 95% CI 1.07-1.17) and RA PLS (HR 0.98; 95% CI 0.97-0.99) showed significant associations with mortality; RA total emptying fraction showed a marginal association., Conclusions: Imaging-based RA assessment qualifies as a relevant prognostic marker in PH. RA area reliably predicts composite end-points and mortality, which underscores its clinical utility. RA PLS emerged as a promising imaging measure, but is currently limited by the number of studies and different acquisition methods., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension is a lethal complication of different connective tissue diseases such as systemic sclerosis, mixed connective tissue disease and systemic lupus erythematosus. Although the treatment possibilities for patients with pulmonary arterial hypertension have increased in the last two decades and survival of patients with idiopathic pulmonary arterial hypertension has improved, the latter is not the case for patients with pulmonary arterial hypertension associated with connective tissue disease. In this narrative review, we review recent literature and describe the improvement of early diagnostic possibilities, screening modalities and treatment options. We also point out the pitfalls in diagnosis in this patient category and describe the unmet needs and what the focus of future research should be., (© 22020 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Aims: Patients with pre-capillary pulmonary hypertension (PH) show poor survival, often related to right ventricular (RV) dysfunction. In this study, we assessed the 5-year prognostic value of a novel echocardiographic measure that examines RV function through the temporal relation between RV strain (ϵ) and area (i.e. RV ϵ-area loop) for all-cause mortality in PH patients., Methods and Results: Echocardiographic assessments were performed in 143 PH patients (confirmed by right heart catheterization). Transthoracic echocardiography was utilized to assess RV ϵ-area loop. Using receiver operating characteristic curve-derived cut-off values, we stratified patients in low- vs. high-risk groups for all-cause mortality. Kaplan-Meier survival curves and uni-/multivariable cox-regression models were used to assess RV ϵ-area loop's prognostic value (independent of established predictors: age, sex, N-terminal pro B-type natriuretic peptide, 6-min walking distance). During follow-up 45 (31%) patients died, who demonstrated lower systolic slope, peak ϵ, and late diastolic slope (all P < 0.05) at baseline. Univariate cox-regression analyses identified early systolic slope, systolic slope, peak ϵ, early diastolic uncoupling, and early/late diastolic slope to predict all-cause mortality (all P < 0.05), whilst peak ϵ possessed independent prognostic value (P < 0.05). High RV loop-score (i.e. based on number of abnormal characteristics) showed poorer survival compared to low RV loop-score (Kaplan-Meier: P < 0.01). RV loop-score improved risk stratification in high-risk patients when added to established predictors., Conclusion: Our data demonstrate the potential for RV ϵ-area loops to independently predict all-cause mortality in patients with pre-capillary PH. The non-invasive nature and simplicity of measuring the RV ϵ-area loop, support the potential clinical relevance of (repeated) echocardiography assessment of PH patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background During uncomplicated pregnancy, left ventricular remodeling occurs in an eccentric way. In contrast, during preeclamptic gestation, the left ventricle hypertrophies concentrically, concurrent with loss in circulatory volume and increased blood pressure. Concentric cardiac structure persists in a substantial proportion of women and may be associated with pressure and volume load after preeclampsia. We hypothesize that low volume load, as indicated by plasma volume (PV) after preeclampsia and increased pressure load, is associated with remote concentric remodeling. Methods and Results In this longitudinal cohort study, we included 100 formerly preeclamptic women. Two visits were performed: at 0.8 years postpartum and at 4.8 years postpartum. During visit 1, we measured blood pressure and PV (I 125 dilution technique, low PV ≤48 mL/kg lean body mass). During the second visit, we assessed cardiac geometry by cardiac ultrasound. Concentric remodeling was defined as relative wall thickness >0.42 and left ventricular mass index ≤95 g/m 2 . We adjusted multivariable analysis for primiparity, systolic blood pressure, PV mL/kg lean body mass, and antihypertensive medication at visit 1. Low PV is associated with remote concentric remodeling (odds ratio [OR], 4.37; 95% CI, 1.06-17.40; and adjusted OR, 4.67; 95% CI, 1.02-21.42). Arterial pressure load (systolic, diastolic, and mean arterial pressure) is also associated with development of concentric remodeling (OR, 1.15 [95% CI, 0.99-1.35]; OR, 1.24 [95% CI, 0.98-1.58]; and OR, 1.20 [95% CI, 0.98-1.47], respectively). Conclusions In former preeclamptic women, development toward left ventricular concentric remodeling is associated with low volume load and increased pressure load.

Chronic changes in left ventricular (LV) hemodynamics, such as those induced by increased afterload (i.e., hypertension), mediate changes in LV function. This study examined the proof of concept that 1 ) the LV longitudinal strain (ε)-volume loop is sensitive to detecting an acute increase in afterload, and 2 ) these effects differ between healthy young versus older men. Thirty-five healthy male volunteers were recruited, including 19 young (24 ± 2 yr) and 16 older participants (67 ± 5 yr). Tests were performed before, during, and after 10-min recovery from acute manipulation of afterload. Real-time hemodynamic data were obtained and LV longitudinal ε-volume loops were calculated from four-chamber images using two-dimensional echocardiography. Inflation of the anti-gravity (anti-G) suit resulted in an immediate increase in heart rate, blood pressure, and systemic vascular resistance and a decrease in stroke volume (all P < 0.05). This was accompanied by a decrease in LV peak ε, slower slope of the ε-volume relationship during early diastole, and an increase in uncoupling (i.e., compared with systole; little change in ε per volume decline during early diastole and large changes in ε per volume decline during late diastole) (all P < 0.05). All values returned to baseline levels after recovery (all P > 0.05). Manipulation of cardiac hemodynamics caused comparable effects in young versus older men (all P > 0.05). Acute increases in afterload immediately change the diastolic phase of the LV longitudinal ε-volume loop in young and older men. This supports the potency of the LV longitudinal ε-volume loop to provide novel insights into dynamic cardiac function in humans in vivo.

Aortic valve replacement (AVR) leads to remodeling of the left ventricle (LV). Adopting a novel technique to examine dynamic LV function, our study explored whether post-AVR changes in dynamic LV function and/or changes in aortic valve characteristics are associated with LV mass regression during follow-up. We retrospectively analyzed 30 participants with severe aortic stenosis who underwent standard transthoracic echocardiographic assessment before AVR [88 (IQR or interquartile range: 22-143) days], post-AVR [13 (6-22) days], and during follow-up [455 (226-907) days]. We assessed standard measures of LV structure, function, and aortic valve characteristics. Novel insight into dynamic LV function was provided through a four-chamber image by examination of the temporal relation between LV longitudinal strain (ε) and volume (ε-volume loops), representing the contribution of LV mechanics to volume change. AVR resulted in immediate changes in structural valve characteristics, alongside a reduced LV longitudinal peak ε and improved coherence between the diastolic and systolic part of the ε-volume loop (all P < 0.05). Follow-up revealed a decrease in LV mass ( P < 0.05) and improvements in LV ejection fraction and LV longitudinal peak ε ( P < 0.05). A significant relationship was present between decline in LV mass during follow-up and post-AVR improvement in coherence of the ε-volume loops ( r  = 0.439, P = 0.03), but not with post-AVR changes in aortic valve characteristics or LV function (all P > 0.05). We found that post-AVR improvements in dynamic LV function are related to long-term remodeling of the LV. This highlights the potential importance of assessing dynamic LV function for cardiac adaptations in vivo. NEW & NOTEWORTHY Combining temporal measures of left ventricular longitudinal strain and volume (strain-volume loop) provides novel insights in dynamic cardiac function. In patients with aortic stenosis who underwent aortic valve replacement, postsurgical changes in the strain-volume loop are associated with regression of left ventricular mass during follow-up. This provides novel insight into the relation between postsurgery changes in cardiac hemodynamics and long-term structural remodeling, but also supports the potential utility of the assessment of dynamic cardiac function.

Aims: Pulmonary hypertension (PH) is associated with high morbidity and mortality and the predictive capacity of traditional functional echocardiographic measures is poor. Recent studies assessed the predictive capacity of right ventricular longitudinal strain (RVLS). Diversity in methods between these studies resulted in conflicting outcomes. The purpose of this systematic review and meta-analysis was to determine the independent prognostic value of RVLS for PH-related events and all-cause mortality., Methods and Results: A systematic search in Pubmed (MEDLINE), Embase, the Cochrane Library, and Web of Science was performed to identify studies that examined the prognostic value of RVLS in patients with PH. Studies reporting Cox regression based hazard ratios (HRs) for a combined endpoint of mortality and PH-related events or all-cause mortality for echocardiographic derived RVLS were included. A weighted mean of the multivariate HR was used to determine the independent predictive value of RVLS. Eleven studies met our criteria, including 1169 patients with PH (67% female, 0.6-3.8 years follow-up). PH patients with a relative reduction of RVLS of 19% had a significantly higher risk for the combined endpoint [HR 1.22, 95% confidence interval (CI) 1.07-1.40], while patients with a relative reduction of RVLS of 22% had a significantly higher risk for all-cause mortality (HR 2.96, 95% CI 2.00-4.38)., Conclusion: This systematic review and meta-analysis showed that RVLS has independent prognostic value for a combined endpoint and all-cause mortality in patients with PH. Collectively, these findings emphasize that RVLS may have value for optimizing current predictive models for clinical events or mortality in patients with PH., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Background: Stenting of coarctation of the aorta (CoA) generally results in good angiographic results and a decrease in transcoarctation pressure gradient. However, effect on blood pressure control is less clear. The goal of the current retrospective analysis was to investigate the effects of CoA stenting on blood pressure control., Methods: A retrospective analysis was conducted in consecutive adult patients with a CoA who underwent a percutaneous intervention at one of the three participating hospitals. Measurements included office blood pressure, invasive peak-to-peak systolic pressure over the CoA, diameter of the intima lumen at the narrowest part of the CoA and use of medication. The follow-up data were obtained, based on the most recent examination date., Results: There were 26 native CoA and 17 recurrent CoAs (total n = 43). Seven of them underwent two procedures. Mean peak-to-peak gradient decreased from 27 mmHg to 3 mmHg (p < 0.001), and minimal diameter increased from a mean of 11 mm to 18 mm (p < 0.001). Mean systolic blood pressure decreased from 151 ± 18 mmHg to 135 ± 19 mmHg at first follow-up of 3.8 ± 1.9 months and 137 ± 22 mmHg at latest follow-up of 19.5 ± 10.9 months (p = 0.001 and p = 0.009, compared to baseline, respectively). The total number of hypertensive patients decreased from 74% to 27% at latest follow-up. No significant change in antihypertensive medication was observed., Conclusion: A clinically significant decrease in systolic blood pressure of approximately 16 mmHg was shown after (re)intervention in CoA patients, which sustained at follow-up. This sustained decrease of blood pressure can be expected to lead to less future adverse cardiovascular events., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: We evaluate pregnancy outcome and anticoagulation regimes in women with mechanical and biological prosthetic heart valves (PHV) for congenital heart disease., Methods: Retrospective multicenter cohort studying pregnancy outcomes in an existing cohort of patients with PHV., Results: 52 women had 102 pregnancies of which 78 pregnancies (46 women) ≥20 weeks duration (59 biological, 19 mechanical PHV). Miscarriages (n = 19, ≤20 weeks) occurred more frequently in women using anticoagulation (P < .05). During 42% of pregnancies of women with mechanical PHV a combined low molecular weight heparin (LMWH) vitamin-K-antagonist anticoagulation regime was used (n = 8). Overall, cardiovascular, obstetric and fetal/neonatal complications occurred in 17% (n = 13), 68% (n = 42) and 42% (n = 27) of the pregnancies. Women with mechanical PHV had significantly higher cardiovascular (12% vs 32%, P < .05), obstetric (59% vs 85%, P = .02) and fetal/neonatal (34% vs 61%, P < .05) complication rates than women with biological PHV. This was related to PHV thrombosis (n = 3, P < .02), post-partum hemorrhage (P < .02), cesarean section (P < .02), low birth weight and small for gestational age (both P < .05). PHV thrombosis occurred in 3 pregnancies, including 2/5 pregnancies with pulmonary mechanical PHV. PHV thrombosis was related to necessary cessation of anticoagulation therapy or insufficient monitoring of LMWH. Other cardiovascular complications occurred equally frequent in both groups., Conclusion: Complications occur more often in pregnancies of women with a mechanical PHV than in women with a biological PHV, mainly caused by PHV thrombosis and bleeding complications. Meticulous monitoring of anticoagulation in pregnant women is necessary. Women with a pulmonary mechanical PHV are at high risk of complications., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: Pre-eclampsia (PE) is associated with both postpartum endothelial dysfunction and asymptomatic structural heart alterations consistent with heart failure Stage B (HF-B). In this study, we assessed the relationship between endothelial function, measured by flow-mediated dilation (FMD), and HF-B in women with a history of PE., Methods: This was an observational study in which 67 formerly pre-eclamptic women (≥ 4 years postpartum) and 37 healthy parous controls were assessed ultrasonographically for cardiac function and geometry, as well as for endothelial function by means of brachial artery FMD. HF-B was diagnosed as left ventricular hypertrophy (left ventricular mass index (LVMi) > 95 g/m 2 ), concentric remodeling (relative wall thickness > 0.42 and LVMi ≤ 95 g/m 2 ), mild systolic dysfunction (left ventricular ejection fraction > 40% and < 55%) or asymptomatic valvular disease. Cardiovascular and metabolic syndrome variables were compared between women with history of PE and controls, as well as between those in the formerly pre-eclamptic group who had HF Stage A, HF-B or no HF. Logistic regression analysis was performed to assess the associations of FMD with PE, metabolic syndrome risk factors and obstetric parameters., Results: The prevalence of HF-B amongst formerly pre-eclamptic women was three-fold higher than that observed for controls (25% vs 8%, P < 0.05), while FMD was lower in formerly pre-eclamptic women compared with controls (6.12% vs 8.22%, P < 0.01); history of PE remained associated independently with lower FMD after adjusting for metabolic syndrome risk factors and obstetric parameters (β, -1.88; 95% CI, -3.59 to -0.18). However, HF-B did not relate to low FMD in formerly pre-eclamptic women., Conclusions: Years after pregnancy, formerly pre- eclamptic women have lower FMD and have HF-B more often compared with healthy parous controls. Nonetheless, HF-B was not related to reduced FMD. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Background: The effect of angiotensin II receptor blockers on right ventricular (RV) function is still unknown. Angiotensin II receptor blockers are beneficial in patients with acquired left ventricular dysfunction, and recent findings have suggested a favorable effect in symptomatic patients with systemic RV dysfunction. The current study aimed to determine the effect of losartan, an angiotensin II receptor blocker, on subpulmonary RV dysfunction in adults after repaired tetralogy of Fallot., Methods: The REDEFINE trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) is an investigator-initiated, multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled study. Adults with repaired tetralogy of Fallot and RV dysfunction (RV ejection fraction [EF] <50%) but without severe valvular dysfunction were eligible. Patients were randomly assigned between losartan (150 mg daily) and placebo with target treatment duration between 18 and 24 months. The primary outcome was RV EF change, determined by cardiovascular MRI in intention-to-treat analysis., Results: Of 95 included patients, 47 patients received 150 mg losartan daily (age, 38.0±12.4 years; 74% male), and 48 patients received placebo (age, 40.6±11.4 years; 63% male). Overall, RV EF did not change in patients allocated to losartan (n=42) (44.4±5.1% to 45.2±5.0%) and placebo (n=46) (43.2±6.3% to 43.6±6.9%). Losartan did not significantly improve RV EF in comparison with placebo (+0.51%; 95% confidence interval, -1.0 to +2.0; P =0.50). No significant treatment effects were found on secondary outcomes: left ventricular EF, peak aerobic exercise capacity, and N-terminal pro-brain natriuretic peptide ( P >0.30 for all). In predefined subgroup analyses, losartan did not have a statistically significant impact on RV EF in subgroups with symptoms, restrictive RV, RV EF<40%, pulmonary valve replacement, or QRS fragmentation. However, in a post hoc analysis, losartan was associated with improved RV EF in a subgroup (n=30) with nonrestrictive RV and incomplete remodeling (QRS fragmentation and previous pulmonary valve replacement) (+2.7%; 95% confidence interval, +0.1 to +5.4; P =0.045)., Conclusions: Losartan had no significant effect on RV dysfunction or secondary outcome parameters in repaired tetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02010905., (© 2017 American Heart Association, Inc.)

Background Endurance exercise training induces cardio-protective effects, but athletes are not exempted from a myocardial infarction. Evidence from animal studies suggests that exercise training attenuates pathological left ventricular remodelling following myocardial infarction. We tested the hypothesis that lifelong exercise training is related to attenuated pathological left ventricular remodelling after myocardial infarction as evidenced by better left ventricular systolic function in veteran athletes compared to sedentary peers. Design This was a cross-sectional study. Methods Sixty-five males (60 ± 6 years) were included and allocated to four groups based on lifelong exercise training volumes: (a) athletes ( n = 18), (b) post-myocardial infarction athletes (athletes + myocardial infarction, n = 20), (c) sedentary controls ( n = 13), and (d) post-myocardial infarction controls (sedentary controls + myocardial infarction, n = 14). Athletes were lifelong (≥20 years) highly physically active (≥30 metabolic equivalent of task (MET)-h/week), whereas sedentary controls did not meet the exercise guidelines (<10 MET-h/week) for the past 20 years. left ventricular systolic function, diastolic function and wall strain were measured using echocardiography. Results Cardiac enzyme markers (creatine-kinase, creatinine, aspartate transaminase and lactate dehydrogenase) following myocardial infarction and infarct location did not differ between athletes + myocardial infarction and sedentary controls + myocardial infarction. Left ventricular ejection fraction was significantly higher in athletes (61% ± 4), athletes + myocardial infarction (58% ± 4) and sedentary controls (57% ± 6) compared to sedentary controls + myocardial infarction (51% ± 7; p < 0.01). Left ventricular circumferential strain was superior in athletes (-19% (-21% to -17%), athletes + myocardial infarction (-16% (-20% to -12%)), and sedentary controls (-15% (-18% to -14%) compared to sedentary controls + myocardial infarction (-13% (-15% to -8%), p < 0.01). Diastolic function parameters did not differ across groups. Conclusion These findings suggest that lifelong exercise training may preserve left ventricular systolic function and possibly attenuates or minimises the deleterious effects of pathological post-myocardial infarction left ventricular remodelling in veteran athletes.

Key Points: Severe aortic valve diseases are common cardiac abnormalities that are associated with poor long-term survival. Before any reduction in left ventricular (LV) function, the left ventricle undergoes structural remodelling under the influence of changing haemodynamic conditions. In this study, we combined temporal changes in LV structure (volume) with alterations in LV functional characteristics (strain, ԑ) into a ԑ-volume loop, in order to provide novel insight into the haemodynamic cardiac consequences of aortic valve diseases in those with preserved LV ejection fraction. We showed that our novel ԑ-volume loop and the specific loop characteristics provide additional insight into the functional and mechanical haemodynamic consequences of severe aortic valve diseases (with preserved LV ejection fraction). Finally, we showed that the ԑ-volume loop characteristics provide discriminative capacity compared with conventional measures of LV function., Abstract: The purpose of this study was to examine left ventricular (LV) strain (ԑ)-volume loops to provide novel insight into the haemodynamic cardiac consequences of aortic valve stenosis (AS) and aortic valve regurgitation (AR). Twenty-seven participants were retrospectively recruited: AR (n = 7), AS (n = 10) and control subjects (n = 10). Standard transthoracic echocardiography was used to obtain apical four-chamber images to construct ԑ-volume relationships, which were assessed using the following parameters: early systolic ԑ (ԑ&#95;ES); slope of ԑ-volume relationship during systole (Sslope); end-systolic peak ԑ (peak ԑ); and diastolic uncoupling (systolic ԑ-diastolic ԑ at same volume) during early diastole (UNCOUP&#95;ED) and late diastole (UNCOUP&#95;LD). Receiver operating characteristic curves were used to determine the ability to detect impaired LV function. Although LV ejection fraction was comparable between groups, longitudinal peak ԑ was reduced compared with control subjects. In contrast, ԑ&#95;ES and Sslope were lower in both pathologies compared with control subejcts (P < 0.01), but also different between AS and AR (P < 0.05). UNCOUP&#95;ED and UNCOUP&#95;LD were significantly higher in both patient groups compared with control subjects (P < 0.05). Receiver operating characteristic curves revealed that loop characteristics (AUC = 0.99, 1.00 and 1.00; all P < 0.01) were better able then peak ԑ (AUC = 0.75, 0.89 and 0.76; P = 0.06, <0.01 and 0.08, respectively) and LV ejection fraction (AUC = 0.56, 0.69 and 0.69; all P > 0.05) to distinguish AS vs control, AR vs control and AS vs AR groups, respectively. Temporal changes in ԑ-volume characteristics provide novel insight into the haemodynamic cardiac impact of AS and AR. Contrary to traditional measures (i.e. ejection fraction, peak ԑ), these novel measures successfully distinguish between the haemodynamic cardiac impact of AS and AR., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Importance: Adults late after total correction of tetralogy of Fallot (TOF) are at risk for major complications. Cardiovascular magnetic resonance (CMR) imaging is recommended to quantify right ventricular (RV) and left ventricular (LV) function. However, a commonly used risk model by Khairy et al requires invasive investigations and lacks CMR imaging to identify high-risk patients., Objective: To implement CMR imaging in noninvasive risk stratification to predict major adverse clinical outcomes., Design, Setting, and Participants: This multicenter study included 575 adult patients with TOF (4.083 patient-years at risk) from a prospective nationwide registry in whom CMR was performed. This study involved 5 tertiary referral centers with a specialized adult congenital heart disease unit. Multivariable Cox hazards regression analysis was performed to determine factors associated with the primary end point. The CMR variables were combined with the noninvasive components of the Khairy et al risk model, and the C statistic of the final noninvasive risk model was determined using bootstrap sampling. The data analysis was conducted from January to December 2016., Main Outcomes and Measures: The composite primary outcome was defined as all-cause mortality or ventricular arrhythmia, defined as aborted cardiac arrest or documented ventricular fibrillation and ventricular tachycardia (lasting ≥30 seconds or recurrent symptomatic)., Results: Of the 575 patients with TOF, 57% were male, and the mean (SD) age was 31 (11) years. During a mean (SD) follow-up of 7.1 (3.5) years, the primary composite end point occurred in 35 patients, including all-cause mortality in 13 patients. Mean (SD) RV ejection fraction (EF) was 44% (10%), and mean (SD) LV EF was 53% (8%). There was a correlation between RV EF and LV EF (R, 0.36; 95% CI, 0.29-0.44; P < .001). Optimal thresholds for ventricular function (RV EF <30%: hazard ratio, 3.90; 95% CI, 1.84-8.26; P < .001 and LV EF <45%: hazard ratio, 3.23; 95% CI, 1.57-6.65; P = .001) were independently predictive in multivariable analysis. Both thresholds were included in a point-based noninvasive risk model (C statistic, 0.75; 95% CI, 0.63-0.85) and combined with the noninvasive components of the Khairy et al risk model., Conclusions and Relevance: In patients with repaired TOF, biventricular dysfunction on CMR imaging was associated with major adverse clinical outcomes. The quantified thresholds (RV EF <30% and LV EF <45%) may be implemented in noninvasive risk stratification.

Background: Although QRS duration >180 ms has prognostic value in adults with tetralogy of Fallot (TOF), its sensitivity to predict mortality is low. Fragmented QRS complexes, a simple measurement on ECG, are related to myocardial fibrosis and dysfunction in patients with TOF. Our objective was to determine whether QRS fragmentation predicts major outcomes in TOF., Methods: This multicentre study included adult patients with TOF from a prospective registry. Notches in the QRS complex in ≥2 contiguous leads on a 12-lead ECG, not related to bundle branch block, were defined as QRS fragmentation, which was classified as none, moderate (≤4 leads) or severe (≥5 leads). The primary and secondary outcomes were all-cause mortality and clinical ventricular arrhythmia, respectively., Results: A total of 794 adult patients with TOF (median age 27 years, 55% male; 52% no QRS fragmentation, 32% moderate, 16% severe) were included. During long-term (median 10.4 years) follow-up, 46 (6%) patients died and 35 (4%) patients had ventricular arrhythmias. Overall, 10-year survival was 98% in patients without fragmented QRS complexes, 93% in patients with moderate QRS fragmentation and 81% in patients with severe QRS fragmentation. In multivariable Cox hazards regression analysis, extent of QRS fragmentation (HR: 2.24/class, 95% CI 1.48 to 3.40, p<0.001) remained independently predictive for mortality, whereas QRS duration was not predictive (p=0.85). The extent of QRS fragmentation was also independently predictive for ventricular arrhythmia (HR: 2.00/class, 95% CI 1.26 to 3.16, p=0.003)., Conclusions: The extent of QRS fragmentation is superior to QRS duration in predicting mortality in adult patients with TOF and may be used in risk stratification., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Renin-angiotensin-aldosterone system (RAAS) inhibition with angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors is beneficial in patients with acquired left ventricular dysfunction. Adult patients with tetralogy of Fallot (TOF) with right ventricular (RV) dysfunction are at high risk for heart failure, arrhythmias, and sudden cardiac death. However, the efficacy of RAAS inhibition has not been established in these patients., Methods: The REDEFINE is an investigator-initiated, multicenter, prospective, randomized, double-blind, placebo-controlled trial to study the effects of the angiotensin II receptor blocker losartan (target dosage of 150 mg once daily) in adult patients with TOF. Patients with RV dysfunction in the absence of severe valvular dysfunction are eligible for inclusion. The primary end point is the change in RV ejection fraction after 18 to 24 months, as measured by cardiovascular magnetic resonance imaging. In addition, laboratory measurements, echocardiography, and cardiopulmonary exercise testing are performed., Conclusion: The REDEFINE trial will study the effects of RAAS inhibition with losartan in TOF patients with RV dysfunction., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Pre-eclampsia (PE) is associated with both postpartum structural asymptomatic heart disease (i.e. heart failure Stage B (HF-B)) and conventional cardiovascular (CV) risk factors. We aimed to evaluate the extent to which PE, adjusted for conventional CV risk factors, is associated independently with asymptomatic cardiac abnormalities postpartum., Methods: In this cross-sectional cohort study, 107 formerly pre-eclamptic women and 41 women with uneventful previous pregnancy (controls) were invited for CV risk assessment 4-10 years postpartum. This included cardiac ultrasound, blood pressure (BP) measurement and evaluation of metabolic syndrome determinants. Asymptomatic structural and functional cardiac abnormalities were classified as HF-B, according to the American Heart Association guidelines. Prehypertension was defined as systolic BP of 120-139 mmHg and/or diastolic BP of 80-89 mmHg. Univariate and multivariate regression analyses were performed to calculate associations of PE and conventional risk factors with HF-B., Results: The prevalence of asymptomatic HF-B was approximately 3.5-fold higher in the PE group compared with controls (25% vs 7%, P < 0.01); 67% of this group had concentric remodeling and 22% had mildly impaired ejection fraction. After adjustment for postpartum interval, hypertension and high-density lipoprotein, PE was significantly associated with HF-B (adjusted odds ratio, 4.4 (95% CI, 1.0-19.1)). Moreover, in the formerly pre-eclamptic group, prehypertension was associated significantly with HF-B (odds ratio, 4.3 (95% CI, 1.4-12.7)), while metabolic syndrome determinants were not., Conclusion: PE is associated with a four-fold increased female-specific risk of asymptomatic cardiac abnormalities. Prehypertension apparently increases this risk significantly, while metabolic syndrome determinants do not. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: After pre-eclampsia (PE), the prevalence of structural heart disease without symptoms, i.e. heart failure Stage B (HF-B), may be as high as one in four women in the first year postpartum. We hypothesize that a significant number of formerly pre-eclamptic women with HF-B postpartum are still in their resolving period and will not have HF-B during follow-up., Methods: In this prospective longitudinal cohort study, we included 69 formerly pre-eclamptic women who underwent serial echocardiographic measurements at 1 and 4 years postpartum. HF-B was diagnosed as left ventricular hypertrophy (left ventricular mass index (LVMi) > 95 g/m 2 ), concentric remodeling (relative wall thickness > 0.42 and LVMi ≤ 95 g/m 2 ), mild systolic dysfunction (left ventricular ejection fraction > 40% and < 55%) or asymptomatic valvular disease. Women were subdivided and analyzed according to HF-B outcome: no HF-B at either visit; HF-B at first visit only; HF-B at second visit only; HF-B at both visits., Results: The prevalence of HF-B in formerly pre-eclamptic women was 23% in the first year postpartum and 23% after 4 years. At the second visit, HF-B had resolved in 62.5% of affected women but was newly developed in 19% of initially unaffected women. At the first visit, 56% of women diagnosed with HF-B had reduced systolic function whereas at the second visit 69% of women with HF-B had concentric remodeling with mostly normal ejection fraction, consistent with diastolic dysfunction., Conclusions: The prevalence of HF-B can be considered consistently high (1 in 4) amongst formerly pre-eclamptic women at follow-up. Nonetheless, at an individual level, more than 60% of women found initially to be affected by HF-B will recover, whilst about 20% of formerly pre-eclamptic women with normal echocardiography in the first year postpartum will develop HF-B over the following years. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: N-terminal B‑type natriuretic peptide (NT-proBNP) is an important biomarker for the detection of heart failure. Adults with congenital heart disease (ACHD) and a prosthetic heart valve are at risk for heart failure. This study aimed to determine the value of NT-proBNP in ACHD patients with a prosthetic valve and investigate its relationship with cardiac function and exercise capacity., Methods: In this multi-centre cross-sectional observational study, data regarding medical history, echocardiography, exercise testing (VO 2 peak) and laboratory blood evaluation (including NT-proBNP) were collected in ACHD patients with a single prosthetic valve (either homografts, heterografts or mechanical valves)., Results: A total of 306 ACHD patients with pulmonary valve replacement (PVR, n = 139), aortic valve replacement (n = 141), mitral valve replacement (n = 21) or tricuspid valve replacement (n = 5) were investigated. The majority of patients (77 %) were in NYHA class I or II. Elevated NT-proBNP levels (cut-off ≥125 pg/ml) were found in 50 % of the patients, with the highest levels in patients with mitral valve replacements. In this study population, NT-proBNP levels were associated with gender (p = 0.029) and VO 2 max (p < 0.001). In PVR patients, NT-proBNP levels were associated with lower VO 2 peak, also after adjustment for age, gender and age at valve replacement in a multivariate model (p = 0.015)., Conclusions: In patients with ACHD and a prosthetic valve, elevated NT-proBNP levels are frequently observed despite preserved NYHA class. In PVR patients, a higher NT-proBNP level was associated with a lower VO 2 peak. These results may be of importance in the ongoing discussion about the timing of valve replacement in patients with CHD., Competing Interests: Conflict of interestR. C. Schoonbeek, P. G. Pieper, Y. J. van Slooten, H. G. Freling, G. T. Sieswerda, A. P. J. van Dijk, M. R. M. Jongbloed, M. C. Post, B. J. Bouma, R. M. F. Berger, T. Ebels and J. P. van Melle state that they have no competing interest.

Objectives: To provide a comprehensive overview of all reported cardiac magnetic resonance (CMR) findings that predict clinical deterioration in pulmonary arterial hypertension (PAH)., Methods: MEDLINE and EMBASE electronic databases were systematically searched for longitudinal studies published by April 2015 that reported associations between CMR findings and adverse clinical outcome in PAH. Studies were appraised using previously developed criteria for prognostic studies. Meta-analysis using random effect models was performed for CMR findings investigated by three or more studies., Results: Eight papers (539 patients) investigating 21 different CMR findings were included. Meta-analysis showed that right ventricular (RV) ejection fraction was the strongest predictor of mortality in PAH (pooled HR 1.23 [95 % CI 1.07-1.41], p = 0.003) per 5 % decrease. In addition, RV end-diastolic volume index (pooled HR 1.06 [95 % CI 1.00-1.12], p = 0.049), RV end-systolic volume index (pooled HR 1.05 [95 % CI 1.01-1.09], p = 0.013) and left ventricular end-diastolic volume index (pooled HR 1.16 [95 % CI 1.00-1.34], p = 0.045) were of prognostic importance. RV and LV mass did not provide prognostic information (p = 0.852 and p = 0.983, respectively)., Conclusion: This meta-analysis substantiates the clinical yield of specific CMR findings in the prognostication of PAH patients. Decreased RV ejection is the strongest and most well established predictor of mortality., Key Points: • Cardiac magnetic resonance imaging is useful for prognostication in pulmonary arterial hypertension. • Right ventricular ejection fraction is the strongest predictor of mortality. • Serial CMR evaluation seems to be of additional prognostic importance. • Accurate prognostication can aid in adequate and timely intensification of PAH-specific therapy.

Objective: Pregnancy in women with congenital heart disease (CHD) is associated with deterioration in cardiac function. However, longitudinal data are scarce. This study describes serial changes in cardiac dimensions and function during pregnancy in women with CHD and compares these with healthy pregnant women (controls)., Methods: Eight tertiary centres prospectively enrolled 125 pregnant women with CHD (pregnancy duration <20 weeks). Controls (N=49) were recruited from low-risk midwife practices. Standardised echocardiography at 20 and 32 weeks gestation and 1 year postpartum was performed., Results: Age and parity were comparable between both groups (p>0.1). Left ventricular ejection fraction (LVEF) <45% was present in 3.2% of women with CHD and 14.4% had tricuspid annular plane systolic excursion (TAPSE) <16 mm. Absolute values of ventricular function parameters and diameters were less favourable in women with CHD. No permanent changes occurred in right and left ventricular function parameters and dimensions in women with CHD. The patterns of change in cardiac function and dimensions were comparable between women with CHD and controls, except for LVEF (p=0.026). In women with right-sided CHD the pattern of TAPSE over time differed from controls (p=0.043) (no decrease in TAPSE postpregnancy in CHD). In women with left-sided CHD left ventricular end-diastolic diameter (LVEDD) tended to increase compared with controls (p=0.045)., Conclusions: Absolute levels of ventricular function parameters and diameters differ between CHD and controls, but changes during and after pregnancy are generally comparable. However, different patterns over time seen for TAPSE and LVEDD in women with right-sided and left-sided CHD, respectively, compared with controls indicate the importance of echocardiographic follow-up during pregnancy in women with CHD., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background and Design: Previous studies have demonstrated that endurance exercise can cause an acute transient decrease in cardiac function in healthy subjects. Whether this also occurs in cardiac patients is unknown. We investigated the impact of prolonged single day and three-day walking exercise on cardiac function and cardiac biomarkers between cardiac patients and healthy controls in an observational study., Methods: We recruited 10 cardiac patients (nine males, one female, 68 ± 5 years) and 10 age- and sex-matched healthy control subjects (nine males, one female, 68 ± 4 years) to perform 30 or 40 km of walking exercise per day for three consecutive days. Cardiac function was examined using echocardiography and cardiac biomarkers (cardiac troponin and B-type natriuretic peptide) with blood samples. Data were collected before walking and directly after walking on day 1 and day 3., Results: Post-exercise early systolic tissue contraction velocity of the left ventricle (p = 0.005) and global longitudinal left ventricle strain (P = 0.026) were increased in both groups compared with baseline. Post-exercise right ventricle peak early diastolic tissue filling velocity and systolic blood pressure/left ventricle end-systolic volume ratio decreased in both groups (p = 0.043 and p = 0.028, respectively). Post-exercise cardiac troponin levels increased (p = 0.045) but did not differ across groups (p = 0.60), whereas B-type natriuretic peptide levels did not change (p = 0.43)., Conclusion: This study suggests that stable cardiac patients are capable of performing three days of prolonged walking exercise without clinically significant acute overall deterioration in cardiac function or more pronounced increase in cardiac biomarkers compared with healthy controls., (© The European Society of Cardiology 2016.)

Background: Identification of patients at risk of deterioration is essential to guide clinical management in pulmonary arterial hypertension (PAH). This study aims to provide a comprehensive overview of well-investigated echocardiographic findings that are associated with clinical deterioration in PAH., Methods: MEDLINE and EMBASE databases were systematically searched for longitudinal studies published by April 2015 that reported associations between echocardiographic findings and mortality, transplant or clinical worsening. Meta-analysis using random effect models was performed for echocardiographic findings investigated by four or more studies. In case of statistical heterogeneity a sensitivity analysis was conducted., Results: Thirty-seven papers investigating 51 echocardiographic findings were included. Meta-analysis of univariable hazard ratios (HRs) and sensitivity analysis showed that presence of pericardial effusion (pooled HR 1.70; 95 % CI 1.44-1.99), right atrial area (pooled HR 1.71; 95 % CI 1.38-2.13) and tricuspid annular plane systolic excursion (TAPSE; pooled HR 1.72; 95 % CI 1.34-2.20) were the most well-investigated and robust predictors of mortality or transplant., Conclusions: This meta-analysis substantiates the clinical yield of specific echocardiographic findings in the prognostication of PAH patients in day-to-day practice. In particular, pericardial effusion, right atrial area and TAPSE are of prognostic value.

Background: Adults with pulmonary arterial hypertension due to congenital heart disease (PAH-CHD) have a poor prognosis. Identifying patients with a high risk for clinical events and death is important because their prognosis can be improved by intensifying their treatment. Cystatin C, a novel cardiac biomarker, correlates with right ventricular dimensions in patients with idiopathic PAH, giving it potential to determine prognosis in PAH-CHD patients. We investigated the predictive value of cystatin C for long-term mortality and clinical events., Methods: Fifty-nine PAH-CHD patients (mean age 42 SD 13 years, 42% male) were included in this prospective observational study, with cystatin C measurements between 2005 and 2015 on the outpatient clinic. Patients were evaluated with a standardized evaluation protocol including laboratory, functional and echocardiographic variables. Clinical events comprised worsening functional classification, worsening heart failure, symptomatic hyperviscosity, haemoptysis and arrhythmia. We used Cox regression to determine predictors for mortality and clinical events., Results: Mean follow-up was 4.4years, during which 12 (20%) patients died. Cystatin C (HR 1.3, p<0.001), creatinine (HR 1.2, p<0.001), NT-pro-BNP (HR 2.0, p=0.012), hs-troponin T (HR 1.9, p=0.005), 6-MWD (HR 0.8, p=0.044) and TAPSE (HR 0.8, p<0.001) predicted mortality. Similar results were found for the prediction of clinical events. When adjusted for NT-pro-BNP or glomerular filtration rate in multivariate analysis, cystatin C remained predictive for mortality., Conclusions: Cystatin C, a novel cardiac biomarker, predicts long-term mortality and clinical events in patients with PAH-CHD. Consequently, cystatin C may attribute to clinical decision making regarding treatment intensity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)