Sex-Specific Functional Status Decline and Outcomes in Mild-to-Moderate Aortic Stenosis: Results From the PROGRESSA Study.

Background: Little is known about the effect of sex on functional status decline in aortic valve stenosis (AS) patients. Objectives: The purpose of this study was to examine the changes in functional status according to sex in patients with mild-to-moderate AS and its association with the composite of death or aortic valve replacement (AVR). Methods: We included patients with mild-to-moderate AS prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study (NCT01679431). Functional status was assessed using the New York Heart Association classification and the Duke Activity Status Index (DASI). Results: A total of 244 patients (mean age 64 ± 14 years, 29% women) were included. The mean follow-up was 4.3 ± 2.4 years. Women with intermediate-to-fast AS progression rate (median change in peak aortic jet velocity ≥0.11 m/s/year) had significantly faster decline in DASI score compared to men with similar progression rate (P < 0.05). In linear mixed analysis adjusted for several clinical and echocardiographic factors, female sex and change in peak aortic jet velocity remained strongly associated with the worsening of New York Heart Association class and the decline of DASI score (all, P < 0.001). The composite of death or AVR occurred in 115 patients (16 deaths and 99 AVRs). In multivariable Cox regression analyses, functional status decline during follow-up remained significantly associated with the composite of death or AVR (HR: 2.13; 95% CI: 1.22-3.73; P = 0.008). Conclusions: In patients with mild-to-moderate AS at baseline, intermediate-to-fast progression rate of AS was associated with a more rapid decline of functional status during follow-up, particularly in women. Functional status decline during follow-up was strongly associated with the incidence of death or AVR, with comparable effect in both women and men.

Plasma and Myocardial miRNomes Similarities and Differences during Cardiac Remodelling and Reverse Remodelling in a Murine Model of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterised by multiple risk factors touching various organs outside the heart. Using a murine HFpEF model, we studied cardiac reverse remodelling (RR) after stopping the causing metabolic-hypertensive stress (MHS; Angiotensin II [AngII] and a high-fat diet [HFD]) after 28 days and introducing voluntary exercise (VE) for four more weeks. We measured the effects of MHS and RR on the plasma and myocardial microRNA (miR) profile (miRNome) to characterise better cardiac and non-cardiac responses to HFpEF-inducing risk factors and their reversibility. AngII alone, the HFD or the MHS caused cardiac hypertrophy (CH), left ventricular (LV) concentric remodelling and left atrial enlargement in females. Only AngII and the MHS, but not HFD, did in males. After RR, CH, LV concentric remodelling and atrial enlargement were normalised. Among the 25 most abundant circulating miRs, 10 were modulated by MHS. Plasma miRNomes from AngII, HFD or MHS mice shared 31 common significantly modulated miRs (24 upregulated and 7 downregulated), suggesting that the response of organs producing the bulk of those circulating miRs was similar even for seemingly different stress. In the LV, 19 out of 25 most expressed miRs were modulated. RR restored normality for the plasma miRNome but not for the LV miRNome, which remained mostly unchanged. Our results suggest that abnormalities persist in the myocardium of the HFpEF mice and that the normalisation of circulatory markers may be falsely reassuring after recovery.

Grading of Aortic Valve Calcification Severity and Risk Stratification in Aortic Stenosis.

BACKGROUND: Thresholds of aortic valve calcification (AVC) to define hemodynamically moderate aortic stenosis (AS) from mild are lacking. We aimed to establish a novel grading classification of AVC as quantified by computed tomography and determine its prognostic value. METHODS AND RESULTS: This study included 915 patients with at least mild AS (mean age 70±12 years, 30% women) from a multicenter prospective registry. All patients underwent Doppler-echocardiography and noncontrast computed tomography within 3 months. Primary end point was the occurrence of all-cause death. Receiver operating characteristic curves analyses were used to determine the sensitivity and specificity of sex-specific thresholds of AVC to identify hemodynamically moderate AS. Optimal thresholds (ie, with best sensitivity/specificity) of AVC to distinguish moderate (aortic valve area 1.0-1.5 cm2 and mean gradient 20-39 mm Hg) from mild AS (aortic valve area >1.5 cm2 and mean gradient <20 mm Hg) were AVC ≥360 arbitrary units in women and ≥1037 arbitrary units in men. Based on the guidelines' thresholds for severe AS and the new thresholds in our study for moderate AS, 312 (34%) patients had mild, 253 (28%) moderate, and 350 (38%) severe AVC. During a mean follow-up of 5.6±3.9 years, 183 (27%) deaths occurred. In Cox multivariable models, AVC remained associated with an increased risk of death (adjusted hazard ratio per grade increase, 1.94 [95% CI, 1.53-2.56]; P<0.001). CONCLUSIONS: A novel grading classification of anatomic AS severity based on sex-specific thresholds of AVC provides significant prognostic value for predicting mortality. These findings support the complementarity of computed tomography-calcium scoring to Doppler-echocardiography to corroborate AS severity and enhance risk stratification in patients with AS.

Biological sex, sex steroids and sex chromosomes contribute to mouse cardiac aging.

After menopause, the incidence of cardiovascular disease rapidly rises in women. The disappearing protection provided by sex steroids is a consequence of the development of many risk factors. Preclinical studies are necessary to understand better the effects of ovarian hormones loss cardiac aging. To mimic menopause in mice and study its consequences, we delayed ovariectomy at 12 months and followed animals for 12 months. Using RNA sequencing, we investigated changes in the myocardial exome with aging. In addition, with four-core genotypes (FCG) transgenic mice, we studied sex chromosome effects on cardiac aging. Heart weight increased from 3 to 24 months (males + 35%, females + 29%). In males, 75% of this increase had occurred at 12 months; in females, only 30%. Gonadectomy of mice at 12 months blocked cardiac hypertrophy in both sexes during the second year of life. The dosage of the X chromosomes did not influence cardiac growth in young and older mice. We performed an RNA sequencing study in young and old mice. We identified new highly expressed genes modulated during aging (Bdh, Myot, Cpxm2, and Slc38a1). The myocardial exome in older animals displayed few differences related to the animal's sex or the presence or absence of sex steroids for a year. We show that the morphological evolution of the heart depends on the biological sex via gonadal sex hormone actions. The myocardial exome of old male and female mice is relatively similar. Our study emphasizes the need to consider sex steroid effects in studying cardiac aging.

A murine model of hypertensive heart disease in older women.

We propose a new mouse (C57Bl6/J) model combining several features of heart failure with preserved ejection fraction encountered in older women, including hypertension from Angiotensin II infusion (AngII), menopause, and advanced age. To mimic menopause, we delayed ovariectomy (Ovx) at 12 months of age. We also studied the effects of AngII infusion for 28 days in younger animals and the impact of losing gonadal steroids earlier in life. We observed that AngII effects on heart morphology were different in younger and adult mice (3- and 12-month-old; 20 and 19% increase in heart weight. P < 0.01 for both) than in older animals (24-month-old; 6%; not significant). Ovariectomy at 12 months restored the hypertrophic response to AngII in elderly females (23%, p = 0.0001). We performed a bulk RNA sequencing study of the left ventricle (LV) and left atrial gene expression in elderly animals, controls, and Ovx. AngII modulated (|Log2 fold change| ≥ 1) the LV expression of 170 genes in control females and 179 in Ovx ones, 64 being shared. In the left atrium, AngII modulated 235 genes in control females and 453 in Ovx, 140 shared. We observed many upregulated genes associated with the extracellular matrix regulation in both heart chambers. Many of these upregulated genes were shared between the ventricle and the atrium as well as in control and Ovx animals, namely for the most expressed Ankrd1, Nppb, Col3a1, Col1a1, Ctgf Col8a1, and Cilp. Several circadian clock LV genes were modulated differently by AngII between control and Ovx females (Clock, Arntl, Per2, Cry2, and Ciart). In conclusion, sex hormones, even in elderly female mice, modulate the heart's hypertrophic response to AngII. Our study identifies potential new markers of hypertensive disease in aging female mice and possible disturbances of their cardiac circadian clock.

Cardiac reverse remodeling in a mouse model with many phenotypical features of heart failure with preserved ejection fraction: effects of modifying lifestyle.

Multiple factors cause heart failure with preserved ejection fraction (HFpEF) and involve various systems. HFpEF prevalence is rapidly rising, and its prognosis remains poor after the first hospitalization. Adopting a more active lifestyle has been shown to provide beneficial clinical outcomes for patients with HFpEF. Using a two-hit HfpEF murine model, we studied cardiac reverse remodeling (RR) after stopping the causing stress and introducing voluntary exercise (VE). We checked in 2-mo-old male and female C57Bl6/J mice the heart's response to angiotensin II (ANG II; 1.5 mg/kg/day for 28 days) fed or not with a high-fat diet (HFD). Then, ANG II and/or the HFD were stopped, and VE was started for an additional 4 wk. ANG II and ANG II + HFD (metabolic-hypertensive stress, MHS) caused cardiac hypertrophy (CH) and myocardial fibrosis, left ventricular (LV) concentric remodeling, atrial enlargement, and reduced exercise capacity. HFD alone induced CH and LV concentric remodeling in female mice only. CH and LV concentric remodeling were reversed 4 wk after stopping ANG II, starting VE, and a low-fat diet. Left atrial enlargement and exercise capacity were improved but differed from controls. We performed bulk LV RNA sequencing and observed that MHS upregulated 58% of the differentially expressed genes (DEGs) compared with controls. In the RR group, compared with MHS animals, 60% of the DEGs were downregulated. In an HfpEF mouse model, we show that correcting hypertension, diet, and introducing exercise can lead to extensive cardiac reverse remodeling.NEW & NOTEWORTHY Using a two-hit murine model of heart failure with preserved ejection fraction (HfpEF), combining elevated blood pressure, obesity, and exercise intolerance in male and female animals, we showed that correction of hypertension, normalization of the diet, and introduction of voluntary exercise could help reverse the remodeling of the left ventricle and double exercise capacity. We also identify genes that escape normalization after myocardial recovery and differences between males' and females' responses to stress and recovery.

Age and sex hormones modulate left ventricle regional response to angiotensin II in male and female mice.

Age, hypertension, and the female sex are among the risk factors in the development of heart failure with preserved ejection fraction. We studied by standard and speckle-tracking echocardiography (STE), the response of the left ventricle (LV) to aging and angiotensin II continuous infusion (ANG II; 1.5 mg/kg/day for 28 days) in 2- and 12-mo-old male and female C57Bl6/J mice. We also investigated the effects of the loss of sex steroids by gonadectomy (GDX). To do so, we used STE data from 48 points or regions of interest (ROIs) around the LV endocardium from B-mode images and generated profiles of maximal strain, strain rate (SR), and reverse SR for each experimental group of mice. In young mice, LV strain, strain rate (SR), and reverse SR profile levels were higher in females than in males. Aging was characterized by concentric LV remodeling and a decrease of strain, SR, and reverse SR. GDX at 6 wk of age slowed normal cardiac growth in male mice. In females, GDX reduced LV strain, SR, and reverse SR but did not influence cardiac growth. ANG II caused similar levels of hypertrophy in young and older mice. In young mice, ANG II had little effect on STE parameters, whereas in older animals, strain, SR, and reverse SR were reduced, mainly for the LV posterior wall. In older GDX mice, hypertrophic response to ANG II was decreased compared with intact animals. Generating detailed STE profile for the LV wall can help detect differences linked to sex, age, or a stressor better than global strain measurements.NEW & NOTEWORTHY We propose a new method for the study of regional strain data by analyzing individually the software-generated 48 regions of interest (ROI) from an LV wall tracing in B-mode. This helps obtain a more comprehensive profile of strain data. Using these new tools, we studied in mice how sex, sex hormones, age, or a pathological stress influenced strain parameters. We show that for similar cardiac hypertrophy, regional strain shows important differences related to sex, sex hormones, and age.

Effects of Cyproheptadine on Mitral Valve Remodeling and Regurgitation After Myocardial Infarction.

BACKGROUND: Ischemic mitral regurgitation (MR) is primarily caused by left ventricle deformation, but leaflet thickening with fibrotic changes are also observed in the valve. Increased levels of 5-hydroxytryptamine (5-HT; ie, serotonin) are described after myocardial infarction (MI); 5-HT can induce valve fibrosis through the 5-HT type 2B receptor (5-HT2BR). OBJECTIVES: This study aims to test the hypothesis that post-MI treatment with cyproheptadine (5-HT2BR antagonist) can prevent ischemic MR by reducing the effect of serotonin on mitral biology. METHODS: Thirty-six sheep were divided into 2 groups: inferior MI and inferior MI treated with cyproheptadine (0.5 mg/kg/d). Animals were followed for 90 days. Blood 5-HT, infarct size, left ventricular volume and function, MR fraction and mitral leaflet size were assessed. In a complementary in vitro study, valvular interstitial cells were exposed to pre-MI and post-MI serum collected from the experimental animals. RESULTS: Increased 5-HT levels were observed after MI in nontreated animals, but not in the group treated with cyproheptadine. Infarct size was similar in both groups (11 ± 3 g vs 9 ± 5 g; P = 0.414). At 90 days, MR fraction was 16% ± 7% in the MI group vs 2% ± 6% in the cyproheptadine group (P = 0.0001). The increase in leaflet size following MI was larger in the cyproheptadine group (+40% ± 9% vs +22% ± 12%; P = 0.001). Mitral interstitial cells overexpressed extracellular matrix genes when treated with post-MI serum, but not when exposed to post-MI serum collected from treated animals. CONCLUSIONS: Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve size and less MR.

Determinants of Aortic Stenosis Progression in Bicuspid and Tricuspid Aortic Valves.

Background: Bicuspid aortic valve (BAV) is associated with a faster progression of aortic stenosis (AS). Whether the determinants of AS progression are the same or different in patients with BAV vs tricuspid aortic valve (TAV) is unknown. The aim of this study was to identify the factors associated with the progression of AS in patients with BAV vs patients with TAV. Methods: Patients with AS were prospectively recruited in the Metabolic Determinants of the Progression of Aortic Stenosis (PROGRESSA) study (ClinicalTrials.gov Identifier: NCT01679431). The haemodynamic progression rate of AS was assessed by the annualized progression rate of peak aortic jet velocity (Vpeak). Univariable and multivariable linear regression analyses were used to identify the factors associated with a faster progression of AS in patients with BAV vs patients with TAV. Results: There were 79 patients with BAV and 208 patients with TAV. The baseline severity of AS was similar between the 2 groups of patients as well as the annualized progression rate of AS. In patients with BAV, obesity (ß = 0.25, P = 0.04), diabetes (ß = 0.26, P = 0.02), and BAV with right-noncoronary cusp fusion (ß = 0.29, P = 0.01) were found to be independently associated with a faster progression of AS, whereas in patients with TAV, AS baseline severity (baseline Vpeak, ß = 0.14, P = 0.04) and chronic kidney disease (ß = 0.16, P = 0.02) were significantly associated with AS progression. Conclusion: Factors associated with progression rate of AS are different in BAV and TAV. The main factors associated with a faster progression of AS appear to be obesity, diabetes, right-noncoronary cusp fusion in patients with BAV vs chronic kidney disease in patients with TAV.

Contexte: La bicuspidie valvulaire aortique (BVA) est associée à une progression plus rapide de la sténose aortique (SA). On ignore toutefois si les facteurs en cause dans la progression de la SA sont les mêmes chez les patients qui présentent une BVA et chez ceux qui présentent une valve aortique tricuspide. Le but de cette étude était de déterminer les facteurs associés à la progression de la SA chez les patients présentant une BVA par rapport à ceux ayant une valve aortique tricuspide. Méthodologie: Des patients présentant une SA ont été recrutés dans l'étude PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis), une étude prospective sur les déterminants métaboliques de la progression de la SA (ClinicalTrials.gov : NCT01679431). Pour calculer le taux de progression hémodynamique de la SA, on a utilisé les mesures annualisées de la vélocité maximale du jet transaortique (Vmax). Des analyses de régression linéaire univariées et multivariées ont permis de mettre en évidence les facteurs associés à une progression plus rapide de la SA en présence d'une BVA par rapport à une valve aortique tricuspide. Résultats: Parmi les patients évalués, 79 présentaient une BVA et 208, une valve aortique tricuspide. La gravité de la SA au départ était comparable entre les deux groupes de patients, tout comme le taux de progression annualisé de la SA. Chez les patients avec BVA, l'obésité (ß = 0,25, P = 0,04), le diabète (ß = 0,26, P = 0,02) et la BVA avec fusion des feuillets coronaire droit et non coronaire (ß = 0,29, P = 0,01) ont été associés de manière indépendante à une progression plus rapide de la SA, tandis que chez les patients ayant une valve tricuspide, la gravité de la SA au départ (Vmax initiale, ß = 0,14, P = 0,04) et la présence d'une néphropathie chronique (ß = 0,16, P = 0,02) ont été significativement associées à une progression de la SA. Conclusion: Les facteurs associés au taux de progression de la SA sont différents selon qu'il y a ou non présence d'une BVA. Les principaux facteurs associés à une progression plus rapide de la SA semblent être l'obésité, le diabète et la fusion des feuillets coronaire droit et non coronaire pour la BVA, tandis que la néphropathie chronique serait le facteur aggravant chez les patients présentant une valve aortique tricuspide.

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.

OBJECTIVE: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN: Randomised controlled, adaptive, open label clinical trial. SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362085.

Recurrent bleeding and thrombotic events after resumption of oral anticoagulants following gastrointestinal bleeding: Communication from the ISTH SSC Subcommittee on Control of Anticoagulation.

BACKGROUND: Gastrointestinal bleeding frequently complicates anticoagulant therapy causing treatment discontinuation. Data to guide the decision regarding whether and when to resume anticoagulation based on the risks of thromboembolism and recurrent bleeding are scarce. OBJECTIVES: We aimed to retrospectively evaluate the incidence of these events after anticoagulant-related gastrointestinal bleeding and assess their relationship with timing of anticoagulation resumption. METHODS: Patients hospitalized because of gastrointestinal bleeding during oral anticoagulation for any indication were eligible. All patients were followed up to 2 years after the index bleeding for recurrent major or clinically relevant non-major bleeding, venous or arterial thromboembolism, and mortality. RESULTS: We included 948 patients hospitalized for gastrointestinal bleeding occurring during treatment with vitamin K antagonists (n = 531) or direct oral anticoagulants (n = 417). In time-dependent analysis, anticoagulant treatment was associated with a higher risk of recurrent clinically relevant bleeding (hazard ratio [HR] 1.55; 95% confidence interval [CI] 1.08-2.22), but lower risk of thromboembolism (HR 0.34; 95% CI 0.21-0.55), and death (HR 0.50; 95% CI 0.36-0.68). Previous bleeding, index major bleeding, and lower glomerular filtration rate were associated with a higher risk of recurrent bleeding. The incidence of recurrent bleeding increased after anticoagulation restart independently of timing of resumption. CONCLUSIONS: Anticoagulant treatment after gastrointestinal bleeding is associated with a lower risk of thromboembolism and death, but higher risk of recurrent bleeding. The latter seemed to be influenced by patient characteristics and less impacted by time of anticoagulation resumption.

Heparin for Moderately Ill Patients with Covid-19.

BACKGROUND: Heparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death. METHODS: We randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat. RESULTS: At 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85). CONCLUSIONS: In moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days. Trial registration numbers: NCT04362085 ; NCT04444700.

Segmental analysis by speckle-tracking echocardiography of the left ventricle response to isoproterenol in male and female mice.

We studied by conventional and speckle-tracking echocardiography, the response of the left ventricle (LV) to a three-week continuous infusion of isoproterenol (Iso), a non-specific beta-adrenergic receptor agonist in male and female C57Bl6/J mice. Before and after Iso (30 mg/kg/day), we characterized LV morphology and function as well as global and segmental strain. We observed that Iso reduced LV ejection in both male (-8.7%) and female (-14.7%) mice. Several diastolic function parameters were negatively regulated in males and females such as E/A, E/E', isovolumetric relaxation time. Global longitudinal (GLS) and circumferential (GCS) strains were reduced by Iso in both sexes, GLS by 31% and GCS by about 20%. For the segmental LV analysis, we measured strain, strain rate, reverse strain rate, peak speckle displacement and peak speckle velocity in the parasternal long axis. We observed that radial strain of the LV posterior segments were more severely modulated by Iso than those of the anterior wall in males. In females, on the other hand, both posterior and anterior wall segments were negatively impacted by Iso. Longitudinal strain showed similar results to the radial strain for both sexes. Strain rate, on the other hand, was only moderately changed by Iso. Reverse strain rate measurements (an index of diastolic function) showed that posterior LV segments were negatively regulated by Iso. We then studied the animals 5 and 17 weeks after Iso treatment. Compared to control mice, LV dilation was still present in males. Ejection fraction was decreased in mice of both sex compared to control animals. Diastolic function parameters, on the other hand, were back to normal. Taken together, our study indicates that segmental strain analysis can identify LV regions that are more negatively affected by a cardiotoxic agent such as Iso. In addition, cessation of Iso was not accompanied with a complete restoration of cardiac function after four months.

Left ventricular asymmetric remodeling and subclinical left ventricular dysfunction in patients with calcific aortic valve stenosis - Results from a subanalysis of the PROGRESSA study.

BACKGROUND: LV asymmetric remodeling (LVAR) is a feature commonly found in AS patients and it is presumed to be mainly related to the severity of valve stenosis. The aim of this study was to determine the associated factors and impact on left ventricular (LV) systolic function of LVAR in patients with mild and moderate aortic valve stenosis (AS). METHODS: Clinical, Doppler-echocardiographic and computed-tomographic data of 155 AS patients with preserved LV ejection fraction (≥50%) prospectively recruited in the PROGRESSA study (NCT01679431) were analyzed. LVAR was defined as a septal wall thickness ≥ 13 mm and a ratio of septal/posterior wall thickness > 1.5. LV global longitudinal strain (LV-GLS) was available in 129 patients. Plasma levels of N-terminal natriuretic B-type peptides (Nt-proBNP) were also measured. RESULTS: Mean age was 63 ± 15 years (70% men). LVAR was present in 21% (n = 33) of patients. A series of nested multivariate analysis revealed that age was the only factor associated with LVAR (all p ≤ 0.03). Additionally, these patients had higher baseline Nt-proBNP ratio (median [25-75 percentiles]: 1.04 [0.66-2.41] vs. 0.65 [0.33-1.19], p = 0.02), and significantly reduced LV-GLS (17.9[16.6-19.5] vs. 19.3[17.4-20.7] |%|, p = 0.04). A 1:1 matched analysis showed a significant association of LVAR with reduced LV-GLS (17.9[16.6-19.5] vs. 19.8[18.1-20.7] |%|, p = 0.02) and elevated Nt-proBNP (134[86-348] vs. 83[50-179]pg/ml, p = 0.03). Multivariable analysis also revealed that LVAR remains significantly associated with reduced LV-GLS (p = 0.03) and elevated Nt-proBNP (p = 0.001). LVAR was significantly associated with increased risk of major adverse cardiac events and death (Hazard ratio [95% confidence interval]: 2.32[1.28-4.22], p = 0.006). CONCLUSIONS: LVAR was found in ~20% of patients with mild or moderate AS and was not related to the degree of AS severity or concomitant comorbidities, but rather to older age. LVAR was significantly associated with reduced LV longitudinal systolic function, increased Nt-proBNP levels, and higher risk of major adverse events and death. These findings provide support for closer clinical and echocardiographic surveillance of patients harboring this adverse LV remodeling feature.

Effect of Regional Upper Septal Hypertrophy on Echocardiographic Assessment of Left Ventricular Mass and Remodeling in Aortic Stenosis.

BACKGROUND: Transthoracic echocardiography (TTE) is the reference method for evaluation of aortic stenosis (AS), and it is extensively used to quantitate left ventricular (LV) mass and volumes. Regional upper septal hypertrophy (USH) or septal bulge is a frequent finding in patients with AS and may lead to overestimation of LV mass when using linear measurements. The objective of this study was to compare estimates of LV mass obtained by two-dimensional transthoracic echocardiographic LV dimensions measured at different levels of the LV cavity with those obtained by cardiovascular magnetic resonance (CMR). METHODS: One hundred six patients (mean age, 63 ± 15 years; 68% men) with AS were included in this subanalysis of the PROGRESSA study. Two-dimensional transthoracic echocardiographic measurements of LV dimensions were obtained at the basal level (BL; as recommended in guidelines), immediately below the septal bulge (BSB), and at a midventricular level (ML). Regional USH was defined as a basal interventricular septal thickness ≥ 13 mm and >1.3 times the thickness of the septal wall at the ML. Agreement between transthoracic echocardiographic and CMR measures was evaluated using Bland-Altman analysis. RESULTS: The distribution of AS severity was mild in 23%, moderate in 57%, and severe in 20% of patients. Regional USH was present in 28 patients (26%). In the whole cohort, two-dimensional TTE overestimated LV mass (bias: BL, +60 ± 31 g; BSB, +59 ± 32 g; ML, +54 ± 32 g; P = .02). The biplane Simpson method slightly but significantly underestimated LV end-diastolic volume (bias -10 ± 20 mL, P < .001) compared with CMR. Overestimation of LV mass was more marked in patients with USH when measuring at the BL and was significantly lower when measuring LV dimensions at the ML (P < .025 vs BL and BSB). CONCLUSIONS: Two-dimensional TTE systematically overestimated LV mass and underestimated LV volumes compared with CMR. However, the bias between TTE and CMR was less important when measuring at the ML. Measurements at the BL as suggested in guidelines should be avoided, and measurements at the ML should be preferred in patients with AS, especially in those with USH.

Ventricular Arrhythmia in Septal and Apical Hypertrophic Cardiomyopathy: The French-Canadian Experience.

Background: Apical hypertrophic cardiomyopathy (aHCM) is thought to have a more benign clinical course compared to septal HCM (sHCM), but most data have been derived from Asian cohorts. Comparative data on clinical outcome in Caucasian aHCM cohorts are scarce, and the results are conflicting. The aim of this study was to estimate the prevalence and outcome of aHCM in French-Canadians of Caucasian descent. Methods and results: We conducted a retrospective, single-center cohort study. The primary endpoint was a composite of documented sustained ventricular arrhythmia (VA), appropriate ICD therapy, arrhythmogenic syncope, cardiac arrest, or all-cause mortality. A total of 301 HCM patients (65% males) were enrolled including 80/301 (27%) with aHCM and 221/301 (73%) with sHCM. Maximal wall thickness was similar in both groups. Left ventricular apical aneurysm was significantly more common in aHCM (10 vs. 0.5%; p < 0.001). The proportion of patients with myocardial fibrosis ≥ 15% of the left ventricular mass was similar between aHCM and sHCM (21 vs. 24%; p = 0.68). Secondary prevention ICDs were more often implanted in aHCM patients (16 vs. 7%; p = 0.02). The primary endpoint occurred in 26% of aHCM and 10.4% of sHCM patients (p = 0.001) and was driven by an increased incidence of sustained VA (10 vs. 2.3%; p = 0.01). Multivariate analysis identified apical aneurysm and a phenotype of aHCM as independent predictors of the primary endpoint and the occurrence of sustained ventricular tachycardia. Unexplained syncope and a family history of sudden cardiac death were additional predictors for sustained VA. Apical HCM was associated with an increased risk of ventricular arrhythmia even when excluding patients with apical aneurysm. Conclusions: The phenotype of apical HCM is much more common in French-Canadians (27%) of Caucasian descent compared to other Caucasian HCM populations. Apical HCM in French-Canadians is associated with an increased risk for ventricular arrhythmia.

New evidence in diagnosis of pulmonary embolism during pregnancy.

Diagnosis of pulmonary embolism (PE) in pregnancy is notoriously difficult and lacking high quality evidence. Three studies (DiPEP, ARTEMIS and CT-PE-Pregnancy) evaluating a systematic approach to PE diagnosis have recently been published. DiPEP is a retrospective case-control study that found a poor utility of clinical decision rules or D-dimer testing for PE diagnosis in pregnancy. ARTEMIS and CT-PE-Pregnancy are well conducted prospective management studies that proposed two algorithms with different clinical decision rules and D-dimer criteria for the diagnosis of PE in pregnancy. They included few events in high risk patients, which makes difficult the assessment of both algorithm's safety in women with a high probability of PE. Considering this new evidence, D-dimer testing might be useful to avoid radiation imaging in pregnant women considered at low risk for PE. In contrast, a negative D-dimer cannot be considered sufficiently safe to rule out PE when clinicians estimate that PE is the most likely diagnosis.

Estimation of Stroke Volume and Aortic Valve Area in Patients with Aortic Stenosis: A Comparison of Echocardiography versus Cardiovascular Magnetic Resonance.

BACKGROUND: In aortic stenosis, accurate measurement of left ventricular stroke volume (SV) is essential for the calculation of aortic valve area (AVA) and the assessment of flow status. Current American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines suggest that measurements of left ventricular outflow tract diameter (LVOTd) at different levels (at the annulus vs 5 or 10 mm below) yield similar measures of SV and AVA. The aim of this study was to assess the effect of the location of LVOTd measurement on the accuracy of SV and AVA measured on transthoracic echocardiography (TTE) compared with cardiovascular magnetic resonance (CMR). METHODS: One hundred six patients with aortic stenosis underwent both TTE and CMR. SV was estimated on TTE using the continuity equation with LVOTd measurements at four locations: at the annulus and 2, 5, and 10 mm below annulus. SV was also determined on CMR using phase contrast acquired in the aorta (SVCMR-PC), and a hybrid AVACMR-PC was calculated by dividing SVCMR-PC by the transthoracic echocardiographic Doppler aortic velocity-time integral. Comparison between methods was made using Bland-Altman analysis. RESULTS: Compared with the referent method of phase-contrast CMR for the estimation of SVCMR-PC and AVACMR-PC (SVCMR-PC 83 ± 16 mL, AVACMR-PC 1.27 ± 0.35 cm2), the best agreement was obtained by measuring LVOTd at the annulus or 2 mm below (P = NS), whereas measuring 5 and 10 mm below the annulus resulted in significant underestimation of SV and AVA by up to 15.9 ± 17.3 mL and 0.24 ± 0.28 cm2, respectively (P < .01 for all). Accuracy for classification of low flow was best at the annulus (86%) and 2 mm below (82%), whereas measuring 5 and 10 mm below the annulus significantly underperformed (69% and 61%, respectively, P < .001). CONCLUSIONS: Measuring LVOTd at the annulus or very close to it provides the most accurate measures of SV and AVA, whereas measuring LVOTd 5 or 10 mm below significantly underestimates these parameters and leads to significant overestimation of the severity of aortic stenosis and prevalence of low-flow status.

Effect of bicuspid aortic valve phenotype on progression of aortic stenosis.

AIMS: To compare the progression of aortic stenosis (AS) in patients with bicuspid aortic valve (BAV) or tricuspid aortic valve (TAV). METHODS AND RESULTS: One hundred and forty-one patients with mild-to-moderate AS, recruited prospectively in the PROGRESSA study, were included in this sub-analysis. Baseline clinical, Doppler echocardiography and multidetector computed tomography characteristics were compared between BAV (n = 32) and TAV (n = 109) patients. The 2-year haemodynamic [i.e. peak aortic jet velocity (Vpeak) and mean transvalvular gradient (MG)] and anatomic [i.e. aortic valve calcification density (AVCd) and aortic valve calcification density ratio (AVCd ratio)] progression of AS were compared between the two valve phenotypes. The 2-year progression rate of Vpeak was: 16 (-0 to 40) vs. 17 (3-35) cm/s, P = 0.95; of MG was: 1.8 (-0.7 to 5.8) vs. 2.6 (0.4-4.8) mmHg, P = 0.56; of AVCd was 32 (2-109) vs. 52 (25-85) AU/cm2, P = 0.15; and of AVCd ratio was: 0.08 (0.01-0.23) vs. 0.12 (0.06-0.18), P = 0.16 in patients with BAV vs. TAV. In univariable analyses, BAV was not associated with AS progression (all, P ≥ 0.26). However, with further adjustment for age, AS baseline severity, and several risk factors (i.e. sex, history of hypertension, creatinine level, diabetes, metabolic syndrome), BAV was independently associated with faster haemodynamic (Vpeak: ß = 0.31, P = 0.02) and anatomic (AVCd: ß = 0.26, P = 0.03 and AVCd ratio: ß = 0.26, P = 0.03) progression of AS. CONCLUSION: In patients with mild-to-moderate AS, patients with BAV have faster haemodynamic and anatomic progression of AS when compared to TAV patients with similar age and risk profile. This study highlights the importance and necessity to closely monitor patients with BAV and to adequately control and treat their risk factors. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov Unique identifier: NCT01679431.