Sex Differences in Characteristics, Outcomes, and Treatment Response With Dapagliflozin Across the Range of Ejection Fraction in Patients With Heart Failure: Insights From DAPA-HF and DELIVER.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of sodium-glucose cotransporter-2 inhibitors remains unclear. Our analyses aim to assess the effect of sex on the efficacy and safety of dapagliflozin. METHODS: In a prespecified patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), clinical outcomes were compared by sex (including the composite of cardiovascular death or worsening HF events, cardiovascular death, all-cause death, total events [first and recurrent HF hospitalization and cardiovascular death], and Kansas City Cardiomyopathy Questionnaire scores) across the spectrum of left ventricular ejection fraction. RESULTS: Of a total of 11 007 randomized patients, 3856 (35%) were women. Women with HF were older and had higher body mass index but were less likely to have a history of diabetes and myocardial infarction or stroke and more likely to have hypertension and atrial fibrillation compared with men. At baseline, women had higher ejection fraction but worse Kansas City Cardiomyopathy Questionnaire scores than men did. After adjustment for baseline differences, women were less likely than men to experience cardiovascular death (adjusted hazard ratio, 0.69 [95% CI, 0.60-0.79]), all-cause death (adjusted hazard ratio, 0.69 [95% CI, 0.62-0.78]), HF hospitalizations (adjusted hazard ratio, 0.82 [95% CI, 0.72-0.94]), and total events (adjusted rate ratio, 0.77 [95% CI, 0.71-0.84]). Dapagliflozin reduced the primary end point in both men and women similarly (Pinteraction=0.77) with no sex-related differences in secondary outcomes (all Pinteraction>0.35) or safety events. The benefit of dapagliflozin was observed across the entire ejection fraction spectrum and was not modified by sex (Pinteraction>0.40). There were no sex-related differences in serious adverse events, adverse events, or drug discontinuation attributable to adverse events. CONCLUSIONS: In DAPA-HF and DELIVER, the response to dapagliflozin was similar between men and women. Sex did not modify the treatment effect of dapagliflozin across the range of ejection fraction.

Dual antiplatelet therapy is associated with high α-tubulin acetylation in circulating platelets from coronary artery disease patients.

Platelet inhibition is the main treatment strategy to prevent atherothrombotic complications after acute coronary syndrome or percutaneous coronary intervention. Despite dual antiplatelet therapy (DAPT) combining aspirin and a P2Y12 receptor inhibitor, high on-treatment platelet reactivity (HPR) persists in some patients due to poor response to treatment and is associated with ischemic risk. Tubulin acetylation has been pointed out as a hallmark of stable microtubules responsible for the discoid shape of resting platelets. However, the impact of antiplatelet treatments on this post-translational modification has never been studied. This study investigated whether tubulin acetylation differs according to antiplatelet therapy and on-treatment platelet reactivity. Platelets were isolated from arterial blood samples of 240 patients admitted for coronary angiography, and levels of α-tubulin acetylation on lysine 40 (α-tubulin K40 acetylation) were assessed by western blot. We show that platelet α-tubulin K40 acetylation was significantly increased in DAPT-treated patients. In addition, the proportion of patients with high levels of α-tubulin K40 acetylation was drastically reduced among DAPT-treated patients with HPR. Multivariate logistic regression confirmed that DAPT resulting in adequate platelet inhibition was strongly associated with elevated α-tubulin K40 acetylation. In conclusion, our study highlights the role of elevated platelet α-tubulin K40 acetylation as a marker of platelet inhibition in response to DAPT.Clinical trial registration: https://clinicaltrials.gov - NCT03034148.

What is the context? High on-treatment platelet reactivity due to dual antiplatelet therapy poor response is associated with thrombotic risk.Acetylation of α-tubulin K40 plays a crucial role in regulating platelet shape.High α-tubulin K40 acetylation is a hallmark of stable microtubules.What is new? α-tubulin K40 acetylation is increased in platelets from dual antiplatelet therapy-treated patients.High platelet α-tubulin K40 acetylation is mainly observed in clopidogrel-responsive patients.What is the impact? Elevated acetylated K40 α-tubulin could be used as a readout of adequate platelet inhibition in response to dual antiplatelet therapy.High α-tubulin K40 acetylation could contribute to maintaining the resting morphology of circulating platelets and therefore modify their capacity to be involved in thrombotic events.

Mean platelet volume: a prognostic marker in heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with high burden of comorbidities known to increase the mean platelet volume (MPV). This parameter has been associated with morbidity and mortality in HF. However, the role of platelets and the prognostic relevance of MPV in HFpEF remain largely unexplored. We aimed to evaluate the clinical usefulness of MPV as a prognostic marker in HFpEF. We prospectively enrolled 228 patients with HFpEF (79 ± 9 years; 66% females) and 38 controls of similar age and gender (78 ± 5 years; 63% females). All subjects underwent two-dimensional echocardiography and MPV measurements. Patients were followed-up for a primary end point of all-cause mortality or first HF hospitalization. The prognostic impact of MPV was determined using Cox proportional hazard models. Mean MPV was significantly higher in HFpEF patients compared with controls (MPV: 10.7 ± 1.1fL vs. 10.1 ± 1.1fL, p = .005). HFpEF patients (n = 56) with MPV >75th percentile (11.3 fL) displayed more commonly a history of ischemic cardiomyopathy. Over a median follow-up of 26 months, 136 HFpEF patients reached the composite endpoint. MPV >75th percentile was a significant predictor of the primary endpoint (HR: 1.70 [1.08; 2.67], p = .023) adjusted for NYHA class, chronic obstructive pulmonary disease, loop diuretics, renal function, and hemoglobin. We demonstrated that MPV was significantly higher in HFpEF patients compared with controls of similar age and gender. Elevated MPV was a strong and independent predictor of poor outcome in HFpEF patients and may be relevant for clinical use.

What is the context? Heart failure with preserved ejection fraction (HFpEF) is associated with several comorbidities known to increase the mean platelet volume (MPV).MPV is a measure of platelet size and a potential marker of platelet reactivity. An increased MPV results from an increased platelet turnover.MPV has been associated with morbidity and mortality from heart failure.No study has previously compared MPV between HFpEF and controls and investigated the prognostic relevance of MPV in HFpEF disease.What is new? In this study, we compared the MPV between HFpEF patients and controls of similar age and gender, prospectively enrolled between 2015 and 2021. We evaluated the prognostic role of elevated MPV in HFpEF patients.Our main results:The MPV was higher in HFpEF patients compared to controls of similar age and gender.HFpEF patients with elevated MPV displayed more commonly a history of ischemic cardiomyopathy.Elevated MPV was a strong and independent predictor of poor outcome in HFpEF patients.What is the impact? MPV may be relevant for clinical use to predict clinical outcome in HFpEF patients.Elevated MPV reflecting platelet activity supports the potential role of platelets in HFpEF's pathophysiology.

Impact of progressive aortic regurgitation on outcomes after left ventricular assist device implantation.

Aortic regurgitation (AR) following continuous flow left ventricular assist device implantation (cf-LVAD) may adversely impact outcomes. We aimed to assess the incidence and impact of progressive AR after cf-LVAD on prognosis, biomarkers, functional capacity and echocardiographic findings. In an analysis of the PCHF-VAD database encompassing 12 European heart failure centers, patients were dichotomized according to the progression of AR following LVAD implantation. Patients with de-novo AR or AR progression (AR_1) were compared to patients without worsening AR (AR_0). Among 396 patients (mean age 53 ± 12 years, 82% male), 153 (39%) experienced progression of AR over a median of 1.4 years on LVAD support. Before LVAD implantation, AR_1 patients were less frequently diabetic, had lower body mass indices and higher baseline NT-proBNP values. Progressive AR did not adversely impact mortality (26% in both groups, HR 0.91 [95% CI 0.61-1.36]; P = 0.65). No intergroup variability was observed in NT-proBNP values and 6-minute walk test results at index hospitalization discharge and at 6-month follow-up. However, AR_1 patients were more likely to remain in NYHA class III and had worse right ventricular function at 6-month follow-up. Lack of aortic valve opening was related to de-novo or worsening AR (P < 0.001), irrespective of systolic blood pressure (P = 0.67). Patients commonly experience de-novo or worsening AR when exposed to continuous flow of contemporary LVADs. While reducing effective forward flow, worsening AR did not influence survival. However, less complete functional recovery and worse RV performance among AR_1 patients were observed. Lack of aortic valve opening was associated with progressive AR.

Diabetic phenotype and prognosis of patients with heart failure and preserved ejection fraction in a real life cohort.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, with several underlying etiologic and pathophysiologic factors. The presence of diabetes might identify an important phenotype, with implications for therapeutic strategies. While diabetes is associated with worse prognosis in HFpEF, the prognostic impact of glycemic control is yet unknown. Hence, we investigated phenotypic differences between diabetic and non-diabetic HFpEF patients (pts), and the prognostic impact of glycated hemoglobin (HbA1C). METHODS: We prospectively enrolled 183 pts with HFpEF (78 ± 9 years, 38% men), including 70 (38%) diabetics (type 2 diabetes only). They underwent 2D echocardiography (n = 183), cardiac magnetic resonance (CMR) (n = 150), and were followed for a combined outcome of all-cause mortality and first HF hospitalization. The prognostic impact of diabetes and glycemic control were determined with Cox proportional hazard models, and illustrated by adjusted Kaplan Meier curves. RESULTS: Diabetic HFpEF pts were younger (76 ± 9 vs 80 ± 8 years, p = 0.002), more obese (BMI 31 ± 6 vs 27 ± 6 kg/m2, p = 0.001) and suffered more frequently from sleep apnea (18% vs 7%, p = 0.032). Atrial fibrillation, however, was more frequent in non-diabetic pts (69% vs 53%, p = 0.028). Although no echocardiographic difference could be detected, CMR analysis revealed a trend towards higher LV mass (66 ± 18 vs 71 ± 14 g/m2, p = 0.07) and higher levels of fibrosis (53% vs 36% of patients had ECV by T1 mapping > 33%, p = 0.05) in diabetic patients. Over 25 ± 12 months, 111 HFpEF pts (63%) reached the combined outcome (24 deaths and 87 HF hospitalizations). Diabetes was a significant predictor of mortality and hospitalization for heart failure (HR: 1.72 [1.1-2.6], p = 0.011, adjusted for age, BMI, NYHA class and renal function). In diabetic patients, lower levels of glycated hemoglobin (HbA1C < 7%) were associated with worse prognosis (HR: 2.07 [1.1-4.0], p = 0.028 adjusted for age, BMI, hemoglobin and NT-proBNP levels). CONCLUSION: Our study highlights phenotypic features characterizing diabetic patients with HFpEF. Notably, they are younger and more obese than their non-diabetic counterpart, but suffer less from atrial fibrillation. Although diabetes is a predictor of poor outcome in HFpEF, intensive glycemic control (HbA1C < 7%) in diabetic patients is associated with worse prognosis.

Multivendor comparison of global and regional 2D cardiovascular magnetic resonance feature tracking strains vs tissue tagging at 3T.

BACKGROUND: Cardiovascular magnetic resonance (CMR) 2D feature tracking (FT) left ventricular (LV) myocardial strain has seen widespread use to characterize myocardial deformation. Yet, validation of CMR FT measurements remains scarce, particularly for regional strain. Therefore, we aimed to perform intervendor comparison of 3 different FT software against tagging. METHODS: In 61 subjects (18 healthy subjects, 18 patients with chronic myocardial infarction, 15 with dilated cardiomyopathy, and 10 with LV hypertrophy due to hypertrophic cardiomyopathy or aortic stenosis) were prospectively compared global (G) and regional transmural peak-systolic Lagrangian longitudinal (LS), circumferential (CS) and radial strains (RS) by 3 FT software (cvi42, Segment, and Tomtec) among each other and with tagging at 3T. We also evaluated the ability of regional LS, CS, and RS by different FT software vs tagging to identify late gadolinium enhancement (LGE) in the 18 infarct patients. RESULTS: GLS and GCS by all 3 software had an excellent agreement among each other (ICC = 0.94-0.98 for GLS and ICC = 0.96-0.98 for GCS respectively) and against tagging (ICC = 0.92-0.94 for GLS and ICC = 0.88-0.91 for GCS respectively), while GRS showed inconsistent agreement between vendors (ICC 0.10-0.81). For regional LS, the agreement was good (ICC = 0.68) between 2 vendors but less vs the 3rd (ICC 0.50-0.59) and moderate to poor (ICC 0.44-0.47) between all three FT software and tagging. Also, for regional CS agreement between 2 software was higher (ICC = 0.80) than against the 3rd (ICC = 0.58-0.60), and both better agreed with tagging (ICC = 0.70-0.72) than the 3rd (ICC = 0.57). Regional RS had more variation in the agreement between methods ranging from good (ICC = 0.75) to poor (ICC = 0.05). Finally, the accuracy of scar detection by regional strains differed among the 3 FT software. While the accuracy of regional LS was similar, CS by one software was less accurate (AUC 0.68) than tagging (AUC 0.80, p < 0.006) and RS less accurate (AUC 0.578) than the other two (AUC 0.76 and 0.73, p < 0.02) to discriminate segments with LGE. CONCLUSIONS: We confirm good agreement of CMR FT and little intervendor difference for GLS and GCS evaluation, with variable agreement for GRS. For regional strain evaluation, intervendor difference was larger, especially for RS, and the diagnostic performance varied more substantially among different vendors for regional strain analysis.

Impact of paced left ventricular dyssynchrony on left ventricular reverse remodeling after cardiac resynchronization therapy.

INTRODUCTION: We investigated whether pacing-induced electrical dyssynchrony at the time of cardiac resynchronization therapy (CRT) device implantation was associated with chronic CRT response. METHODS AND RESULTS: We included a total of 69 consecutive heart failure patients who received a CRT device. Left (LVp-RVs) and right (RVp-LVs) pacing-induced interlead delays were measured intraoperatively and used to determine if there was paced left ventricular (LV) dyssynchrony, defined as present when LVp-RVs is larger than RVp-LVs. CRT response was defined as a reduction in LV end-systolic volume ≥15%, 6 months after implantation. Paced left ventricular dyssynchrony (PLVD) was associated with ischemic cardiomyopathy (ICM) (χ2 : 8; P = .005) but not with QRS morphology nor with pacing lead positions. In a univariate analysis, PLVD (odds ratio [OR], 6.53; 95% confidence interval [CI], 2.2-18.9; P = .001), atypical left bundle branch block (LBBB) (OR, 3.3; 95% CI, 1.2-9.4; P = .022), and ICM (OR, 5.2; 95% CI, 1.6-17; P = .006) were associated with nonresponse. In a multivariate analysis, both PLVD (OR, 9.74; 95% CI, 2.8-33.9; P < .0001) and atypical LBBB (OR, 5.6; 95% CI, 1.5-20.3; P = .009) were independently associated with nonresponse. Adding PLVD to a model based on QRS morphology provided a significant and meaningful incremental value to predict LV reverse remodeling after CRT (χ2 to enter: 8; P < .005). Computer simulations corroborate these findings by showing that, while intrinsic electrical dyssynchrony is a prerequisite, the level of pacing-induced dyssynchrony modulates acute CRT response. CONCLUSION: In addition to the intrinsic electrical substrate, PLVD is strongly associated with less LV reverse remodeling, demonstrating that measuring the electrical substrate during pacing has additional value for prediction of CRT response in an already well-selected patient population.

Pulmonary hypertension due to left heart disease: diagnostic value of pulmonary artery distensibility.

OBJECTIVES: To evaluate how pulmonary artery (PA) distensibility performs in detecting pulmonary hypertension due to left heart disease (PH-LHD) in comparison with parameters from ungated computed tomography (CT) and echocardiography. METHODS: One hundred patients (79 men, mean age = 63 ± 17 years) with either severe heart failure with reduced ejection fraction (HFrEF), aortic stenosis, or primary mitral regurgitation prospectively underwent right heart catheterization, ungated CT, ECG-gated CT, and echocardiography. During the ECG-gated CT, the right PA distensibility was calculated. In ungated CT, dPA, dPA/AA, the ratio of dPA to the diameter of the vertebra, segmental PA diameter, segmental PA-to-bronchus ratio, and the main PA volume were measured; the egg-and-banana sign was recorded. During echocardiography, the tricuspid regurgitation (TR) gradient was measured. The areas under the ROC curves (AUC) of these signs were computed and compared with DeLong test. Correlation between PA distensibility and PA pressure (PAP) was investigated through Pearson's coefficient. RESULTS: PA distensibility was lower in patients with PH than in those without PH (11.4 vs. 21.2%, p < 0.001) and correlated negatively with mean PAP (r = - 0.72, p < 0.001). Age, PA size, and mean PAP were independent predictors of PA distensibility. PA distensibility < 18% detected PH-LHD with 96% sensitivity and 73% specificity; its AUC was 0.92, larger than that of any other sign at ungated CT and TR gradient (AUC ranging from 0.54 to 0.83, DeLong: p ranging from 0.020 to < 0.001). CONCLUSION: PA distensibility on an ECG-gated CT can detect PH-LHD better than the parameters reflecting PA dilatation in ungated CT or TR gradient in the echocardiography of patients with severe HFrEF, aortic stenosis, or mitral regurgitation. KEY POINTS: • In left heart disease, pulmonary artery distensibility is lower in patients with PH than in those without pulmonary hypertension (11.4 vs. 21.2%, p < 0.001). • In left heart disease, pulmonary artery distensibility detects pulmonary hypertension with an area under the receiver operating curve of 0.92. • In left heart disease, the area under the receiver operating curve of pulmonary artery distensibility for detecting pulmonary hypertension is larger than that of all other signs at ungated CT (p from 0.019 to < 0.001) and tricuspid regurgitation gradient at echocardiography (p = 0.020).

Pulmonary hypertension due to left heart disease: diagnostic and prognostic value of CT in chronic systolic heart failure.

OBJECTIVES: To evaluate the ability of chest computed tomography (CT) to predict pulmonary hypertension (PH) and outcome in chronic heart failure with reduced ejection fraction (HFrEF). METHODS: We reviewed 119 consecutive patients with HFrEF by CT, transthoracic echocardiography (TTE) and right heart catheterization (RHC). CT-derived pulmonary artery (PA) diameter and PA to ascending aorta diameter ratio (PA:A ratio), left atrial, right atrial, right ventricular (RV) and left ventricular volumes were correlated with RHC mean pulmonary arterial pressure (mPAP) . Diagnostic accuracy to predict PH and ability to predict primary composite endpoint of all-cause mortality and HF events were evaluated. RESULTS: RV volume was significantly higher in 81 patients with PH compared to 38 patients without PH (133 ml/m2 vs. 79 ml/m2, p < 0.001) and was moderately correlated with mPAP (r=0.55, p < 0.001). Also, RV volume had higher ability to predict PH (area under the curve: 0.88) than PA diameter (0.79), PA:A ratio (0.76) by CT and tricuspid regurgitation gradient (0.83) and RV basal diameter by TTE (0.84, all p < 0.001). During the follow-up period (median: 3.4 years), 51 patients (43%) had HF events or died. After correction for important clinical, TTE and RHC parameters, RV volume (adjusted hazard ratio [HR]: 1.71, 95% CI 1.31-2.23, p < 0.001) and PA diameter (HR: 1.61, 95% CI 1.18-2.22, p = 0.003) were independent predictors of the primary endpoint. CONCLUSION: In patients with HFrEF, measurement of RV volume and PA diameter on ungated CT are non-invasive markers of PH and may help to predict the patient outcome. KEY POINTS: • Right ventricular (RV) volume measured by chest CT has good ability to identify pulmonary hypertension (PH) in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF). • The accuracy of pulmonary artery (PA) diameter and PA to ascending aorta diameter ratio (PA:A ratio) to predict PH was similar to previous studies, however, with lower cut-offs (28.1 mm and 0.92, respectively). • Chest CT-derived PA diameter and RV volume independently predict all-cause mortality and HF events and improve outcome prediction in patients with advanced HFrEF.

Associations and prognostic significance of diffuse myocardial fibrosis by cardiovascular magnetic resonance in heart failure with preserved ejection fraction.

BACKGROUND: Increased myocardial fibrosis may play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology. The study aim was to evaluate the presence, associations, and prognostic significance of diffuse fibrosis in HFpEF patients compared to age- and sex-matched controls. METHODS: We prospectively included 118 consecutive HFpEF patients. Diffuse myocardial fibrosis was estimated by extracellular volume (ECV) quantified by cardiovascular magnetic resonance with the modified Look-Locker inversion recovery sequence. We determined an ECV age- and sex-adjusted cutoff value (33%) in 26 controls. RESULTS: Mean ECV was significantly higher in HFpEF patients versus healthy controls (32.9 ± 4.8% vs 28.2 ± 2.4%, P <  0.001). Multivariate logistic regression showed that body mass index (BMI) (odds ratio (OR) =0.92 [0.86-0.98], P = 0.011), diabetes (OR = 2.62 [1.11-6.18], P = 0.028), and transmitral peak E wave velocity (OR = 1.02 [1.00-1.03], P = 0.022) were significantly associated with abnormal ECV value. During a median follow-up of 11 ± 6 months, the primary outcome (all-cause mortality or first heart failure hospitalization) occurred in 38 patients. In multivariate Cox regression analysis, diabetes (hazard ratio (HR) =1.98 [1.04; 3.76], P = 0.038) and hemoglobin level (HR = 0.81 [0.67; 0.98], P = 0.028) were significant predictors of composite outcome. The ECV ability to improve this model added significant prognostic information. We then developed a risk score including diabetes, hemoglobin and ECV > 33% demonstrating significant prediction of risk and validated this score in a validation cohort of 53 patients. Kaplan-Meier curves showed a significant difference according to tertiles of the probability score (P <  0.001). CONCLUSION: Among HFpEF patients, high ECV, likely reflecting abnormal diffuse myocardial fibrosis, was associated with a higher rate of all-cause death and first HF hospitalization in short term follow up. TRIAL REGISTRATION: Characterization of Heart Failure With Preserved Ejection Fraction. TRIAL REGISTRATION NUMBER: NCT03197350 . Date of registration: 20/06/2017. This trial was retrospectively registered.

Age and sex corrected normal reference values of T1, T2 T2* and ECV in healthy subjects at 3T CMR.

BACKGROUND: Myocardial T1, T2 and T2* imaging techniques become increasingly used in clinical practice. While normal values for T1, T2 and T2* times are well established for 1.5 Tesla (T) cardiovascular magnetic resonance (CMR), data for 3T remain scarce. Therefore we sought to determine normal reference values relative to gender and age and day to day reproducibility for native T1, T2, T2* mapping and extracellular volume (ECV) at 3T in healthy subjects. METHODS: After careful exclusion of cardiovascular abnormality, 75 healthy subjects aged 20 to 90 years old (mean 56 ± 19 years, 47% women) underwent left-ventricular T1 (3-(3)-3-(3)-5 MOLLI)), T2 (8 echo- spin echo-imaging) and T2 * (8 echo gradient echo imaging) mapping at 3T CMR (Philips Ingenia 3T and computation of extracellular volume after administration of 0.2 mmol/kg Gadovist). Inter- and intra-observer reproducibility was estimated by intraclass correlation coefficient (ICC). Day to day reproducibility was assessed in 10 other volunteers. RESULTS: Mean myocardial T1 at 3T was 1122 ± 57 ms, T2 52 ± 6 ms, T2* 24 ± 5 ms and ECV 26.6 ± 3.2%. T1 (1139 ± 37 vs 1109 ± 73 ms, p < 0.05) and ECV (28 ± 3 vs 25 ± 2%, p < 0.001), but not T2 (53 ± 8 vs 51 ± 4, p = NS) were significantly greater in age matched women than in men. T1 (r = 0.40, p < 0.001) and ECV (r = 0.37, p = 0.001) increased, while T2 decreased significantly (r = -0.25, p < 0.05) with increasing age. T2* was not influenced by either gender or age. Intra and inter-observer reproducibility was high (ICC ranging between 0.81-0.99), and day to day coefficient of variation was low (6.2% for T1, 7% for T2, 11% for T2* and 11.5% for ECV). CONCLUSIONS: We provide normal myocardial T2, T2*,T1 and ECV reference values for 3T CMR which are significantly different from those reported at 1.5 Tesla CMR. Myocardial T1 and ECV values are gender and age dependent. Measurement had high inter and intra-observer reproducibility and good day-to-day reproducibility.

Impact of left ventricular outflow tract ellipticity on the grading of aortic stenosis in patients with normal ejection fraction.

BACKGROUND: The pathophysiology of paradoxical low-gradient (LG) severe aortic stenosis (SAS) remains controversial. As low transvalvular flow has been implicated, we sought to investigate the impact of left ventricular outflow tract (LVOT) ellipticity on the estimation of the LV stroke volume, the calculation of the aortic valve area (AVA) by use of the continuity equation and on AS severity grading. METHODS: We studied 190 consecutive patients (mean age: 72 ± 13 years; male: 57%) with SAS (indexed AVA < 0.6 cm2/m2) and preserved LV ejection fraction, including 120 patients with severe high gradient (HG) AS and 70 with severe paradoxical LG-AS. AS severity, LV volumes and LVOT ellipticity were assessed by 2D-Doppler echocardiography and cardiac magnetic resonance (CMR). RESULTS: The LVOT exhibited an elliptical shape on CMR images, with a shorter anterior-posterior than median-lateral diameter (2.2 ± 0.2 vs 2.8 ± 0.3 cm, p < 0.01). Accordingly, the LVOT area measured by planimetry was larger than by 2D-echocardiography, assuming a circular orifice (4.9 ± 0.9 cm2 vs 3.7 ± 0.8 cm2, p < 0.01). Inputting the elliptical LVOT area into the continuity equation resulted in a 29% increase in the indexed AVA (from 0.41 ± 0.09 cm2 to 0.54 ± 0.10 cm2). Accordingly, 30 (43%) patients with severe paradoxical LG-SAS were reclassified as having moderate AS. Similar results were obtained when considering 3D-echo for direct planimetry of the LVOT in a subset of 75 patients. CONCLUSIONS: Our results confirm that the LVOT is elliptical in shape and that taking this parameter into account in the calculation of the AVA results in reclassification of 43% of patients with severe paradoxical LG-AS into moderate AS.

Enhanced expression of ß3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase.

BACKGROUND: ß1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. ß3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown. METHODS AND RESULTS: Mice with cardiac myocyte-specific expression of human ß3-AR (ß3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). ß3-TG and WT had similar morphometric and hemodynamic parameters at baseline. ß3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in ß3-TG mice, which also had less re-expression of fetal genes and transforming growth factor ß1. Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of ß3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, ß3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. CONCLUSIONS: Cardiac-specific overexpression of ß3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac ß3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling.

Histological Validation of measurement of diffuse interstitial myocardial fibrosis by myocardial extravascular volume fraction from Modified Look-Locker imaging (MOLLI) T1 mapping at 3 T.

BACKGROUND: Gadolinium (Gd) Extracellular volume fraction (ECV) by Cardiovascular Magnetic Resonance (CMR) has been proposed as a non-invasive method for assessment of diffuse myocardial fibrosis. Yet only few studies used 3 T CMR to measure ECV, and the accuracy of ECV measurements at 3 T has not been established. Therefore the aims of the present study were to validate measurement of ECV by MOLLI T1 mapping by 3 T CMR against fibrosis measured by histopathology. We also evaluated the recently proposed hypothesis that native-T1 mapping without contrast injection would be sufficient to detect fibrosis. METHODS: 31 patients (age = 58 ± 17 years, 77% men) with either severe aortic stenosis (n = 12) severe aortic regurgitation (n = 9) or severe mitral regurgitation (n = 10), all free of coronary artery disease, underwent 3 T-CMR with late gadolinium enhancement (LGE) and pre- and post-contrast MOLLI T1 mapping and ECV computation, prior to valve surgery. LV biopsies were performed at the time of surgery, a median 13 [1-30] days later, and stained with picrosirius red. Pre-, and post-contrast T1 values, ECV, and amount of LGE were compared against magnitude of fibrosis by histopathology by Pearson correlation coefficients. RESULTS: The average amount of interstitial fibrosis by picrosirius red staining in biopsy samples was 6.1 ± 4.3%. ECV computed from pre-post contrast MOLLI T1 time changes was 28.9 ± 5.5%, and correlated (r = 0.78, p < 0.001) strongly with the magnitude of histological fibrosis. By opposition, neither amount of LGE (r = 0.17, p = 0.36) nor native pre-contrast myocardial T1 time (r = -0.18, p = 0.32) correlated with fibrosis by histopathology. CONCLUSIONS: ECV determined by 3 T CMR T1 MOLLI images closely correlates with histologically determined diffuse interstitial fibrosis, providing a non-invasive estimation for quantification of interstitial fibrosis in patients with valve diseases. By opposition, neither non-contrast T1 times nor the amount of LGE were indicative of the magnitude of diffuse interstitial fibrosis measured by histopathology.

Cardiac structure, function, and coronary anatomy 10 years after isolated contemporary adjuvant radiotherapy in breast cancer patients with low cardiovascular baseline risk.

AIMS: The effects of isolated contemporary low-dose breast cancer (BC) radiotherapy (RT) on the heart remain poorly understood. This study aims to assess the long-term impacts of BC-RT on cardiac structure and function. METHODS AND RESULTS: Seventy-six women (62 ± 7 years) without history of prior heart disease, who had undergone RT for either first left (n = 36) or right (n = 40) BC, without additional medical oncology therapy apart from hormonal treatment 11 ± 1 years earlier, underwent transthoracic echocardiography, cardiac magnetic resonance imaging (CMR), computed tomography coronary angiography (CTCA), NT-proBNP, and a 6-min walk test (6MWT). They were compared with 54 age-matched healthy female controls. By CTCA, 68% of BC patients exhibited no or very mild coronary disease, while only 11% had moderate stenosis (50-69%) and 3% had significant stenosis (>70%). Despite slightly reduced regional echocardiographic midventricular strains, BC patients exhibited similar global left and right ventricular volumes, ejection fractions, and global strains by echocardiography and CMR as controls. Mitral E/e' ratios were slightly higher, and mitral deceleration times were slightly lower, but NT-proBNP was similar to controls. Also, 6MWT was normal. None had late gadolinium enhancement, and extracellular volume fraction was similar in BC (28 ± 3 vs. 29 ± 3, P = 0.15) and controls. No differences were observed relative to dose or side of RT. CONCLUSION: Aside from minor alterations of regional strains and diastolic parameters, women who received isolated RT for BC had low prevalence of coronary disease, normal global systolic function, NT-proBNP, and exercise capacity and showed no structural changes by CMR, refuting significant long-term cardiotoxicity in such low-risk patients.

Carbohydrate antigen 125: a useful marker of congestion, fibrosis, and prognosis in heart failure with preserved ejection fraction.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) is a disease associated with high morbidity and mortality, for which it is difficult to identify patients with the poorest prognosis in routine clinical practice. Carbohydrate antigen 125 (CA 125) has been shown to be a potential marker of congestion and prognosis in HF. We sought to better characterize HFpEF patients with high CA 125 levels by using a multimodal approach. METHODS AND RESULTS: We prospectively enrolled 139 HFpEF patients (78 ± 8 years; 60% females) and 25 controls matched for age and sex (77 ± 5 years; 60% females). They underwent two-dimensional echocardiography, cardiac magnetic resonance with late gadolinium enhancement [including extracellular volume (ECV) measurement], and serum measurements of CA 125 level. The primary endpoint of the study was a composite of all-cause mortality or first HF hospitalization. The prognostic impact of CA 125 was determined using Cox proportional hazard models. Median CA 125 levels were significantly higher in HFpEF patients compared with controls [CA 125: 23.5 (14.5-44.7) vs. 14.6 (10.3-21.0) U/mL, P = 0.004]. CA 125 levels were positively correlated with a congestion marker [N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, Pearson's r = 0.37, P < 0.001] and markers of cardiac fibrosis estimated by both ECV (Pearson's r = 0.26, P = 0.003) and fibroblast growth factor 23 levels (Pearson's r = 0.50, P < 0.001). Over a median follow-up of 49 (22-64) months, 97 HFpEF patients reached the composite endpoint. Even after adjustment for the Meta-Analysis Global Group in Chronic risk score, a CA 125 level ≥35 U/mL was still a significant predictor of the composite endpoint [hazard ratio (HR): 1.58 (1.04-2.41), P = 0.032] and more particularly of HF hospitalization [HR: 1.81 (1.13-2.92), P = 0.014]. In contrast, NT-proBNP levels were not an independent predictor. CONCLUSIONS: CA 125 levels were significantly higher in HFpEF patients compared with controls matched for age and sex and were associated with markers of congestion and cardiac fibrosis. CA 125 levels were a strong and independent predictor of HF hospitalization in HFpEF patients. These data suggest a potential value of CA 125 as a biomarker for staging and risk prediction in HFpEF.

Quantifying the Survival Loss Linked to Late Therapeutic Indication in High-Gradient Severe Aortic Stenosis.

Background: International guidelines recommend aortic valve replacement (AVR) as Class I triggers in high-gradient severe aortic stenosis (HGSAS) patients with symptoms and/or left ventricular ejection fraction (LVEF) <50%. The association between waiting for these triggers and postoperative survival penalty is poorly studied. Objectives: The purpose of this study was to examine the impact of guideline-based Class I triggers on long-term postoperative survival in HGSAS patients. Methods: 2,030 patients operated for HGSAS were included and classified as follows: no Class I triggers (no symptoms and LVEF >50%, n = 853), symptoms with LVEF >50% (n = 965), or LVEF <50% regardless of symptoms (n = 212). Survival was compared after matching (inverse probability weighting) for clinical differences. Restricted mean survival time was analyzed to quantify lifetime loss. Results: Ten-year survival was better without any Class I trigger than with symptoms or LVEF <50% (67.1% ± 3% vs 56.4% ± 3% vs 53.1% ± 7%, respectively, P < 0.001). Adjusted death risks increased significantly in operated patients with symptoms (HR: 1.45 [95% CI: 1.15-1.82]) or LVEF <50% (HR: 1.47 [95% CI: 1.05-2.06]) than in those without Class I triggers. Performing AVR with LVEF >60% produced similar outcomes to that of the general population, whereas operated patients with LVEF <60% was associated with a 10-year postoperative survival penalty. Furthermore, according to restricted mean survival time analyses, operating on symptomatic patients or with LVEF <60% led to 8.3- and 11.4-month survival losses, respectively, after 10 years, compared with operated asymptomatic patients with a LVEF >60%. Conclusions: Guideline-based Class I triggers for AVR in HGSAS have profound consequences on long-term postoperative survival, suggesting that HGSAS patients should undergo AVR before trigger onset. Operating on patients with LVEF <60% is already associated with a 10-year postoperative survival penalty questioning the need for an EF threshold recommending AVR in HGSAS patients.

Acute effects of withdrawal of cardiac resynchronization therapy on left and right ventricular function, dyssynchrony, and contractile function in patients with New York Heart Association functional class I/II heart failure: MADIT-CRT.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves left ventricular (LV) function, size, mitral regurgitation, and clinical outcomes. Whether these improvements are due to the short-term effects of improvement in synchrony or contractile performance, or to long-term improvement in ventricular structure and function remains insufficiently elucidated. METHODS AND RESULTS: We used echocardiographic data from 63 patients enrolled in the MADIT-CRT trial who, after 1 year of CRT therapy, underwent echocardiographic evaluation with CRT turned both on and off within minutes. LV volumes, LV ejection fraction, left atrial (LA) volumes, and right ventricular function were assessed at baseline and in the on and off modes within a 5-minute time-frame at 12 months. Speckle-tracking strain analysis was used to assess LV dyssynchrony and contractile function. Interruption of long-term CRT resulted in acute deterioration of LV and RV function and acute increase in LV and LA volumes, although not to baseline. Acute withdrawal was also associated with increased dyssynchrony (SD time to peak transverse strain 178 ± 68 ms vs 195 ± 62 ms; P = .16; and SD time to peak longitudinal strain 108 ± 46 ms vs 125 ± 55 ms; P = .046). However, there was no deterioration in contractile function (global longitudinal strain), which had improved with CRT (-9.8 ± 4.3% vs -10.0 ± 3.7%; P = .93). CONCLUSIONS: Despite substantial LV reverse remodeling with CRT, interruption of long-term CRT after 12 months resulted in an acute worsening of LV size and function, LA volumes, and right ventricular function, with concomitant worsening of ventricular synchrony despite minimal change to the observed improvement in LV strain measures of contractile function. These findings suggest that the beneficial reverse remodeling associated with CRT may be mostly dependent on active pacing, although intrinsic improvements in contractile function may persist beyond termination of pacing.

CA125, Galectin-3 and FGF-23 are interrelated in heart failure with reduced ejection fraction.

Background: Carbohydrate Antigen 125 (CA125) is the most widely used biomarker in ovarian cancer screening. In patients with heart failure (HF), increased levels of CA125 have been observed and related to disease severity. Our objective was to determine the association of CA125 levels with two biomarkers of adverse remodeling in HF patients with reduced ejection fraction (HFrEF). Methods: CA125 circulating levels were determined with an electrochemiluminscent immunoassay. Concentrations of B-type natriuretic peptide (BNP), N-terminal proBNP (Nt-proBNP), Galectin-3 and Fibroblast Growth Factor 23 (FGF23) were also measured by immunoassays. Results: CA125 levels were increased in HFrEF, were associated to disease severity according NYHA classes. Median CA125 concentration was also significantly related to cardiovascular mortality. CA125 concentrations were positively and significantly associated to Galectin-3 and FGF23. Conclusions: Concentrations of CA125 are increased in patients with HFrEF, associated to disease severity and adverse cardiovascular outcomes. CA125 levels are also correlated to Galectin-3 and FGF-23, two biomarkers related to fibrosis and cardiovascular remodeling.