Association of Active and Passive Components of LV Diastolic Filling With Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Mechanistic Insights From Spironolactone Response

ObjectivesThis study sought to investigate the association of left ventricular (LV) untwisting rate (UT) and E/e’ ratio with the response of exercise capacity to spironolactone in heart failure with preserved ejection fraction (HFpEF).BackgroundIn most patients with HFpEF, LV filling abnormalities represent a central component in the development of dyspnea. LV diastolic filling is determined by the interplay of passive (LV stiffness and myocardial collagen content, reflected by E/e’ ratio) and active myocardial properties (UT, a precursor to isovolumic pressure decay and contributor to diastolic suction).MethodsIn 194 patients with HFpEF (64 ± 8 years), a complete echocardiogram (including assessment of myocardial deformation and rotational mechanics) was performed. Echocardiography following maximal exercise was undertaken to assess LV systolic and diastolic responses to stress. A subset of 105 patients with an exercise-induced increase in estimated LV filling pressure were randomly assigned to spironolactone 25 mg (n = 51) or placebo (n = 54) for 6 months.ResultsBaseline peak Vo₂ was associated with UT (β = 0.19; p = 0.01) and E/e’ (β = −0.16; p = 0.03), independent of clinical data and exercise reserve in longitudinal deformation and ventricular-arterial coupling. An increase in peak Vo₂ with treatment was independently associated with changes in UT (β = 0.28; p = 0.003) and exertional increase in E/e′ (β = −0.23; p = 0.01) from baseline to follow-up. A significant interaction with the use of spironolactone on peak Vo₂ was found for E/e′ (p = 0.02) but not for UT (p = 0.62).ConclusionsBoth active and passive determinants of LV filling, as reflected by UT and E/e′, contribute to reduced exercise capacity in HFpEF. Improvement in functional capacity with a 6-month therapy with spironolactone is associated with improvements in both indices. However, the possible mediating effect of this medication is observed only on E/e′.     

Exercise E/e′ Is a Determinant of Exercise Capacity and Adverse Cardiovascular Outcomes in Chronic Kidney Disease

ObjectivesThis study sought to assess the relationship between E/e′ and exercise capacity in patients with chronic kidney disease (CKD) and evaluate its prognostic role.BackgroundPatients with CKD have diastolic dysfunction, reduced physical fitness, and elevated risk of cardiovascular disease.MethodsPatients with stage 3 and 4 CKD without previous cardiac disease underwent resting and exercise stress echocardiograms with assessment of exercise E/e′. Patients were compared to age-, sex-, and risk factor–matched control individuals and were followed annually for 5 years for cardiovascular death and major adverse cardiovascular event(s) (MACE). Exercise capacity was assessed as metabolic equivalents (METs), with reduced exercise capacity defined as METs of ≤7. Raised exercise E/e′ was defined as >13.ResultsA total of 156 patients with CKD (age 62.8 ± 10.6 years; male: 62%) were compared to 156 matched control individuals. Patients with CKD were more likely to be anemic (p < 0.01) and had increased left ventricular mass (p < 0.01), larger left atrial volumes (p < 0.01), and higher resting (p < 0.01) and exercise E/e′ (p < 0.01). Patients with CKD achieved lower exercise METs (p < 0.01), and more patients with CKD had METs of ≤7 (p < 0.01). Receiver-operating characteristic curves showed exercise E/e′ (area under the curve [AUC]: 0.89; 95% CI: 0.84 to 0.95; p < 0.01) as the strongest predictor of reduced exercise capacity in patients with CKD. Over a follow-up period of 41.4 months, a raised exercise E/e′ of >13 was an independent predictor of cardiovascular death and MACE on unadjusted and adjusted hazard models.ConclusionE/e′ is a strong predictor of exercise capacity and METs achieved by patients with CKD. Exercise capacity was reduced in patients with CKD, presumably consequent to diastolic dysfunction. Elevated exercise E/e′ in patients with CKD is an independent predictor of cardiovascular death and MACE.     

Deep-Learning Models for the Echocardiographic Assessment of Diastolic Dysfunction

ObjectivesThe authors explored a deep neural network (DeepNN) model that integrates multidimensional echocardiographic data to identify distinct patient subgroups with heart failure with preserved ejection fraction (HFpEF).BackgroundThe clinical algorithms for phenotyping the severity of diastolic dysfunction in HFpEF remain imprecise.MethodsThe authors developed a DeepNN model to predict high- and low-risk phenogroups in a derivation cohort (n = 1,242). Model performance was first validated in 2 external cohorts to identify elevated left ventricular filling pressure (n = 84) and assess its prognostic value (n = 219) in patients with varying degrees of systolic and diastolic dysfunction. In 3 National Heart, Lung, and Blood Institute–funded HFpEF trials, the clinical significance of the model was further validated by assessing the relationships of the phenogroups with adverse clinical outcomes (TOPCAT [Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function] trial, n = 518), cardiac biomarkers, and exercise parameters (NEAT-HFpEF [Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction] and RELAX-HF [Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure] pooled cohort, n = 346).ResultsThe DeepNN model showed higher area under the receiver-operating characteristic curve than 2016 American Society of Echocardiography guideline grades for predicting elevated left ventricular filling pressure (0.88 vs. 0.67; p = 0.01). The high-risk (vs. low-risk) phenogroup showed higher rates of heart failure hospitalization and/or death, even after adjusting for global left ventricular and atrial longitudinal strain (hazard ratio [HR]: 3.96; 95% confidence interval [CI]: 1.24 to 12.67; p = 0.021). Similarly, in the TOPCAT cohort, the high-risk (vs. low-risk) phenogroup showed higher rates of heart failure hospitalization or cardiac death (HR: 1.92; 95% CI: 1.16 to 3.22; p = 0.01) and higher event-free survival with spironolactone therapy (HR: 0.65; 95% CI: 0.46 to 0.90; p = 0.01). In the pooled RELAX-HF/NEAT-HFpEF cohort, the high-risk (vs. low-risk) phenogroup had a higher burden of chronic myocardial injury (p < 0.001), neurohormonal activation (p < 0.001), and lower exercise capacity (p = 0.001).ConclusionsThis publicly available DeepNN classifier can characterize the severity of diastolic dysfunction and identify a specific subgroup of patients with HFpEF who have elevated left ventricular filling pressures, biomarkers of myocardial injury and stress, and adverse events and those who are more likely to respond to spironolactone.     

Arterial Stiffness and Vascular Load in HFpEF: Differences Among Women and Men

BackgroundMechanisms underlying sex differences in heart failure with preserved ejection fraction (HFpEF) are poorly understood. We sought to examine sex differences in measures of arterial stiffness and the association of arterial stiffness measures with left ventricular hemodynamic responses to exercise in men and women.MethodsWe studied 83 men (mean age 62 years) and 107 women (mean age 59 years) with HFpEF who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and arterial stiffness measurement (augmentation pressure [AP], augmentation index [AIx], and aortic pulse pressure [AoPP]). Sex differences were compared using multivariable linear regression. We examined the association of arterial stiffness with abnormal left ventricular diastolic response to exercise, defined as a rise in pulmonary capillary wedge pressure relative to cardiac output (?PCWP/?CO) ≥ 2 mmHg/L/min by using logistic regression models.ResultsWomen with HFpEF had increased arterial stiffness compared with men. AP was nearly 10 mmHg higher, and AIx was more than 10% higher in women compared with men (P < 0.0001 for both). Arterial stiffness measures were associated with a greater pulmonary capillary wedge pressure response to exercise, particularly among women. A 1-standard deviation higher AP was associated with > 3-fold increased odds of abnormal diastolic exercise response (AP: OR 3.16, 95% CI 1.34–7.42; P = 0.008 [women] vs OR 2.07, 95% CI 0.95–5.49; P = 0.15 [men]) with similar findings for AIx and AoPP.ConclusionsArterial stiffness measures are significantly higher in women with HFpEF than in men and are associated with abnormally steep increases in pulmonary capillary wedge pressure with exercise, particularly in women. Arterial stiffness may preferentially contribute to abnormal diastolic function during exercise in women with HFpEF compared with men.     

Evolution of Myocardial Dysfunction in Asymptomatic Patients at Risk of Heart Failure

ObjectivesThe determinants of changes in systolic and diastolic parameters in patients age >65 years, at risk of heart failure (HF), and with and without asymptomatic type 2 diabetes mellitus (T2DM) was assessed by echocardiography. The association between metformin and myocardial function was also assessed.BackgroundThe increasing prevalence of T2DM will likely further fuel the epidemic of HF. Understanding the development or progression of left ventricular (LV) dysfunction may inform effective measures for HF prevention.MethodsA total of 982 patients with at least one HF risk factor (hypertension, obesity, or T2DM) were recruited from 2 community-based populations and divided into 2 groups: T2DM (n = 431, age 71 ± 4 years) and non-T2DM (n = 551, age 71 ± 5 years). Associations of metformin therapy were evaluated in the T2DM group. All underwent a comprehensive echocardiogram, including global longitudinal strain (GLS) and diastolic function (transmitral flow [E], annular velocity [e’]) at baseline and follow-up (median 19 months [interquartile range: 17 to 26 months]). Comparisons were facilitated by propensity matching.ResultsA reduction in GLS was observed in the T2DM group (baseline ?17.8 ± 2.6% vs. follow-up ?17.4 ± 2.8%; p = 0.003), but not in the non-T2DM group (?18.7 ± 2.7% vs. ?18.6 ± 3.0%; p = 0.41). Estimated LV filling pressures increased in both the T2DM group (p = 0.001) and the non-T2DM group (p = 0.04). Metformin-treated patients with T2DM did not increase estimated LV filling pressure (E/e’ baseline 8.9 ± 2.7 vs. follow-up 9.1 ± 2.7; p = 0.485) or change e’ (7.6 ± 1.5 cm/s vs. 7.6 ± 1.8 cm/s; p = 0.88). After propensity matching, metformin was associated with a smaller change in e’ (β = 0.58 [95% CI: 0.13 to 1.03]; p = 0.013) and E/e’ (β = ?0.96 [95% CI: ?1.66 to ?0.26]; p = 0.007) but was not associated with a change in GLS (p = 0.46).ConclusionsOver 2 years, there is a worsening of GLS and LV filling pressures in asymptomatic diabetic patients with HF risk factors. Metformin use is associated with less deterioration of LV filling pressures and myocardial relaxation but had no association with systolic function.     

Sex-Related Differences of Coronary Atherosclerosis Regression Following Maximally Intensive Statin Therapy: Insights From SATURN

ObjectivesThe study sought to explore sex-related differences in coronary atheroma regression following high-intensity statin therapy.BackgroundGuidelines now recommend high-intensity statins in all individuals with atherosclerotic cardiovascular disease.MethodsSATURN (Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin) employed serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The treatment groups did not differ significantly in change from baseline of percent atheroma volume (PAV) or total atheroma volume (TAV) on intravascular ultrasound, nor in safety or clinical outcomes.ResultsCompared with men (n = 765), women (n = 274) were older (p < 0.001) and more likely to have hypertension (p < 0.001), diabetes (p = 0.002), and higher low-density lipoprotein cholesterol (LDL-C) (p = 0.01), high-density lipoprotein cholesterol (p < 0.001), and C-reactive protein (CRP) (p = 0.004) levels. At follow-up, women had higher high-density lipoprotein cholesterol (p < 0.001) and CRP (p < 0.001), but similar LDL-C (p = 0.46) levels compared with men. Compared with men, women had lower baseline PAV (34.0 ± 8.0% vs. 37.2 ± 8.2%, p < 0.001) and TAV (122.4 ± 55 mm³ vs. 151.9 ± 63 mm³, p < 0.001), yet demonstrated greater PAV regression (–1.52 ± 0.18% vs. –1.07 ± 0.10%, p = 0.03) and TAV regression (–8.27 ± 0.9 mm³ vs. –6.59 ± 0.50 mm³, p = 0.11) following treatment. Greater PAV regression in women versus men occurred with rosuvastatin (p = 0.004), those with diabetes (p = 0.01), stable coronary disease (p = 0.01), higher baseline LDL-C (p = 0.02), and higher CRP (p = 0.04) levels. On multivariable analysis, female sex was independently associated with PAV regression (p = 0.01), and a sex-treatment interaction was found (p = 0.036). For participants with on-treatment LDL-C levels <70 mg/dl, women achieved greater PAV regression (–1.81 ± 0.22% vs. –1.12 ± 0.13%, p = 0.007) and TAV regression (–10.1 ± 1.1 mm³ vs. –7.16 ± 0.65 mm³, p = 0.023) than men, whereas PAV and TAV regression did not differ by sex, with LDL-C levels ≥70 mg/dl.ConclusionsWomen with coronary disease demonstrate greater coronary atheroma regression than men when empirically prescribed guideline-driven potent statin therapy. This benefit appears in the setting of lower on-treatment LDL-C levels. (CRESTOR Athero Imaging Head to Head IVUS Study [SATURN]; NCT000620542)     

Utility of E/e′ Ratio During Low-Level Exercise to Diagnose Heart Failure With Preserved Ejection Fraction

BackgroundE/e′ ratio during exercise is the key parameter in identifying elevated pulmonary capillary wedge pressure (PCWP), and thus heart failure with preserved ejection fraction (HFpEF). However, its diagnostic value is limited when mitral inflow or tissue velocities are fused during elevated heart rate.ObjectivesThe authors hypothesized that E/e‘ ratio during low-level (20 W) exercise (E/e′_20W) can help diagnose HFpEF.MethodsErgometric exercise stress echocardiography was performed in 215 dyspneic patients with an EF ≥50%. The authors determined the feasibility of E/e′ ratio at each stage (frequency of patients who had measurable E/e′ without E-A fusion among 215 participants) and examined whether E/e′_20W could predict normal E/e′ ratio during peak exercise (E/e′_peak ≤15). The authors also evaluated whether E/e′_20W could predict normal PCWP during exercise (PCWP <25 mm Hg) in a subset of participants (n = 45) who underwent exercise right heart catheterization.ResultsThe feasibility of the E/e′ ratio decreased from 100% at rest to 96.3% during 20-W exercise and 74.9% during peak exercise caused by E-A fusion. In patients with E/e′_peak >15, there was an increase in E/e′ ratio from rest to 20-W exercise (11.2 ± 2.1 to 16.3 ± 3.5; P < 0.0001), but it did not change significantly from 20-W exercise to peak exercise (P = 0.12). E/e′_20W predicted E/e′_peak ≤15 (AUC: 0.91; P < 0.0001) with the cutoff value of ≤12.4 showing high specificity (94%) and positive predictive value (98%). During 20-W exercise, 93% of the HFpEF patients developed PCWP ≥25 mm Hg. E/e′_20W predicted normal PCWP during exercise (AUC: 0.77; P = 0.01) with the cutoff value of ≤12.4 showing high specificity (83%).ConclusionsE/e′ ratio during low-level exercise is highly feasible and predicts normal E/e′ ratio or PCWP during peak exercise with high specificity. These data suggest that E/e′_20W could be used as an alternative to the peak exercise value to rule out HFpEF in patients with dyspnea.     

Subclinical Pulmonary Congestion and Abnormal Hemodynamics in Heart Failure With Preserved Ejection Fraction

ObjectivesThe authors hypothesized that quantitative computed tomography (QCT) imaging would reveal subclinical increases in lung congestion in patients with heart failure and preserved ejection fraction (HFpEF) and that this would be related to pulmonary vascular hemodynamic abnormalities.BackgroundGross evidence of lung congestion on physical examination, laboratory tests, and radiography is typically absent among compensated ambulatory patients with HFpEF. However, pulmonary gas transfer abnormalities are commonly observed and associated with poor outcomes.MethodsPatients referred for invasive hemodynamic exercise testing who had undergone chest computed tomography imaging within 1 month were identified (N = 137). A novel artificial intelligence QCT algorithm was used to measure pulmonary fluid content.ResultsCompared with control subjects with noncardiac dyspnea, patients with HFpEF displayed increased mean lung density (–758 HU [–793, –709 HU] vs –787 HU [–828, –747 HU]; P = 0.002) and a higher ratio of extravascular lung water to total lung volume (EVLWV/TLV) (1.25 [0.80, 1.76] vs 0.66 [0.01, 1.03]; P < 0.0001) by QCT imaging, indicating greater lung congestion. EVLWV/TLV was directly correlated with pulmonary vascular pressures at rest, with stronger correlations observed during exercise. Patients with increasing tertiles of EVLWV/TLV demonstrated higher mean pulmonary artery pressures at rest (34 ± 11 mm Hg vs 39 ± 14 mm Hg vs 45 ± 17 mm Hg; P = 0.0003) and during exercise (55 ± 17 mm Hg vs 59 ± 17 mm Hg vs 69 ± 22 mm Hg; P = 0.0003).ConclusionsQCT imaging identifies subclinical lung congestion in HFpEF that is not clinically apparent but is related to abnormalities in pulmonary vascular hemodynamics. These data provide new insight into the long-term effects of altered hemodynamics on pulmonary structure and function in HFpEF.     

CMR-Verified Diffuse Myocardial Fibrosis Is Associated With Diastolic Dysfunction in HFpEF

ObjectivesThe purpose of this study was to investigate diffuse myocardial fibrosis in patients with systolic heart failure (SHF) and in patients with heart failure with preserved ejection fraction (HFpEF) and the association with diastolic dysfunction of the left ventricle (LV).BackgroundIncreased diffuse myocardial fibrosis may impair LV diastolic function. However, no study has verified the association between the degree of diffuse myocardial fibrosis and the severity of impaired diastolic function in SHF and HFpEF.MethodsForty patients with SHF, 62 patients with HFpEF, and 22 patients without HF underwent cardiac magnetic resonance (CMR), including T1 mapping and cine CMR on a 3-T system. Extracellular volume fraction (ECV), a measure of diffuse myocardial fibrosis, was quantified from T1 mapping. Systolic and diastolic functions of the LV were assessed by cine CMR. The ECV values and LV functional indexes were compared among the 3 groups. Associations between ECV and LV diastolic function were also investigated.ResultsCompared with patients without HF, significantly higher ECV was found in patients with SHF (31.2% [interquartile range (IQR): 29.0% to 34.1%] vs. 27.9% [IQR: 26.2% to 29.4%], p < 0.001) and HFpEF (28.9% [IQR: 27.8% to 31.3%] vs. 27.9% [IQR: 26.2% to 29.4%], p = 0.006). Peak filling rate, a diastolic functional index assessed by cine CMR, was significantly decreased in patients with SHF (1.00 s⁻¹ [IQR: 0.79 to 1.49 s⁻¹] vs. 3.86 s⁻¹ [IQR: 3.34 to 4.48 s⁻¹], p < 0.001) and HFpEF (2.89 s⁻¹ [IQR: 2.13 to 3.50 s⁻¹] vs. 3.86 s⁻¹ [IQR: 3.34 to 4.48 s⁻¹], p < 0.001). Myocardial ECV was significantly correlated with peak filling rate in the HFpEF group (r = −0.385, p = 0.002), but no correlation was found in the SHF and non-HF groups (r = 0.030, p = 0.856 and r = −0.238, p = 0.285, respectively).ConclusionsIn patients with HF, only those with HFpEF show a significant correlation between increased diffuse myocardial fibrosis and impaired diastolic function. Diffuse myocardial fibrosis plays a unique role in the pathogenesis of HFpEF.     

Impact of metabolically healthy obesity on carotid intima-media thickness - The Brazilian Longitudinal Study of Adult Health

Background and aimsObesity increases the risk of metabolic abnormalities, which contributes to elevated cardiovascular risk. However, the independent role of obesity in the development of cardiovascular disease is still debatable. There are individuals with an obesity phenotype without metabolic abnormalities: “metabolically healthy obesity” (MHO). This study evaluates the association between MHO and carotid intima-media thickness (CIMT), an early marker of subclinical atherosclerosis.Methods and resultsThis is a cross-sectional analysis of the baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). We used a strict definition to classify MHO: body mass index ≥30 kg/m² and meeting none of the four metabolic syndrome criteria. Data from 10,335 participants were analyzed. The obesity prevalence in our population was 21.2% (n = 2191). The prevalence of MHO was 5.6% (n = 124). When individuals were stratified according to metabolic health, we found the metabolically healthy individuals were younger, more likely to be women and never smokers. The mean CIMT of the sample was 0.81 mm (±0.20). The mean CIMT of the metabolically healthy subsample was 0.70 mm (±0.13) in individuals without obesity and 0.76 mm (±0.13) in individuals with obesity (p < 0.001). The mean CIMT of the metabolically unhealthy subsample was 0.81 mm (±0.20) in individuals without obesity and 0.88 mm (±0.20) in individuals with obesity (p < 0.001). These findings remained essentially unchanged after multivariate adjustment for confounding factors.ConclusionThe concept of MHO, even with the strict definition, seems inadequate, as even in this population, obesity is associated with higher CIMT levels.     

Decreased handgrip strength in patients with type 2 diabetes: A cross-sectional study in a tertiary care hospital in north India

Background and aimsType 2 diabetes mellitus (T2DM) has been associated with low muscle mass and strength. India has second highest number of diabetes cases worldwide. Till date, muscle mass and strength of Asian Indians with T2DM are not well studied. Aim of the study was to compare the skeletal muscle mass and muscle strength between individuals with and without T2DM.MethodsThis cross-sectional study, included subjects with T2DM, age 18–70 years and age and sex-matched individuals without diabetes (controls). Body composition was assessed using Inbody 570 body composition analyser. Hand grip strength (HGS) was measured using JAMAR’s Hydraulic Hand Dynamometer.ResultsTotal of 194 subjects (95 T2DM and 99 controls) were studied. Mean HGS (kg) was significantly lower both in men and women with diabetes compared with controls (32.4 ± 7.9 vs 37.9 ± 8.1, p = 0.001 in men and 20.6 ± 6.4 vs 23.1 ± 4.06, p = 0.02 in women). Significantly higher percentage of men and women with diabetes had sarcopenia compared with controls (44.4% vs 15.1% in men and 51% vs 20% in women). In multivariate logistic regression analysis, diabetes was an independent risk factor for low HGS in both men (OR = 6.6) and women (OR = 3.4) after adjusting for age, smoking, alcohol consumption, obesity, physical activity and dietary protein intake.ConclusionHGS was significantly lower in subjects with T2DM compared with subjects without diabetes. Diabetes was an independent risk factor for low HGS.     

Physiological Stratification of Patients With Angina Due to Coronary Microvascular Dysfunction

BackgroundCoronary microvascular dysfunction (CMD) is defined by diminished flow reserve. Functional and structural CMD endotypes have recently been described, with normal and elevated minimal microvascular resistance, respectively.ObjectivesThis study determined the mechanism of altered resting and maximal flow in CMD endotypes.MethodsA total of 86 patients with angina but no obstructive coronary disease underwent coronary pressure and flow measurement during rest, exercise, and adenosine-mediated hyperemia and were classified as the reference group or as patients with CMD by a coronary flow reserve threshold of 2.5; functional or structural endotypes were distinguished by a hyperemic microvascular resistance threshold of 2.5 mm Hg/cm/s. Endothelial function was assessed by forearm blood flow (FBF) response to acetylcholine, and nitric oxide synthase (NOS) activity was defined as the inverse of FBF reserve to N^G-monomethyl-L-arginine.ResultsOf the 86 patients, 46 had CMD (28 functional, 18 structural), and 40 patients formed the reference group. Resting coronary blood flow (CBF) (24.6 ± 2.0 cm/s vs. 16.6 ± 3.9 cm/s vs. 15.1 ± 4.7 cm/s; p < 0.001) and NOS activity (2.27 ± 0.96 vs. 1.77 ± 0.59 vs. 1.30 ± 0.16; p < 0.001) were higher in the functional group compared with the structural CMD and reference groups, respectively. The structural group had lower acetylcholine FBF augmentation than the functional or reference group (2.1 ± 1.8 vs. 4.1 ± 1.7 vs. 4.5 ± 2.0; p < 0.001). On exercise, oxygen demand was highest (rate−pressure product: 22,157 ± 5,497 beats/min/mm Hg vs. 19,519 ± 4,653 beats/min/mm Hg vs. 17,530 ± 4,678 beats/min/mm Hg; p = 0.004), but peak CBF was lowest in patients with structural CMD compared with the functional and reference groups.ConclusionsFunctional CMD is characterized by elevated resting flow that is linked to enhanced NOS activity. Patients with structural CMD have endothelial dysfunction, which leads to diminished peak CBF augmentation and increased demand during exercise. The value of pathophysiologically stratified therapy warrants investigation.     

Comparison of the Diastolic Stress Test With a Combined Resting Echocardiography and Biomarker Approach to Patients With Exertional Dyspnea: Diagnostic and Prognostic Implications

ObjectivesThis study sought to establish the diagnostic and prognostic value of a strategy for prediction of abnormal diastolic response to exercise (AbnDR) using clinical, biochemical, and resting echocardiographic markers in dyspneic patients with mild diastolic dysfunction.BackgroundAn AbnDR (increase in left ventricular filling pressure) may indicate heart failure with preserved ejection fraction as the cause of symptoms in dyspneic patients, despite a nonelevated noncardiac at rest. However, exercise testing may be inconclusive in patients with noncardiac limitations to physical activity.MethodsIn 171 dyspneic patients (64 ± 8 years) with suspected heart failure with preserved ejection fraction but resting peak early diastolic mitral inflow velocity/peak early diastolic mitral annular velocity ratio (E/e′) <14, a complete echocardiogram (including assessment of myocardial deformation and rotational mechanics) and blood assays for biomarkers were performed. Echocardiography following maximal exercise was undertaken to assess AbnDR (exertional E/e′ >14). Patients were followed over 26.2 ± 4.6 months for endpoints of cardiovascular hospitalization and death.ResultsAbnDR was present in 103 subjects (60%). Independent correlates of AbnDR were resting E/e′ (odds ratio [OR]: 8.23; 95% confidence interval [CI]: 3.54 to 9.16; p < 0.001), left ventricular untwisting rate (OR: 0.60; 95% CI: 0.42 to 0.86; p = 0.006), and galectin-3—a marker of fibrosis (OR: 1.80; 95% CI: 1.21 to 2.67; p = 0.004). The use of resting E/e′ >11.3 and galectin-3 <1.17 ng/ml to select patients for further diagnostic processing would have allowed exercise testing to be avoided in 65% of subjects, at the cost of misclassification of 13%. The composite outcome of cardiovascular hospitalization or death occurred in 47 patients (27.5%). The predictive value of an AbnDR response and the combined strategy (resting echocardiography and galectin-3 or exercise testing in case of an inconclusive first step) showed similar event prediction (36 vs. 34; p = 0.95).ConclusionsThe implementation of a 2-step algorithm (echocardiographic evaluation of resting E/e′ followed by the assessment of galectin-3) may improve the diagnosis and prognostic assessment of individuals with suspected heart failure with preserved ejection fraction who are unable to perform a diagnostic exercise test.     

Pericardial Fat and the Risk of Heart Failure

BackgroundObesity is a well-established risk factor for heart failure (HF). However, implications of pericardial fat on incident HF is unclear.ObjectivesThis study sought to examine the association between pericardial fat volume (PFV) and newly diagnosed HF.MethodsThis study ascertained PFV using cardiac computed tomography in 6,785 participants (3,584 women and 3,201 men) without pre-existing cardiovascular disease from the MESA (Multi-Ethnic Study of Atherosclerosis). Cox proportional hazards regression was used to evaluate PFV as continuous and dichotomous variable, maximizing the J-statistic: (Sensitivity + Specificity – 1).ResultsIn 90,686 person-years (median: 15.7 years; interquartile range: 11.7 to 16.5 years), 385 participants (5.7%; 164 women and 221 men) developed newly diagnosed HF. PFV was lower in women than in men (69 ± 33 cm³ vs. 92 ± 47 cm³; p < 0.001). In multivariable analyses, every 1-SD (42 cm³) increase in PFV was associated with a higher risk of HF in women (hazard ratio [HR]: 1.44; 95% confidence interval [CI]: 1.21 to 1.71; p < 0.001) than in men (HR: 1.13; 95% CI: 1.01 to 1.27; p = 0.03) (interaction p = 0.01). High PFV (≥70 cm³ in women; ≥120 cm³ in men) conferred a 2-fold greater risk of HF in women (HR: 2.06; 95% CI: 1.48 to 2.87; p < 0.001) and a 53% higher risk in men (HR: 1.53; 95% CI: 1.13 to 2.07; p = 0.006). In sex-stratified analyses, greater risk of HF remained robust with additional adjustment for anthropometric indicators of obesity (p ≤ 0.008), abdominal subcutaneous or visceral fat (p ≤ 0.03) or biomarkers of inflammation and hemodynamic stress (p < 0.001) and was similar among Whites, Blacks, Hispanics, and Chinese (interaction p = 0.24). Elevated PFV predominantly augmented the risk of HF with preserved ejection fraction (p < 0.001) rather than reduced ejection fraction (p = 0.31).ConclusionsIn this large, community-based, ethnically diverse, prospective cohort study, pericardial fat was associated with an increased risk of HF, particularly HF with preserved ejection fraction, in women and men.     

Sex Differences in Exercise Capacity and Quality of Life in Heart Failure With Preserved Ejection Fraction: A Secondary Analysis of the RELAX and NEAT-HFpEF Trials

BackgroundFew studies have compared clinical characteristics, echocardiographic parameters, exercise capacity, and quality of life between women and men with heart failure with preserved ejection fraction (HFpEF).Methods and ResultsSubjects in the NIH-sponsored RELAX (N = 216) and NEAT (N = 107) trials completed baseline echocardiography, the Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-minute walk test (6MWT). In an exploratory analysis, multivariable linear regression models were used to associate clinical and imaging characteristics with baseline 6MWT distance and MLHFQ score in women and men. Our cohort included 158 (49%) men and 165 (51%) women. Men had higher prevalence of atrial arrhythmias, ischemic heart disease, diabetes, anemia, and left ventricular (LV) hypertrophy. 6MWT and MLHFQ score did not differ between sexes. In multivariable analysis, ischemic heart disease, diastolic dysfunction, and exercise capacity predicted MLHFQ score for men, whereas only age and body mass index predicted MLHFQ score for women.ConclusionsMen with HFpEF had more comorbidities and LV hypertrophy than women with HFpEF. In men, quality of life was associated with diastolic dysfunction, ischemic heart disease, and exercise capacity. Further research is needed to identify determinants of quality of life in women with HFpEF.     

The impact of obesity and dyslipidemia on Remdesivir effectiveness in hospitalized patients with SARS-CoV-2-related pneumonia: An observational study

Background and aimsRemdesivir (GS-5734), an inhibitor of the viral RNA-dependent, RNA polymerase was early identified as a promising therapeutic candidate against COVID-19. Our aim was to evaluate the impact of several metabolic parameters on Remdesivir effectiveness among hospitalized COVID-19 patients.Methods and resultsWe conducted an observational study on patients with SARS-CoV-2-related pneumonia admitted between May 2020 and September 2021 to the COVID-19 Units of Internal Medicine, Pneumology and Intensive Care of Garibaldi Hospital, Catania, Italy, and treated with Remdesivir. The “Ordinal Scale For Clinical Improvement” was used to assess patients’ clinical improvement within 28 days of hospitalization. Short-term mortality rate was also evaluated.A total of 142 patients with SARS-CoV-2-related pneumonia were studied. The prevalence of obesity (20.7% vs. 41.9%, p = 0.03), the average BMI (27.1 ± 4.4 vs. 31.1 ± 6.1, p < 0.01) and the mean LDL-C levels (78 ± 19 mg/dl vs. 103 ± 18 mg/dl, p = 0.03) were significantly lower in early-improved (EI) compared to not-improved (NI) individuals. Obesity was negatively associated to clinical improvement after Remdesivir (OR 0.48, 95%CI 0.17–0.97, p = 0.04). Both obesity (OR 2.82, 95% CI 1.05–7.71, p = 0.04) and dyslipidemia (OR 2.78, 95%CI 1.17–7.16, p = 0.03) were significantly related to patients’ mortality. Dyslipidemic subjects experienced a slower clinical improvement than non-dyslipidemic ones (Long-Rank p = 0.04).ConclusionOur study showed that unfavorable metabolic conditions such as obesity and dyslipidemia could predict a worse clinical response to Remdesivir as well as the mortality in hospitalized COVID-19 patients. Further prospective and larger-scale studies are needed to confirm these preliminary findings.     

Effect of fitness on cardiac structure and function in overweight and obesity (the FATCOR study)

Background and aimsObesity is associated with reduced left ventricular (LV) systolic myocardial function. We aimed to explore by means of a cross-sectional study whether this effect is offset in the presence of good fitness.Methods and resultsWe studied clinical and echocardiographic data from 469 overweight (body mass index [BMI] >27 kg/m²) and obese (BMI ≥30 kg/m²) women and men without known cardiovascular (CV) disease in the FAT associated CardiOvasculaR dysfunction (FATCOR) study. The participants were grouped according to obesity and sex- and age adjusted peak oxygen uptake, obtained by ergospirometry. LV systolic myocardial function was assessed by peak systolic global longitudinal strain (GLS) measured by speckle tracking echocardiography. The association of fitness with GLS was tested in logistic regression analyses and reported as odds ratio (OR) with 95% confidence interval (CI).In the total study population, participants were 47 years old, 60% were women, and mean BMI was 32.0 kg/m². GLS did not differ between fit and unfit subjects within the overweight and obese groups (both p > 0.05), but the overweight fit group had higher GLS (more negative value) compared to the obese unfit group (−20.1 ± 2.6 vs. −19.0 ± 3.0, p < 0.05). In obese subjects, fitness was associated with higher GLS (OR 0.88 [95% CI 0.79–0.99, p < 0.05) in multivariable logistic regression analysis, independent of significant associations with higher arterial stiffness and lower fat percentage (all p < 0.05). In the overweight group, fitness was not significantly associated with GLS.ConclusionIn obesity, fitness was independently associated with higher GLS, while no association was found in overweight.Clinical trial registrationURL: http://www.clinicaltrials.gov NCT02805478.     

Cardiovascular Phenotype in HFpEF Patients With or Without Diabetes : A RELAX Trial Ancillary Study

Background

The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) study was a multicenter, randomized trial of sildenafil versus placebo in heart failure with preserved ejection fraction (HFpEF) with rigorous entry criteria and extensive phenotypic characterization of participants.

Objectives

The aim of this study was to characterize clinical features, exercise capacity, and outcomes in patients with HFpEF with or without diabetes and gain insight into contributing pathophysiological mechanisms.

Methods

The RELAX study enrolled 216 stable outpatients with heart failure, an ejection fraction ≥50%, increased natriuretic peptide or intracardiac pressures, and reduced exercise capacity. Prospectively collected data included echocardiography, cardiac magnetic resonance, a comprehensive biomarker panel, exercise testing, and clinical events over 6 months.

Results

Compared with nondiabetic patients (n = 123), diabetic HFpEF patients (n = 93) were younger, more obese, and more often male and had a higher prevalence of hypertension, renal dysfunction, pulmonary disease, and vascular disease (p < 0.05 for all). Uric acid, C-reactive protein, galectin-3, carboxy-terminal telopeptide of collagen type I, and endothelin-1 levels were higher in diabetic patients (p < 0.05 for all). Diabetic patients had more ventricular hypertrophy, but systolic and diastolic ventricular function parameters were similar in diabetic and nondiabetic patients except for a trend toward higher filling pressures (E/e′) in diabetic patients. Diabetic patients had worse maximal (peak oxygen uptake) and submaximal (6-min walk distance) exercise capacity (p < 0.01 for both). Diabetic patients were more likely to have been hospitalized for heart failure in the year before study entry (47% vs. 28%, p = 0.004) and had a higher incidence of cardiac or renal hospitalization at 6 months after enrollment (23.7% vs. 4.9%, p < 0.001).

Conclusions

HFpEF patients with diabetes are at increased risk of hospitalization and have reduced exercise capacity. Multimorbidity, impaired chronotropic reserve, left ventricular hypertrophy, and activation of inflammatory, pro-oxidative, vasoconstrictor, and profibrotic pathways may contribute to adverse outcomes in HFpEF patients with diabetes. (Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure [The RELAX Study]; NCT00763867)     

Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction

BackgroundLarge clinical trials established the benefits of sodium-glucose cotransporter 2 inhibitors in patients with diabetes and with heart failure with reduced ejection fraction (HFrEF). The early and significant improvement in clinical outcomes is likely explained by effects beyond a reduction in hyperglycemia.ObjectivesThe purpose of this study was to assess the effect of empagliflozin on left ventricular (LV) function and volumes, functional capacity, and quality of life (QoL) in nondiabetic HFrEF patients.MethodsIn this double-blind, placebo-controlled trial, nondiabetic HFrEF patients (n = 84) were randomized to empagliflozin 10 mg daily or placebo for 6 months. The primary endpoint was change in LV end-diastolic and -systolic volume assessed by cardiac magnetic resonance. Secondary endpoints included changes in LV mass, LV ejection fraction, peak oxygen consumption in the cardiopulmonary exercise test, 6-min walk test, and quality of life.ResultsEmpagliflozin was associated with a significant reduction of LV end-diastolic volume (?25.1 ± 26.0 ml vs. ?1.5 ± 25.4 ml for empagliflozin vs. placebo, respectively; p < 0.001) and LV end-systolic volume (?26.6 ± 20.5 ml vs. ?0.5 ± 21.9 ml for empagliflozin vs. placebo; p < 0.001). Empagliflozin was associated with reductions in LV mass (?17.8 ± 31.9 g vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively; p < 0.001) and LV sphericity, and improvements in LV ejection fraction (6.0 ± 4.2 vs. ?0.1 ± 3.9; p < 0.001). Patients who received empagliflozin had significant improvements in peak O₂ consumption (1.1 ± 2.6 ml/min/kg vs. ?0.5 ± 1.9 ml/min/kg for empagliflozin vs. placebo, respectively; p = 0.017), oxygen uptake efficiency slope (111 ± 267 vs. ?145 ± 318; p < 0.001), as well as in 6-min walk test (81 ± 64 m vs. ?35 ± 68 m; p < 0.001) and quality of life (Kansas City Cardiomyopathy Questionnaire-12: 21 ± 18 vs. 2 ± 15; p < 0.001).ConclusionsEmpagliflozin administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality of life when compared with placebo. Our observations strongly support a role for sodium-glucose cotransporter 2 inhibitors in the treatment of HFrEF patients independently of their glycemic status. (Are the “Cardiac Benefits” of Empagliflozin Independent of Its Hypoglycemic Activity? [ATRU-4] [EMPA-TROPISM]; NCT03485222)     

Sex-Related Outcomes in Elderly Patients Presenting With Non–ST-Segment Elevation Acute Coronary Syndrome: Insights From the Italian Elderly ACS Study

ObjectivesThis study sought to investigate sex-related differences in treatment and outcomes in elderly patients with non–ST-segment elevation acute coronary syndromes (NSTEACS).BackgroundFemale sex and older age are usually associated with worse outcome in NSTEACS. The Italian Elderly ACS study enrolled NSTEACS patients aged 75 years of age and older in a randomized trial comparing an early aggressive with an initially conservative strategy and in a registry of patients with ≥1 exclusion criteria of the trial.MethodsWe compared sexes in the pooled populations of the trial and registry.ResultsA total of 645 patients (313 from the trial and 332 from the registry), including 301 women (47%), were enrolled. Women were slightly older than men (82.1 ± 5.0 years vs. 81.2 ± 4.5 years; p = 0.02), had lower hemoglobin levels (12.5 ± 1.6 g/dl vs. 13.3 ± 1.9 g/dl; p < 0.001), and underwent fewer coronary revascularizations during the index admission (37.2% vs. 45.0%; p = 0.04). In-hospital adverse event rates were similar in both sexes; severe bleeding was uncommon (0.3% vs. 0%). The 1-year primary endpoint (composite of death, nonfatal myocardial infarction, disabling stroke, cardiac rehospitalization, and severe bleeding) occurred less often in women (27.6% vs. 38.7%; p < 0.01). Women not undergoing revascularization showed a 3-fold higher mortality, both in-hospital (8.5% vs. 2.7%; p = 0.05) and at 1 year (21.6% vs. 8.1%; p = 0.002).ConclusionsElderly women had a similar in-hospital outcome and better 1-year outcome compared with men. Coronary revascularization in women was associated with lower 1-year mortality, without an increase in severe bleeding. Elderly women with NSTEACS should always be considered for early revascularization.