Microvascular Dysfunction in Dilated Cardiomyopathy: A Quantitative Stress Perfusion Cardiovascular Magnetic Resonance Study

ObjectivesThis study sought to quantify myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) in dilated cardiomyopathy (DCM) and examine the relationship between myocardial perfusion and adverse left ventricular (LV) remodeling.BackgroundAlthough regarded as a nonischemic condition, DCM has been associated with microvascular dysfunction, which is postulated to play a role in its pathogenesis. However, the relationship of the resulting perfusion abnormalities to myocardial fibrosis and the degree of LV remodeling is unclear.MethodsA total of 65 patients and 35 healthy control subjects underwent adenosine (140 μg/kg/min) stress perfusion cardiovascular magnetic resonance with late gadolinium enhancement imaging. Stress and rest MBF and MPR were derived using a modified Fermi-constrained deconvolution algorithm.ResultsPatients had significantly higher global rest MBF compared with control subjects (1.73 ± 0.42 ml/g/min vs. 1.14 ± 0.42 ml/g/min; p < 0.001). In contrast, global stress MBF was significantly lower versus control subjects (3.07 ± 1.02 ml/g/min vs. 3.53 ± 0.79 ml/g/min; p = 0.02), resulting in impaired MPR in the DCM group (1.83 ± 0.58 vs. 3.50 ± 1.45; p < 0.001). Global stress MBF (2.70 ± 0.89 ml/g/min vs. 3.44 ± 1.03 ml/g/min; p = 0.017) and global MPR (1.67 ± 0.61 vs. 1.99 ± 0.50; p = 0.047) were significantly reduced in patients with DCM with LV ejection fraction ≤35% compared with those with LV ejection fraction >35%. Segments with fibrosis had lower rest MBF (mean difference: −0.12 ml/g/min; 95% confidence interval: −0.23 to −0.01 ml/g/min; p = 0.035) and lower stress MBF (mean difference: −0.15 ml/g/min; 95% confidence interval: −0.28 to −0.03 ml/g/min; p = 0.013).ConclusionsPatients with DCM exhibit microvascular dysfunction, the severity of which is associated with the degree of LV impairment. However, rest MBF is elevated rather than reduced in DCM. If microvascular dysfunction contributes to the pathogenesis of DCM, then the underlying mechanism is more likely to involve stress-induced repetitive stunning rather than chronic myocardial hypoperfusion.     

Left Ventricular Remodeling After Transcatheter Versus Surgical Therapy in Adults With Coarctation of Aorta

ObjectivesThe purpose of this retrospective cohort study was to compare remodeling of left ventricular (LV) structure and function after transcatheter stent therapy with remodeling of LV structure and function after surgical therapy for COA.BackgroundTranscatheter stent therapy is as effective as surgery in producing acute hemodynamic improvement in patients with coarctation of aorta (COA). However, LV remodeling after transcatheter COA intervention has not been systematically investigated.MethodsLV remodeling was assessed at 1, 3, and 5 years post-intervention by using LV mass index (LVMI), LV end-diastolic dimension, LV ejection fraction, LV global longitudinal strain (LVGLS), LV mitral annular tissue Doppler early velocity (LVe′), and ratio of mitral inflow pulsed wave Doppler early velocity and e′ (E/e′) ratio.ResultsThere were 44 patients in the transcatheter group and 128 patients in the surgical group. Compared to the surgical group, the transcatheter group had less regression of LVMI (−4.6; 95% confidence interval [CI]: −5.5 to −3.7 vs. −7.3; 95% CI: −8.4 to −6.6 g/m²; p < 0.001), less improvement in LVGLS (2.1; 95% CI: 1.8 to 2.4 vs. 2.9; 95% CI: 2.6 to 3.2%; p = 0.024), and in e′ (1.0 ; 95% CI: 0.7 to 1.2 vs. 1.5 ; 95% CI: 1.3 to 1.7 cm/s; p = 0.009) at 5 years post-intervention. Exploratory analysis showed a correlation between change in LVMI and LVGLS, and between change in LVMI and mitral annular tissue Doppler early velocity (e′), and this correlations were independent of the type of intervention received.ConclusionsTranscatheter stent therapy was associated with less remodeling of LV structure and function during mid-term follow-up. As transcatheter stent therapy becomes more widely used in the adult COA population, there is a need for ongoing clinical monitoring to determine if these observed differences in LV remodeling translate to differences in clinical outcomes.     

Biventricular Physiology of Iatrogenic Atrial Septal Defects Following Transcatheter Mitral Valve Edge-to-Edge Repair

ObjectivesThe study sought to assess the acute hemodynamic effects of iatrogenic atrial septal defect (iASD) closure following transcatheter mitral valve edge-to-edge repair (TMVR).BackgroundThe potential hemodynamic and clinical consequences of an iASD following TMVR are currently subject to controversial debates.MethodsIn 21 patients with relevant left-to-right shunt flow (50% [IQR: 38% to 60%] of systemic perfusion volume) across an iASD following TMVR, interventional closure was performed with recordings of left ventricular (LV) and right ventricular (RV) pressure-volume loops during iASD occlusion.ResultsiASD occlusion led to a volume shift from the RV (RV end-diastolic volume index: pre 102 [IQR: 80 to 120] ml/m², post 92 [IQR: 70 to 111] ml/m²; p < 0.001) to the LV (LV end-diastolic volume index: pre 91 [IQR: 74 to 124] ml/m², post 97 [IQR: 77 to 127] ml/m²; p < 0.001) with reduced RV (3.49 [IQR: 2.07 to 3.58] l/min/m² vs. 2.68 [IQR: 2.07 to 3.58] l/min/m²; p < 0.001) but increased LV cardiac index (2.25 [IQR: 1.80 to 3.28] l/min/m² vs. 2.77 [IQR: 1.90 to 3.34] l/min/m²; p = 0.039). Although RV end-diastolic pressure decreased (pre 5.0 [IQR: 4.0 to 8.5] mm Hg, post 4.5 [IQR: 3.0 to 8.3] mm Hg; p = 0.024), LV end-diastolic pressure remained unchanged (pre 11.0 [IQR: 9.5 to 14.0] mm Hg, post 13.0 [IQR: 9.0 to 15.5] mm Hg; p = 0.142). LV transmural pressure increased (7.0 [IQR: 4.0 to 11.0] mm Hg vs. 11.0 [IQR: 7.0 to 15.0] mm Hg; p = 0.001) and LV eccentricity index decreased (p < 0.001). The change in LV transmural pressure correlated significantly with the change in LV-to-RV end-diastolic volume ratio (r = 0.674; p = 0.018). Right heart failure symptoms declined at 1-month follow-up (71% vs. 35%; p = 0.003) as did New York Heart Association functional class (≥III: 48% vs. 25%; p < 0.001).ConclusionsiASD closure following TMVR leads to a volume shift from the RV to the LV with reduced pulmonary but increased systemic cardiac index and with favorable biventricular interaction at maintained LV filling pressure, resulting in a decline in heart failure symptoms at 1-month follow-up.     

Ticagrelor Monotherapy Versus Ticagrelor With Aspirin in Patients With ST-Segment Elevation Myocardial Infarction

ObjectivesThe aim of this study was to assess whether the effects of ticagrelor monotherapy after 3-month dual-antiplatelet therapy (DAPT) are consistent among patients presenting with ST-segment elevation myocardial infarction (STEMI), non–ST-segment elevation myocardial infarction, and unstable angina treated with drug-eluting stents.BackgroundTicagrelor monotherapy after short-term DAPT has not been investigated in patients with STEMI.MethodsThis was a pre-specified, stratified, subgroup analysis of the STEMI cohort from the TICO (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome) trial, which constituted 36% of the total population. The primary outcome was a composite of major bleeding and major adverse cardiac and cerebrovascular events (MACCE; death, myocardial infarction, stent thrombosis, stroke, or target vessel revascularization). The secondary outcomes were major bleeding and MACCE.ResultsThe incidence of the primary outcome was 4.4% in patients with STEMI (n = 1,103), 6.0% in those with non–ST-segment elevation myocardial infarction (n = 1,027), and 4.1% in those with unstable angina (n = 926), without statistical significance (p = 0.09). Compared with ticagrelor-based 12-month DAPT, ticagrelor monotherapy after 3-month DAPT showed consistent effects on the primary outcome across clinical presentations (p for interaction [p_int] = 0.64). Furthermore, the effect of ticagrelor monotherapy on the reduction of major bleeding was consistent across clinical presentations (p_int = 0.36). The effect of ticagrelor monotherapy on MACCE was also consistent in patients with STEMI, without evidence of a higher risk for MACCE (p_int = 0.14).ConclusionsThis pre-specified subgroup analysis revealed no heterogeneity in the effects of ticagrelor monotherapy after 3-month DAPT, compared with 12-month DAPT, for the primary outcome, major bleeding, and MACCE across clinical presentations including STEMI, though larger studies are needed to demonstrate these findings with adequate power. (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome [TICO Study]; NCT02494895)     

Diabetic Cardiomiopathy Progression is Triggered by miR122-5p and Involves Extracellular Matrix: A 5-Year Prospective Study

ObjectivesThe purpose of this study was to follow the long-term progression of diabetic cardiomyopathy by combining cardiac magnetic resonance (CMR) and molecular analysis.BackgroundThe evolution of diabetic cardiomyopathy to heart failure affects patients’morbidity and mortality. CMR is the gold standard to assess cardiac remodeling, but there is a lack of markers linked to the mechanism of diabetic cardiomyopathy progression.MethodsFive-year longitudinal study on patients with type 2 diabetes mellitus (T2DM) enrolled in the CECSID (Cardiovascular Effects of Chronic Sildenafil in Men With Type 2 Diabetes) trial compared with nondiabetic age-matched controls. CMR with tagging together with metabolic and molecular assessments were performed at baseline and 5-year follow-up.ResultsA total of 79 men (age 64 ± 8 years) enrolled, comprising 59 men with T2DM compared with 20 nondiabetic age-matched controls. Longitudinal CMR with tagging showed an increase in ventricular mass (ΔLVMi = 13.47 ± 29.66 g/m²; p = 0.014) and a borderline increase in end-diastolic volume (ΔEDVi = 5.16 ± 14.71 ml/m²; p = 0.056) in men with T2DM. Cardiac strain worsened (Δσ = 1.52 ± 3.85%; p = 0.033) whereas torsion was unchanged (Δθ = 0.24 ± 4.04°; p = 0.737), revealing a loss of the adaptive equilibrium between strain and torsion. Contraction dynamics showed a decrease in the systolic time-to-peak (ΔTtP = ?35.18 ± 28.81 ms; p < 0.001) and diastolic early recoil-rate (ΔRR = ?20.01 ± 19.07 s^-1; p < 0.001). The ejection fraction and metabolic parameters were unchanged. Circulating miR microarray revealed an up-regulation of miR122-5p. Network analysis predicted the matrix metalloproteinases (MMPs) MMP-16 and MMP-2 and their regulator (tissue inhibitors of metalloproteinases) as targets. In db/db mice we demonstrated that miR122-5p expression is associated with diabetic cardiomyopathy, that in the diabetic heart is overexpressed, and that, in vitro, it regulates MMP-2. Finally, we demonstrated that miR122-5p overexpression affects the extracellular matrix through MMP-2 modulation.ConclusionsWithin 5 years of diabetic cardiomyopathy onset, increasing cardiac hypertrophy is associated with progressive impairment in strain, depletion of the compensatory role of torsion, and changes in viscoelastic contraction dynamics. These changes are independent of glycemic control and paralleled by the up-regulation of specific microRNAs targeting the extracellular matrix. (Cardiovascular Effects of Chronic Sildenafil in Men With Type 2 Diabetes [CECSID]; NCT00692237)     

Left Ventricular Remodeling After Transcatheter Mitral Valve Replacement With Tendyne: New Insights From Computed Tomography

ObjectivesThe aim of this study was to describe the anatomic and functional changes in left-sided chambers using computed tomographic angiography (CTA) from baseline to 1 month after transcatheter mitral valve replacement (TMVR) with the Tendyne prosthesis.BackgroundData on changes in left atrial and left ventricular (LV) volumes after TMVR implantation are very limited.MethodsPatients who underwent TMVR with the Tendyne prosthesis between 2015 and 2018 were analyzed. Changes in LV end-diastolic volume, ejection fraction, LV mass, left atrial volume, and global longitudinal strain were assessed at baseline and 1 month after TMVR using CTA. Specific Tendyne implant characteristics were identified and correlated with remodeling changes.ResultsA total of 36 patients (median age 74 years; interquartile range [IQR]: 69 to 78 years; 78% men; 86% with secondary mitral regurgitation) were included in this study. There were significant decreases in LV end-diastolic volume (281 ml [IQR: 210 to 317 ml] vs. 239 ml [IQR: 195 to 291 ml]; p < 0.001), LV ejection fraction (37% [IQR: 31% to 48%] vs. 30% [IQR: 23% to 40%]; p < 0.001), LV mass (126 g [IQR: 96 to 155 g] vs. 116 g [IQR: 92 to 140 g]; p < 0.001), left atrial volume (171 ml [IQR: 133 to 216 ml] vs. 159 ml [IQR: 125 to 201 ml]; p = 0.027), and global longitudinal strain (−11% [IQR: −17% to −8%] vs. −9% [IQR: −12% to −6%]; p < 0.001) from baseline to 1-month follow-up. Favorable LV end-diastolic volume reverse remodeling occurred in the majority (30 of 36 patients [83%]). Closer proximity of the Tendyne apical pad to the true apex (24 mm [IQR: 21 to 29 mm] vs. 35 mm [IQR: 26 to 40 mm]) was predictive of favorable remodeling (p = 0.037).ConclusionsTMVR with Tendyne results in favorable left-sided chamber remodeling in the majority of patients treated, as detected on CTA at 1 month after implantation. CTA identifies favorable post-TMVR changes, which could be related to specific characteristics of the device implantation.     

Empagliflozin Reduces Myocardial Extracellular Volume in Patients With Type 2 Diabetes and Coronary Artery Disease

ObjectivesThis study sought to evaluate the effects of empagliflozin on extracellular volume (ECV) in individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD).BackgroundEmpagliflozin has been shown to reduce left ventricular mass index (LVMi) in patients with T2DM and CAD. The effects on myocardial ECV are unknown.MethodsThis was a prespecified substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes) CardioLink-6 trial in which 97 participants were randomized to receive empagliflozin 10 mg daily or placebo for 6 months. Data from 74 participants were included: 39 from the empagliflozin group and 35 from the placebo group. The main outcome was change in left ventricular ECV from baseline to 6 months determined by cardiac magnetic resonance (CMR). Other outcomes included change in LVMi, indexed intracellular compartment volume (iICV) and indexed extracellular compartment volume (iECV), and the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase (MMP)-2.ResultsBaseline ECV was elevated in the empagliflozin group (29.6 ± 4.6%) and placebo group (30.6 ± 4.8%). Six months of empagliflozin therapy reduced ECV compared with placebo (adjusted difference: –1.40%; 95% confidence interval [CI]: –2.60 to –0.14%; p = 0.03). Empagliflozin therapy reduced iECV (adjusted difference: –1.5 ml/m²; 95% CI: –2.6 to –0.5 ml/m²; p = 0.006), with a trend toward reduction in iICV (adjusted difference: –1.7 ml/m²; 95% CI: –3.8 to 0.3 ml/m²; p = 0.09). Empagliflozin had no impact on MMP-2 or sST2.ConclusionsIn individuals with T2DM and CAD, 6 months of empagliflozin reduced ECV, iECV, and LVMi. No changes in MMP-2 and sST2 were seen. Further investigation into the mechanisms by which empagliflozin causes reverse remodeling is required. (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes [EMPA-HEART]; NCT02998970)     

Left Ventricular Structural and Functional Alterations in Patients With Pheochromocytoma/Paraganglioma Before and After Surgery

ObjectivesThis study sought to evaluate left ventricular (LV) structure and function in pheochromocytoma and paraganglioma (PPGL) patients before and after curative surgery.BackgroundData on catecholamine-induced effects on LV structure and function in patients with PPGL are limited and conflicting.MethodsThe study evaluated 81 consecutive patients with a PPGL, among whom 66 were evaluated 12 months after tumor removal. Fifty patients matched for age, sex, hypertension presence, and blood pressure (BP) levels served as a control group (non-PPGL group). Echocardiography was employed to assess the LV mass index (LVMI), systolic function including speckle tracking echocardiography, and diastolic function.ResultsPatients with PPGL were characterized by higher LVMI (median 103 [interquartile range (IQR): 88 to 132] g/m² vs. median 94 [IQR: 74 to 106] g/m²; p = 0.006) and frequency of LV hypertrophy (44.4% vs. 24.0%; p = 0.018) compared with the non-PPGL group. Patients with PPGLs were characterized by lower global longitudinal strain (GLS) and early diastolic mitral annular velocity compared with patients in the non-PPGL group (median –17.2% [IQR: 15.6% to 18.9%] vs. median –19.3% [IQR: 17.7% to 20.6%]; p < 0.001; and median 11.1 [IQR: 8.3 to 13.0] cm/s vs. median 12.3 [IQR: 10.6 to 14.6] cm/s; p = 0.018, respectively). Presence of LV hypertrophy and GLS were independently associated with plasma free metanephrine concentrations. In operated patients, there were lower frequencies of LV hypertrophy (39.4% vs. 22.7%; p = 0.003), LVMI (median 98 [IQR: 85 to 115] g/m² vs. median 90 [IQR: 76 to 109] g/m²; p < 0.001), and the ratio of transmitral early diastolic velocity to early diastolic mitral annular velocity (median 6.8 [IQR: 5.5 to 8.6] vs. median 6.0 [IQR: 5.0 to 7.6]; p = 0.005) but higher values for GLS (median –17.4 [IQR: –15.8 to 19.1] vs. median −18.5 [IQR: –17.1 to 20.1] p < 0.001) after compared with before surgery.ConclusionsCatecholamine excess in patients with PPGLs can lead not only to LV hypertrophy, but also to impairment of systolic LV function and subclinical alterations of diastolic LV function, independently of BP levels. These structural and functional changes are reversible after surgical intervention.     

Ticagrelor With or Without Aspirin After PCI: The TWILIGHT Platelet Substudy

BackgroundAn evolving strategy in the setting of percutaneous coronary intervention (PCI) involves withdrawal of acetylsalicylic acid (ASA), or aspirin, while maintaining P2Y₁₂ inhibition. However, the pharmacodynamic effects of this approach on blood thrombogenicity and platelet reactivity remain unknown.ObjectivesThis study sought to compare the antithrombotic potency of ticagrelor alone versus ticagrelor plus ASA among high-risk patients undergoing PCI with drug-eluting stents.MethodsThis was a mechanistic substudy within the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, which randomized patients undergoing PCI to ticagrelor plus placebo versus ticagrelor plus ASA following 3 months of dual antiplatelet therapy. Substudy participants were enrolled after randomization, at which time ex vivo assays to quantify thrombus size under dynamic flow conditions and platelet reactivity were performed. Pharmacodynamic assessments were repeated 1 to 6 months thereafter. The primary endpoint was thrombus size at the post-randomization visit with platelet reactivity following stimuli to arachidonic acid, collagen, adenosine diphosphate, and thrombin as secondary endpoints. Results were analyzed using analysis of covariance.ResultsA total of 51 patients were enrolled, among whom 42 underwent perfusion assays at baseline and follow-up with a median time between studies of 1.5 months. The adjusted mean difference in post-randomization thrombus area was similar between groups: −218.2 μm² (95% confidence interval [CI]: −575.9 to 139.9 μm²; p = 0.22). Markers sensitive to cyclo-oxygenase-1 blockade, including platelet reactivity in response to arachidonic acid (mean difference: 10.9 U; 95% CI: 1.9 to 19.9 U) and collagen (mean difference: 9.8 U; 95% CI: 0.8 to 18.8 U) stimuli were higher among patients receiving placebo, whereas levels of platelet reactivity were similar with adenosine diphosphate and thrombin.ConclusionsAmong high-risk patients receiving drug-eluting stents, the antithrombotic potency of ticagrelor monotherapy is similar to that of ticagrelor plus ASA with respect to ex vivo blood thrombogenicity, whereas markers sensitive to cyclo-oxygenase-1 blockade are increased in the absence of ASA. (Platelet Substudy of the TWILIGHT Trial; NCT04001374).     

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)     

Attenuated Mitral Leaflet Enlargement Contributes to Functional Mitral Regurgitation After Myocardial Infarction

BackgroundMitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves.ObjectivesThis study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves.MethodsSheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves.ResultsBoth experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm² vs. 15.1 ± 1.6 cm², p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group.ConclusionsIn these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI.     

Aldosterone-Related Myocardial Extracellular Matrix Expansion in Hypertension in Humans: A Proof-of-Concept Study by Cardiac Magnetic Resonance

ObjectivesThis study sought to assess the respective effects of aldosterone and blood pressure (BP) levels on myocardial fibrosis in humans.BackgroundExperimentally, aldosterone promotes left ventricular (LV) hypertrophy, and interstitial myocardial fibrosis in the presence of high salt intake.MethodsThe study included 20 patients with primary aldosteronism (PA) (high aldosterone and high BP), 20 patients with essential hypertension (HTN) (average aldosterone and high BP), 20 patients with secondary aldosteronism due to Bartter/Gitelman (BG) syndrome (high aldosterone and normal BP), and 20 healthy subjects (HS) (normal aldosterone and normal BP). Participants in each group were of similar age and sex distributions, and asymptomatic. Cardiac magnetic resonance including cine and T1 mapping was performed blind to the study group to quantify global LV mass index, as well as intracellular mass index and extracellular mass index considered as a measure of myocardial fibrosis in vivo.ResultsMedian plasma aldosterone concentration was as follows: PA = 709 pmol/l (interquartile range [IQR]: 430 to 918 pmol/l); HTN = 197 pmol/l (IQR: 121 to 345 pmol/l); BG = 297 pmol/l (IQR: 180 to 428 pmol/l); and HS = 105 pmol/l (IQR: 85 to 227 pmol/l). Systolic BP was as follows: PA = 147 ± 15 mm Hg; HTN = 133 ± 19 mm Hg; BG = 116 ± 9 mm Hg; and HS = 117 ± 12 mm Hg. LV end-diastolic volume showed underloading in BG and overloading in patients with PA (63 ± 13 ml/m² vs. 82 ± 15 ml/m²; p < 0.0001). Intracellular mass index increased with BP across groups (BG: 36 [IQR: 29 to 41]; HS: 40 [IQR: 36 to 46]; HTN: 51 [IQR: 42 to 54]; PA: 50 [IQR: 46 to 67]; p < 0.0001). Extracellular mass index was similar in BG, HS, and HTN (16 [IQR: 12 to 20]; 15 [IQR: 11 to 18]; and 14 [IQR: 12 to 17], respectively) but 30% higher in PA (21 [IQR: 18 to 29]; p < 0.0001) remaining significant after adjustment for mean BP.ConclusionsOnly primary pathological aldosterone excess combined with high BP increased both extracellular myocardial matrix and intracellular mass. Secondary aldosterone excess with normal BP did not affect extracellular myocardial matrix. (Study of Myocardial Interstitial Fibrosis in Hyperaldosteronism; NCT02938910).     

Insufficient Mitral Leaflet Remodeling in Relation to Annular Dilation and Risk of Residual Mitral Regurgitation After MitraClip Implantation

ObjectivesThe purpose of this study was to determine whether the mitral valve (MV) total leaflet area (TLA)-to-mitral annular area (MAA) (TLA/MAA) ratio measured using 3-dimensional (3D) transesophageal echocardiography (TEE) was associated with residual mitral regurgitation (MR) after MitraClip implantation in patients with secondary MR.BackgroundThe factors influencing the results of MitraClip implantation for secondary MR are controversial. This study hypothesized that insufficient remodeling of the mitral leaflets relative to the annular dilation may be associated with significant MR after MitraClip implantation.MethodsThis study included patients with secondary MR treated with MitraClips. Using 3D TEE dataset, the TLA in diastole and MAA in systole were measured with dedicated software.ResultsIn a total cohort of 119 patients (mean age 74 ± 9 years; 61% male), significant residual MR (≥2+) was present in 43 patients (36%). In patients with significant residual MR, MAA was greater than in patients without residual MR (10.7 ± 2.4 cm² vs. 9.0 ± 2.1 cm²; p < 0.001) whereas no significant difference was observed in TLA (12.2 ± 2.6 cm² vs. 12.0 ± 2.9 cm²; p = 0.836). TLA/MAA ratio was lower in patients with significant residual MR as compared to their counterparts (1.14 ± 0.15 vs. 1.34 ± 0.16; p < 0.001), suggesting insufficient leaflet remodeling relative to annular dilation. On receiver-operating characteristic curve analysis, the TLA/MAA ratio had better discriminative power to identify patients who will have significant residual MR compared to MAA alone (area under the curve [AUC]: 0.830 vs. 0.723; p = 0.049).ConclusionsIn patients with secondary MR, insufficient mitral leaflet remodeling relative to the annulus dilation, as reflected by a lower TLA/MAA ratio, is associated with significant residual MR after MitraClip implantation.     

Ticagrelor With or Without Aspirin in High-Risk Patients With Diabetes Mellitus Undergoing Percutaneous Coronary Intervention

BackgroundP2Y₁₂ inhibitor monotherapy with ticagrelor after a brief period of dual antiplatelet therapy can reduce bleeding without increasing ischemic harm after percutaneous coronary intervention (PCI). The impact of this approach among patients with diabetes mellitus (DM) remains unknown.ObjectivesThe purpose of this study was to examine the effect of ticagrelor monotherapy versus ticagrelor plus aspirin among patients with DM undergoing PCI.MethodsThis was a pre-specified analysis of the DM cohort in the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial. After 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The primary endpoint was Bleeding Academic Research Consortium 2, 3, or 5 bleeding. The composite ischemic endpoint was all-cause death, myocardial infarction, or stroke.ResultsPatients with DM comprised 37% (n = 2,620) of the randomized cohort and were characterized by more frequent comorbidities and a higher prevalence of multivessel disease. The incidence of Bleeding Academic Research Consortium 2, 3, or 5 bleeding was 4.5% and 6.7% among patients with DM randomized to ticagrelor plus placebo versus ticagrelor plus aspirin (hazard ratio: 0.65; 95% confidence interval: 0.47 to 0.91; p = 0.012). Ticagrelor monotherapy was not associated with an increase in ischemic events compared with ticagrelor plus aspirin (4.6% vs. 5.9%; hazard ratio: 0.77; 95% confidence interval: 0.55 to 1.09; p = 0.14). In the overall trial population, there was no significant interaction between DM status and treatment group for the primary bleeding or ischemic endpoints.ConclusionsCompared with ticagrelor plus aspirin, the effect of ticagrelor monotherapy in reducing the risk of clinically relevant bleeding without any increase in ischemic events was consistent among patients with or without DM undergoing PCI. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242)     

Pathophysiology of LV Remodeling Following STEMI: A Longitudinal Diffusion Tensor CMR Study

BackgroundAdverse LV remodeling post–ST-segment elevation myocardial infarction (STEMI) is associated with a poor prognosis, but the underlying mechanisms are not fully understood. Diffusion tensor (DT)-cardiac magnetic resonance (CMR) allows in vivo characterization of myocardial architecture and provides unique mechanistic insight into pathophysiologic changes following myocardial infarction.ObjectivesThis study evaluated the potential associations between DT-CMR performed soon after STEMI and long-term adverse left ventricular (LV) remodeling following STEMI.MethodsA total of 100 patients with STEMI underwent CMR at 5 days and 12 months post-reperfusion. The protocol included DT-CMR for assessing fractional anisotropy (FA), secondary eigenvector angle (E2A) and helix angle (HA), cine imaging for assessing LV volumes, and late gadolinium enhancement for calculating infarct and microvascular obstruction size. Adverse remodeling was defined as a 20% increase in LV end-diastolic volume at 12 months.ResultsA total of 32 patients experienced adverse remodeling at 12 months. Compared with patients without adverse remodeling, they had lower FA (0.23 ± 0.03 vs 0.27 ± 0.04; P < 0.001), lower E2A (37 ± 6° vs 51 ± 7°; P < 0.001), and, on HA maps, a lower proportion of myocytes with right-handed orientation (RHM) (8% ± 5% vs 17% ± 9%; P < 0.001) in their acutely infarcted myocardium. On multivariable logistic regression analysis, infarct FA (odds ratio [OR]: <0.01; P = 0.014) and E2A (OR: 0.77; P = 0.001) were independent predictors of adverse LV remodeling after adjusting for left ventricular ejection fraction (LVEF) and infarct size. There were no significant changes in infarct FA, E2A, or RHM between the 2 scans.ConclusionsExtensive cardiomyocyte disorganization (evidenced by low FA), acute loss of sheetlet angularity (evidenced by low E2A), and a greater loss of organization among cardiomyocytes with RHM, corresponding to the subendocardium, can be detected within 5 days post-STEMI. These changes persist post-injury, and low FA and E2A are independently associated with long-term adverse remodeling.     

Sex Differences in LV Remodeling and Hemodynamics in Aortic Stenosis: Sex-Specific Criteria for Severe Stenosis?

BackgroundThe current criteria for aortic stenosis (AS) severity have not incorporated sex-related differences.ObjectivesThe authors investigated sex-related serial changes in left ventricular (LV) structure/function and hemodynamics in AS.MethodsSerial echocardiograms of patients with severe AS (time 0; aortic valve area [AVA] ≤1 cm²) and ≥1 previous echocardiogram were compared between sexes.ResultsOf 927 patients (time 0: AVA 0.87 ± 0.11 cm², peak velocity 4.03 ± 0.65 m/s, mean Doppler systolic pressure gradient [MG] 40.6 ± 13.1 mm Hg), 393 (42%) were women. Women had smaller body surface area (BSA) (1.77 ± 0.22 m² vs 2.03 ± 0.20 m²; P < 0.001), lower stroke volume (SV) (81.1 ± 17.2 mL vs 88.3 ± 18.6 mL; P < 0.001), and more frequent low-gradient severe AS (n = 196 [50%] vs n = 181 [34%]; P < 0.001). Women consistently had smaller AVA, indexed AVA (AVAi), peak velocity, and MG than men. The difference in aortic valve gradient lessened when AVAi ≤0.6 cm²/m² was applied as severe AS (n = 694, women 43%, AVA 0.95 ± 0.17 cm², AVAi 0.50 ± 0.07 cm²/m²). Peak velocity (3.83 ± 0.66 m/s) and MG (36.5 ± 13.2 mm Hg) were lower based on AVAi severity criteria compared to those based on AVA. Men had a lower left ventricular ejection fraction (LVEF) (55.8% ± 14.8% vs 61.1% ± 11.7%; P < 0.001) and greater reduction in SV (?13.3 ± 19.6 mL vs ?7.4 ± 16.4 mL; P < 0.001) as AS progressed from moderate to severe. Concentric LV hypertrophy was more common and E/e? higher in women (21.2 ± 10.9 vs 18.8 ± 9.1; P < 0.001). SV, LVEF, AVA, peak velocity, and MG became precipitously worse when AVA reached 1.2 cm² in both sexes.ConclusionsSmaller BSA in women yields lower SV, resulting in lower aortic valve gradient than men. Indexed parameters by BSA are thus important in sex-related differences of aortic valve hemodynamics, but AVAi ≤0.6 cm²/m² includes individuals with moderate AS. Elevated filling pressure is more common in women. Men experience a larger reduction in SV and LVEF as AS progresses. The definition of AS severity may require different criteria between sexes.     

Progression of Myocardial Fibrosis in Hypertrophic Cardiomyopathy: A Cardiac Magnetic Resonance Study

ObjectivesThis study examined fibrosis progression in hypertrophic cardiomyopathy (HCM) patients, as well as its relationship to patient characteristics, clinical outcomes, and its effect on clinical decision making.BackgroundMyocardial fibrosis, as quantified by late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR), provides valuable prognostic information in patients with HCM.MethodsA total of 157 patients with HCM were enrolled in this study, with 2 sequential CMR scans separated by an interval of 4.7 ± 1.9 years.ResultsAt the first CMR session (CMR-1), 70% of patients had LGE compared with 85% at CMR-2 (p = 0.001). The extent of LGE extent increased between the 2 CMR procedures, from 4.0 ± 5.6% to 6.3 ± 7.4% (p < 0.0001), with an average LGE progression rate of 0.5 ± 1.0%/year. LGE mass progression was correlated with higher LGE mass and extent on CMR-1 (p = 0.0017 and p = 0.007, respectively), greater indexed left ventricular (LV) mass (p < 0.0001), greater LV maximal wall thickness (p < 0.0001), apical aneurysm at CMR-1 (p < 0.0001), and lower LV ejection fraction (EF) (p = 0.029). Patients who were more likely to have a higher rate of LGE progression presented with more severe disease at baseline, characterized by LGE extent >8% of LV mass, indexed LV mass >100 g/m², maximal wall thickness ≥20 mm, LVEF ≤60%, and apical aneurysm. There was a significant correlation between the magnitude of LGE progression and future implantation of insertable cardioverter-defibrillators (p = 0.004), EF deterioration to ≤50% (p < 0.0001), and admission for heart failure (p = 0.0006).ConclusionsMyocardial fibrosis in patients with HCM is a slowly progressive process. Progression of LGE is significantly correlated with a number of clinical outcomes such as progression to EF ≤50% and heart failure admission. Judicious use of serial CMR with LGE can provide valuable information to help patient management.     

Structural Cardiac Remodeling in Atrial Fibrillation

ObjectivesThis study sought to evaluate preablation computed tomography angiography (CTA) for atrial and epicardial features to predict atrial fibrillation (AF) recurrence after ablation.BackgroundStructural atrial remodeling is a process associated with occurrence or persistence of AF. Different anatomical imaging features have been proposed to influence atrial remodeling both negatively and positively as substrate for AF.MethodsPatients with nonvalvular AF underwent cardiac CTA before pulmonary vein isolation at 2 high-volume centers. Left atrial (LA) and right atrial volumes, LA wall thickness (LAWT), and epicardial adipose tissue volume and attenuation were evaluated. Additional subanalyses of electroanatomical maps were made. Follow-up was performed for at least 12 months, including subanalysis of repeated cardiac CTA studies. Interrater variability was assessed.ResultsOf 732 patients, 270 (36.9%) had AF recurrence after a mean of 7 months. CT analysis revealed larger indexed LA volume (47.3 mL/m² vs 43.6 mL/m²; P = 0.0001) and higher mean anterior (1.91 mm vs 1.65 mm; P < 0.0001) and posterior (1.61 mm vs 1.39 mm; P = 0.001) LAWT in patients with AF recurrence. Epicardial adipose tissue volume in patients with AF recurrence was higher (144.5 mm³ vs 128.5 mm³; P < 0.0001) and further progressed significantly in a subset of 85 patients after 2 years (+11.8 mm² vs −3.5 mm²; P = 0.041). Attenuation levels were lower, indicating a higher lipid component associated with AF recurrence (−69.1 HU vs −67.5 HU; P = 0.001). A total of 103 atrial voltage maps were highly predictive of AF recurrence and showed good discriminatory power for patients with low voltage >50% and LAWT (1.55 ± 0.5 mm vs 1.81 ± 0.6 mm; P = 0.032). Net reclassification improvement (NRI) showed a significant incremental benefit (NRI = 0.279; P < 0.0001) when adding LAWT to established risk models.ConclusionsAtrial wall thickness, epicardial fat volume, and attenuation are associated with AF recurrence in patients undergoing ablation therapy.     

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′.     

Ticagrelor Monotherapy Versus Dual-Antiplatelet Therapy After PCI: An Individual Patient-Level Meta-Analysis

ObjectivesThe aim of this study was to compare ticagrelor monotherapy with dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stents.BackgroundThe role of abbreviated DAPT followed by an oral P2Y₁₂ inhibitor after PCI remains uncertain.MethodsTwo randomized trials, including 14,628 patients undergoing PCI, comparing ticagrelor monotherapy with standard DAPT on centrally adjudicated endpoints were identified, and individual patient data were analyzed using 1-step fixed-effect models. The protocol was registered in PROSPERO (CRD42019143120). The primary outcomes were the composite of Bleeding Academic Research Consortium type 3 or 5 bleeding tested for superiority and, if met, the composite of all-cause death, myocardial infarction, or stroke at 1 year, tested for noninferiority against a margin of 1.25 on a hazard ratio (HR) scale.ResultsBleeding Academic Research Consortium type 3 or 5 bleeding occurred in fewer patients with ticagrelor than DAPT (0.9% vs. 1.7%, respectively; HR: 0.56; 95% confidence interval [CI]: 0.41 to 0.75; p < 0.001). The composite of all-cause death, myocardial infarction, or stroke occurred in 231 patients (3.2%) with ticagrelor and in 254 patients (3.5%) with DAPT (HR: 0.92; 95% CI: 0.76 to 1.10; p < 0.001 for noninferiority). Ticagrelor was associated with lower risk for all-cause (HR: 0.71; 95% CI: 0.52 to 0.96; p = 0.027) and cardiovascular (HR: 0.68; 95% CI: 0.47 to 0.99; p = 0.044) mortality. Rates of myocardial infarction (2.01% vs. 2.05%; p = 0.88), stent thrombosis (0.29% vs. 0.38%; p = 0.32), and stroke (0.47% vs. 0.36%; p = 0.30) were similar.ConclusionsTicagrelor monotherapy was associated with a lower risk for major bleeding compared with standard DAPT, without a concomitant increase in ischemic events.