MitraClip: How Do We Reconcile the Inconsistent Findings of MITRA-FR and COAPT?

PURPOSE OF REVIEW: Secondary mitral regurgitation (MR) is a common valvular disorder in patients with left ventricular (LV) dysfunction and is associated with worse morbidity and mortality. New data on percutaneous mitral valve (MV) repair suggest that targeting the valve itself may improve outcomes. Our objective is to review two recent trials (MITRA-FR and COAPT) with regard to percutaneous MV repair. We will dive into their methodology and results and propose potential explanations for their divergent outcomes. RECENT FINDINGS: MITRA-FR and COAPT studied the MitraClip plus guideline-directed medical therapy (GDMT) versus GDMT alone in patients with secondary MR. COAPT found an overwhelming benefit in reduction in HF hospitalization and mortality whereas MITRA-FR found no difference between treatment groups. Patient selection, differences in procedural outcomes, and smaller LV dimensions may explain these diametrically opposed results. Secondary MR is a common valvular disorder with complex pathophysiology. There are certain patients who will not benefit from percutaneous MV repair. The results of MITRA-FR and COAPT suggest that percutaneous MV repair may benefit carefully selected individuals with secondary MR on maximum tolerated doses of GDMT.

Association of Number of Live Births With Electrocardiographic and Cardiac Structural Changes.

Background Pregnancy is a major life event unique to women and leads to significant hemodynamic, hormonal, and metabolic changes. The purpose of this study was to use the DHS (Dallas Heart Study), a multiethnic population-based cohort study of Dallas county adults, to evaluate the association between number of live births and cardiac magnetic resonance imaging and ECG parameters later in life. Methods and Results Women were included if they had data on self-reported live births and ECG or cardiac magnetic resonance imaging measurements. The 3014 women were stratified by number of live births: 0, 1, 2, 3, 4, and ≥5. Higher number of live births was associated with larger left ventricular (LV) end-diastolic volume (ß, 1.31±0.41; P<0.01), LV end-systolic volume (ß, 0.83±0.24; P<0.01), and LV mass (ß, 1.13±0.49; P=0.02) and lower LV ejection fraction (ß, -0.004±0.0014; P<0.01). Increasing parity was associated with longer PR intervals (ß, 1.07±0.38; P<0.01). Subgroup analysis by race demonstrated that the association between number of live births and magnetic resonance imaging parameters (LV end-diastolic volume, LV end-systolic volume, and LV ejection fraction) only remained significant in Black women (P value for interaction <0.05). Conclusions Increasing number of live births was associated with electrocardiographic and cardiac structural changes in a multiethnic population. When stratified by race and ethnicity, magnetic resonance imaging structural changes only remained significant in Black participants. Whether these changes are pathologic and increase the risk of heart failure or arrhythmias in multiparous women warrants further investigation.

Soluble Fms-like tyrosine kinase-1 (sFlt-1) is associated with subclinical and clinical atherosclerotic cardiovascular disease: The Dallas Heart Study.

BACKGROUND AND AIMS: Soluble Fms-like tyrosine kinase-1 (sFlt-1) plays a role in angiogenesis, atherogenesis, and preeclampsia. The relationship of sFlt-1 with markers of subclinical atherosclerosis and future atherosclerotic cardiovascular disease (ASCVD) events in a generally healthy population is unknown. METHODS: Participants in the Dallas Heart Study with sFlt-1 measured were included (n = 3292). Abdominal aortic atherosclerosis was measured by MRI and coronary artery calcium (CAC) by CT. The cohort was also followed for subsequent ASCVD events (CV death, MI, stroke, unstable angina, revascularization). Multivariable linear and logistic regression analyses and Cox regression analyses were performed adjusting for demographics and traditional cardiac risk factors. RESULTS: sFlt-1 levels were higher in older individuals, males, and African Americans, and tracked with most traditional risk factors. sFlt-1 was significantly associated with higher prevalence of aortic plaque [OR 1.33 (95% CI 1.02-1.73)], greater abdominal aortic wall thickness (p<0.01) and aortic plaque area (p<0.02) but no difference in coronary artery calcification. There were 322 ASCVD events over 12 years of follow-up. Higher sFlt-1 levels associated with increased ASCVD events in unadjusted (16.1% vs. 8.9%, p<0.001, quartile 4 vs. quartile 1) and adjusted analyses (HR 1.58 [1.14-2.18], p<0.01, quartile 4 vs. quartile 1). Findings were unchanged when analyzing sFlt-1 as a continuous variable or when excluding those with a history of ASCVD. CONCLUSIONS: In a population-based cohort, sFlt-1 is associated with measures of subclinical aortic atherosclerosis and clinical ASCVD events. Future studies are warranted on the therapeutic potential of targeting sFlt-1 for atherosclerotic disease.

The neuroprotective factor Wld(s) fails to mitigate distal axonal and neuromuscular junction (NMJ) defects in mouse models of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a common autosomal recessive neurodegenerative disorder in humans. Amongst the earliest signs of neurodegeneration are severe and progressive defects of the neuromuscular synapse. These defects, characterized by poor terminal arborization and immature motor endplates, presumably result in a loss of functional synapses. The slow Wallerian degeneration (Wld(s)) mutation in rodents has been shown to have a protective effect on mouse models of motor neuron disease by retarding axonal die-back and preventing neuromuscular synapse loss. In this study we tested the effects of the Wld(s) mutation on the disease phenotype of SMA model mice. Consistent with previous reports, the mutation slows axon and neuromuscular synapse loss following nerve injury in wild-type as well as in SMA mice. However, the synaptic defects found in severely affected SMA patients and model mice persist in the double (Wld(s);SMA) mutants. No delay in disease onset was observed and survival was not significantly altered. Finally, Wld(s) had no effect on the striking phrenic nerve projection defects that we discovered in SMA model mice. Our results indicate that the reported protective effects of Wld(s) are insufficient to mitigate the neuromuscular phenotype due to reduced SMN protein, and that the mechanisms responsible for distal defects of the motor unit in SMA are unlikely to be similar to those causing neurodegeneration in genetic mutants such as the pmn mouse which is partially rescued by the Wld(s) protein.

Identifying a low-flow phenotype in heart failure with preserved ejection fraction: a secondary analysis of the RELAX trial.

AIMS: The relationship between resting stroke volume (SV) and prognostic markers in heart failure with preserved ejection fraction (HFpEF) is not well established. We evaluated the association of SV index (SVI) at rest with exercise capacity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in stable patients with HFpEF. METHODS AND RESULTS: Participants enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial with available data on SVI by the Doppler method were included in this analysis (n = 185). A low-flow state defined by resting SVI < 35 mL/m2 was present in 37% of study participants. Multivariable adjusted linear regression analysis suggested that higher resting heart rate, higher body weight, prevalent atrial fibrillation, and smaller left ventricular (LV) end-diastolic dimension were each independently associated with lower SVI. Patients with low-flow HFpEF had lower systolic blood pressure and smaller LV end-diastolic dimension. In multivariable adjusted linear regression models, lower SVI was significantly associated with lower peak oxygen consumption (peak VO2 ) and higher NT-proBNP levels at baseline, and greater decline in peak VO2 at 6 month follow-up independent of other confounders. Resting LV ejection fraction was not associated with peak VO2 and NT-proBNP levels. CONCLUSIONS: There is heterogeneity in the resting SVI distribution among patients with stable HFpEF, with more than one-third of patients identified with the low-flow HFpEF phenotype (SVI < 35 mL/m2 ). Lower SVI was independently associated with lower peak VO2 , higher NT-proBNP levels, and greater decline in peak VO2 . These findings highlight the potential prognostic utility of SVI assessment in the management of patients with HFpEF.

Management and outcomes of acute myocardial infarction in patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with cardiovascular disease and acute myocardial infarction (AMI). Contemporary management and outcomes of AMI in patients with CKD have not been reported. METHODS: We analyzed United States National Inpatient Sample data for patients admitted with AMI with or without CKD from 2007 to 2012. Propensity score matching was used to identify patients with AMI and CKD with similar baseline characteristics who were managed invasively (cardiac catheterization, percutaneous coronary intervention [PCI], or coronary artery bypass graft surgery [CABG]) or conservatively. The primary outcome was in-hospital all-cause mortality. RESULTS: Among 753,782 patients admitted with AMI, 17.8% had a diagnosis of CKD. Patients with CKD had lower odds of invasive management (49.9% vs. 73.1%; adjusted OR 0.57, 95% CI 0.57-0.58), were less likely to undergo revascularization (adjusted OR 0.60, 95% CI 0.59-0.61), and had higher in-hospital mortality (8.4% vs. 5.0%; adjusted OR 1.55, 95% CI 1.51-1.59) than those without CKD. In a propensity-matched cohort of 89,630 CKD patients treated for AMI with invasive vs. conservative management, invasive management was associated with lower in-hospital mortality overall (5.9% vs. 10.9%, p<0.001; OR=0.51 (0.49-0.54)) as well as in subgroups by MI type and severity of CKD. CONCLUSIONS: Patients with AMI and CKD are less likely to receive invasive management, coronary revascularization, and have higher in-hospital mortality than patients without CKD. Invasive management of AMI was associated with lower in-hospital mortality versus conservative management in all patients, regardless of CKD severity.

Complete Resolution of Tumor Burden of Primary Cardiac Non-Hodgkin's Lymphoma.

Primary cardiac tumors are a rare set of benign and malignant neoplasms found in the heart or pericardium. We describe a patient presenting with nonspecific symptoms and ultimately diagnosed with primary cardiac non-Hodgkin's lymphoma (PCL). Our patient had extensive tumor in the right ventricle, which extended into the right atrium and right ventricular outflow tract. The tumor also encased the right coronary artery, which manifested as ischemic changes on EKG and cardiac MRI. The patient was treated with chemotherapy and achieved complete remission, with dramatic and full resolution of the mass on repeat echocardiography in nine weeks. More studies are needed to understand the optimal management and prognosis of patients with PCL.

Stress Cardiac MRI in Women With Myocardial Infarction and Nonobstructive Coronary Artery Disease.

BACKGROUND: In a prospective study, cardiac MRI (CMR) and intravascular ultrasound were performed in women with myocardial infarction (MI) and nonobstructive coronary artery disease (MINOCA). Forty participants underwent adenosine-stress CMR (sCMR). HYPOTHESIS: Abnormal perfusion may co-localize with ischemic late gadolinium enhancement (LGE) and T2-weighted signal hyperintensity (T2+), suggesting microvascular dysfunction contributed to MI. METHODS: Qualitative perfusion analysis was performed by 2 independent readers. Abnormal myocardial perfusion reserve index (MPRI) was defined as global average ≤1.84. RESULTS: Abnormal rest perfusion was present in 10 patients (25%) and stress perfusion abnormalities in 25 (63%). Abnormal stress perfusion was not associated with LGE but tended to occur with T2+. Among patients with abnormal perfusion and LGE, the LGE pattern was ischemic in half. The locations of abnormal perfusion and LGE matched in 75%, T2+ in 100%. Abnormal stress perfusion was not associated with plaque disruption and matched in location in 63%. MPRI was abnormal in 10 patients (25%) and was not associated with LGE, T2+ or plaque disruption. CONCLUSIONS: Abnormal perfusion on sCMR is common among women with MINOCA. Abnormal perfusion usually co-localized with LGE and/or T2+ when present. Variability in LGE pattern leads to uncertainty about whether the finding of abnormal perfusion was cause or consequence of the tissue state leading to LGE. Low MPRI, possibly indicating diffuse microvascular disease, was observed with and without LGE and T2+. Multiple mechanisms may lead to abnormal perfusion on sCMR. Microvascular dysfunction may contribute to the pathogenesis of and coexist with other causes of MINOCA.

Provoking conditions, management and outcomes of type 2 myocardial infarction and myocardial necrosis.

BACKGROUND: Type 2 myocardial infarction (MI) is defined as myocardial necrosis (myonecrosis) due to an imbalance in supply and demand with clinical evidence of ischemia. Some clinical scenarios of supply-demand mismatch predispose to myonecrosis but limit the identification of symptoms and ECG changes referable to ischemia; therefore, the MI definition may not be met. Factors that predispose to type 2 MI and myonecrosis without definite MI, approaches to treatment, and outcomes remain poorly characterized. METHODS: Patients admitted to an academic medical center with an ICD-9 diagnosis of secondary myocardial ischemia or non-primary diagnosis of non-ST-elevation MI were retrospectively reviewed. Cases were classified as either MI (n=255) or myonecrosis without definite MI (n=220) based on reported symptoms, ischemic ECG changes, and new wall motion abnormalities. RESULTS: Conditions associated with type 2 MI or myonecrosis included non-cardiac surgery (38%), anemia or bleeding requiring transfusion (32%), sepsis (31%), tachyarrhythmia (23%), hypotension (22%), respiratory failure (23%), and severe hypertension (8%). Inpatient mortality was 5%, with no difference between patients with MI and those with myonecrosis (6% vs. 5%, p=0.41). At discharge, only 43% of patients received aspirin and statin therapy. CONCLUSIONS: Type 2 MI and myonecrosis occur frequently in the setting of supply-demand mismatch due to non-cardiac surgery, sepsis, or anemia. Myonecrosis without definite MI is associated with similar in-hospital mortality as type 2 MI; both groups warrant further workup for cardiovascular disease. Antiplatelet and statin prescriptions were infrequent at discharge, reflecting physician uncertainty about the role of secondary prevention in these patients.