Faculty Bibliography

Background: Cardiac dysfunction and cardiovascular (CV) events are prevalent among patients with chronic kidney disease (CKD) without overt obstructive coronary artery disease (CAD) but the mechanisms remain poorly understood. Coronary microvascular dysfunction (CMD) has been proposed as a link between abnormal renal function and impairment of cardiac function and CV events. We sought to investigate the relationships between CKD, CMD, cardiac dysfunction and adverse CV outcomes. Methods: Patients undergoing cardiac stress positron emission tomography (PET), echocardiogram and renal function ascertainment at Brigham and Women's Hospital were studied longitudinally. Patients free of overt coronary (summed stress score < 3 & without history of ischemic heart disease), valvular and end-organ disease were followed for adverse composite outcome of death, hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from PET. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e') and systolic [global longitudinal (GLS), radial (GRS) and circumferential strain (GCS)]. Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic, systolic indices and adverse CV outcomes were assessed in adjusted models and mediation analyses. Results: 352 patients (median age 65 years, 63% women and 22% black) were studied. 35% of patients had eGFR<60 ml/min/1.73 m², median LVEF of 62% and median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future CV events (all p<0.05). In multivariable models, CFR but not eGFR was independently associated with cardiac mechanics and CV events. The associations between eGFR, cardiac mechanics and CV events were partly mediated via CFR. Conclusions: CMD but not eGFR was independently associated with abnormal cardiac mechanics and an increased risk of CV events. CMD may mediate the effect of CKD on abnormal cardiac function and CV events in those without overt CAD.

BACKGROUND:Stress cardiac magnetic resonance imaging (CMR) has demonstrated excellent diagnostic and prognostic value in single-center studies. OBJECTIVES:This study sought to investigate the prognostic value of stress CMR and downstream costs from subsequent cardiac testing in a retrospective multicenter study in the United States. METHODS:In this retrospective study, consecutive patients from 13 centers across 11 states who presented with a chest pain syndrome and were referred for stress CMR were followed for a target period of 4 years. The authors associated CMR findings with a primary outcome of cardiovascular death or nonfatal myocardial infarction using competing risk-adjusted regression models and downstream costs of ischemia testing using published Medicare national payment rates. RESULTS:In this study, 2,349 patients (63 ± 11 years of age, 47% female) were followed for a median of 5.4 years. Patients with no ischemia or late gadolinium enhancement (LGE) by CMR, observed in 1,583 patients (67%), experienced low annualized rates of primary outcome (<1%) and coronary revascularization (1% to 3%), across all years of study follow-up. In contrast, patients with ischemia+/LGE+ experienced a >4-fold higher annual primary outcome rate and a >10-fold higher rate of coronary revascularization during the first year after CMR. Patients with ischemia and LGE both negative had low average annual cost spent on ischemia testing across all years of follow-up, and this pattern was similar across the 4 practice environments of the participating centers. CONCLUSIONS:In a multicenter U.S. cohort with stable chest pain syndromes, stress CMR performed at experienced centers offers effective cardiac prognostication. Patients without CMR ischemia or LGE experienced a low incidence of cardiac events, little need for coronary revascularization, and low spending on subsequent ischemia testing. (Stress CMR Perfusion Imaging in the United States [SPINS]: A Society for Cardiovascular Resonance Registry Study; NCT03192891).

OBJECTIVES:F-florbetapir uptake by positron emission tomography [PET] and/or extracellular volume fraction [ECV] by cardiac magnetic resonance (CMR)]. BACKGROUND:Further knowledge of the pathophysiological basis for RELAPS can help understand the adverse outcomes associated with apical LS impairment. METHODS:F-florbetapir PET for quantification of LV florbetapir retention index (RI). A subset also underwent CMR (n = 22) for ECV quantification. Extracellular LV mass (LV mass*ECV) and total florbetapir binding (extracellular LV mass*florbetapir RI) were also calculated. All parameters were measured globally and regionally (base, mid, and apex). RESULTS:There was a significant base-to-apex gradient in LS (-7.4 ± 3.2% vs. -8.6 ± 4.0% vs. -20.8 ± 6.6%; p < 0.0001), maximal LV wall thickness (15.7 ± 1.9 cm vs. 15.4 ± 2.9 cm vs. 10.1 ± 2.4 cm; p < 0.0001), and LV mass (74.8 ± 21.2 g vs. 60.8 ± 17.3 g vs. 23.4 ± 6.2 g; p < 0.0001). In contrast, florbetapir RI (0.089 ± 0.03 μmol/min/g vs. 0.097 ± 0.03 μmol/min/g vs. 0.085 ± 0.03 μmol/min/g; p = 0.45) and ECV (0.53 ± 0.08 vs. 0.49 ± 0.08 vs. 0.49 ± 0.07; p = 0.15) showed no significant base-to-apex gradient in the tissue concentration or proportion of amyloid infiltration, whereas markers of total amyloid load, such as total florbetapir binding (3.4 ± 1.7 μmol/min vs. 2.8 ± 1.5 μmol/min vs. 0.93 ± 0.49 μmol/min; p < 0.0001) and extracellular LV mass (40.0 ± 15.6 g vs. 30.2 ± 10.9 g vs. 11.6 ± 3.9 g; p < 0.0001), did show a marked base-to-apex gradient. CONCLUSIONS:Segmental differences in the distribution of the total amyloid mass, rather than the proportion of amyloid deposits, appear to explain the marked regional differences in LS in CA. Although these 2 matrices are clearly related concepts, they should not be used interchangeably.

BACKGROUND:The double-blind OMEGA-REMODEL placebo-controlled randomized trial of high-dose omega-3 fatty acids (O-3FA) post-acute myocardial infarction (AMI) reported improved cardiac remodeling and attenuation of non-infarct myocardial fibrosis. Fatty acid desaturase 2 (FADS2) gene cluster encodes key enzymes in the conversion of essential omega-3 and omega-6 fatty acids into active arachidonic (ArA) and eicosapentaenoic acids (EPA), which influence cardiovascular outcomes. METHODS AND RESULTS:We tested the hypothesis that the genotypic status of FADS2 (rs1535) modifies therapeutic response of O-3FA in post-AMI cardiac remodeling in 312 patients. Consistent with known genetic polymorphism of FADS2, patients in our cohort with the guanine-guanine (GG) genotype had the lowest FADS2 activity assessed by arachidonic acid/linoleic acid (ArA/LA) ratio, compared with patients with the adenine-adenine (AA) and adenine-guanine (AG) genotypes (GG:1.62±0.35 vs. AA: 2.01±0.36, p<0.0001; vs. AG: 1.76±0.35, p = 0.03). When randomized to 6-months of O-3FA treatment, GG patients demonstrated significant lowering of LV end-systolic volume index (LVESVi), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and galectin-3 levels compared to placebo (-4.4 vs. 1.2 ml/m2, -733 vs. -181 pg/mL, and -2.0 vs. 0.5 ng/mL; p = 0.006, 0.006, and 0.03, respectively). In contrast, patients with either AA or AG genotype did not demonstrate significant lowering of LVESVi, NT-proBNP, or galectin-3 levels from O-3FA treatment, compared to placebo. The odds ratios for improving LVESVi by 10% with O-3FA treatment was 7.2, 1.6, and 1.2 in patients with GG, AG, and AA genotypes, respectively. CONCLUSION:Genetic profiling using FADS2 genotype can predict the therapeutic benefits of O-3FA treatment against adverse cardiac remodeling during the convalescent phase of AMI. CLINICAL TRIAL REGISTRATION INFORMATION:clinicaltrials.gov Identifier: NCT00729430.

BACKGROUND:Patients with chronic kidney disease are at increased risk of cardiovascular disease (CVD). Even after kidney transplant, the rate of CVD events and death remain elevated. Early detection of patients at risk would be helpful for guiding aggressive preventive therapy. The purpose of this study was to evaluate global longitudinal strain (GLS) as a predictor of CVD events and death after kidney transplant. METHOD/METHODS:Among patients with successful kidney transplant between 3/2009 and 12/2012 at our institution, 111 individuals had an echocardiogram within 6 months of the transplant. Medical records were evaluated for demographics and patient characteristics. Echocardiograms were analyzed for conventional measurements, and GLS was assessed using speckle-tracking analysis. RESULTS:The median age of the study sample was 54 years. Overall, 60% were men; 35% were non-Hispanic black, and 50% Hispanic. After a mean follow-up of 3.8 ± 0.5 years, there were 21 cardiovascular events or deaths. Patients who experienced an event were older, more frequently had a history of coronary artery disease, and had higher LV filling/longitudinal diastolic annular velocity (E/e') than those who did not. GLS was significantly associated with event-free survival even after adjusting for age, sex, race-ethnicity, hypertension, diabetes, history of coronary artery disease or heart failure, and E/e'. CONCLUSION/CONCLUSIONS:Reduced GLS peri-transplant is significantly associated with increased CVD events or death after kidney transplant. Larger studies are required to determine the incremental predictive value of GLS over clinical and other echocardiographic parameters for adverse CVD events following renal transplantation.

Tissue transglutaminase (tTG) is a multifunctional protein with a wide range of enzymatic and non-enzymatic functions. We have recently demonstrated that tTG expression is upregulated in the pressure-overloaded myocardium and exerts fibrogenic actions promoting diastolic dysfunction, while preventing chamber dilation. Our current investigation dissects the in vivo and in vitro roles of the enzymatic effects of tTG on fibrotic remodeling in pressure-overloaded myocardium. Using a mouse model of transverse aortic constriction, we demonstrated perivascular and interstitial tTG activation in the remodeling pressure-overloaded heart. tTG inhibition through administration of the selective small molecule tTG inhibitor ERW1041E attenuated left ventricular diastolic dysfunction and reduced cardiomyocyte hypertrophy and interstitial fibrosis in the pressure-overloaded heart, without affecting chamber dimensions and ejection fraction. In vivo, tTG inhibition markedly reduced myocardial collagen mRNA and protein levels and attenuated transcription of fibrosis-associated genes. In contrast, addition of exogenous recombinant tTG to fibroblast-populated collagen pads had no significant effects on collagen transcription, and instead increased synthesis of matrix metalloproteinase (MMP)3 and tissue inhibitor of metalloproteinases (TIMP)1 through transamidase-independent actions. However, enzymatic effects of matrix-bound tTG increased the thickness of pericellular collagen in fibroblast-populated pads. tTG exerts distinct enzymatic and non-enzymatic functions in the remodeling pressure-overloaded heart. The enzymatic effects of tTG are fibrogenic and promote diastolic dysfunction, but do not directly modulate the pro-fibrotic transcriptional program of fibroblasts. Targeting transamidase-dependent actions of tTG may be a promising therapeutic strategy in patients with heart failure and fibrosis-associated diastolic dysfunction.

A 66-year-old woman presented with frequent premature ventricular contractions (PVC) and akinesis of the basal septum on echocardiography. Coronary angiography was normal. Cardiac magnetic resonance showed mid-wall enhancement. Positron emission tomography showed a perfusion defect at the same location using 13N-ammonia, but increased 18-fluorodeoxyglucose uptake. These findings supported the diagnosis of cardiac sarcoidosis. High-dose steroids initially reduced frequency of PVCs but had to be withdrawn due to severe side effects. An ICD was implanted. Our case demonstrates the utility of multimodality imaging to diagnose and guide management of this entity.