Kayla Piehler

Association Between Extracellular Matrix Expansion Quantified by Cardiovascular Magnetic Resonance and Short-Term Mortality

Background— Extracellular matrix expansion may be a fundamental feature of adverse myocardial remodeling, it appears to be treatable, and its measurement may improve risk stratification. Yet, the relationship between mortality and extracellular matrix is not clear because of difficulties with its measurement. To assess its relationship with outcomes, we used novel, validated cardiovascular magnetic resonance techniques to quantify the full spectrum of extracellular matrix expansion not readily detectable by conventional cardiovascular magnetic resonance. Methods and Results— We recruited 793 consecutive patients at the time of cardiovascular magnetic resonance without amyloidosis or hypertrophic cardiomyopathy as well as 9 healthy volunteers (ages 20–50 years). We measured the extracellular volume fraction (ECV) to quantify the extracellular matrix expansion in myocardium without myocardial infarction. ECV uses gadolinium contrast as an extracellular space marker based on T1 measures of blood and myocardium pre— and post–gadolinium contrast and hematocrit measurement. In volunteers, ECV ranged from 21.7% to 26.2%, but in patients it ranged from 21.0% to 45.8%, indicating considerable burden. There were 39 deaths over a median follow-up of 0.8 years (interquartile range 0.5–1.2 years), and 43 individuals who experienced the composite end point of death/cardiac transplant/left ventricular assist device implantation. In Cox regression models, ECV related to all-cause mortality and the composite end point (hazard ratio, 1.55; 95% confidence interval, 1.27–1.88 and hazard ratio, 1.48; 95% confidence interval, 1.23–1.78, respectively, for every 3% increase in ECV), adjusting for age, left ventricular ejection fraction, and myocardial infarction size. Conclusions— ECV measures of extracellular matrix expansion may predict mortality as well as other composite end points (death/cardiac transplant/left ventricular assist device implantation).

Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in diabetes and associated with mortality and incident heart failure admission

AIMS Diabetes may promote myocardial extracellular matrix (ECM) expansion that increases vulnerability. We hypothesized that: (i) type 2 diabetes would be associated with quantitative cardiovascular magnetic resonance (CMR) measures of myocardial ECM expansion, i.e. extracellular volume fraction (ECV); (ii) medications blocking the renin-angiotensin-aldosterone system (RAAS) would be associated with lower ECV; and (iii) ECV in diabetic individuals would be associated with mortality and/or incident hospitalization for heart failure. METHODS AND RESULTS We enrolled 1176 consecutive patients referred for CMR without amyloidosis and computed ECV from measures of the haematocrit and myocardial and blood T1 pre- and post-contrast. Linear regression modelled ECV; Cox regression modelled mortality and/or hospitalization for heart failure. Diabetic individuals (n = 231) had higher median ECV than those without diabetes (n = 945): 30.2% (IQR: 26.9-32.7) vs. 28.1% (IQR: 25.9-31.0), respectively, P < 0.001). Diabetes remained associated with higher ECV in models adjusting for demographics, comorbidities, and medications (P < 0.001). Renin-angiotensin-aldosterone system blockade was associated with lower ECV (P = 0.028) in multivariable linear models. Over a median of 1.3 years (IQR: 0.8-1.9), 38 diabetic individuals had events (21 incident hospitalizations for heart failure; 24 deaths), and ECV was associated with these events (HR: 1.52, 95% CI: 1.21-1.89 per 3% ECV increase) in multivariable Cox regression models. CONCLUSION Diabetes is associated with increased ECV. Extracellular volume fraction detects amelioration of ECM expansion associated with RAAS blockade, and is associated with mortality and/or incident hospitalization for heart failure in diabetic individuals. Extracellular matrix expansion may be an important intermediate phenotype in diabetic individuals that is detectable and treatable.

Myocardial fibrosis quantified by extracellular volume is associated with subsequent hospitalization for heart failure, death, or both across the spectrum of ejection fraction and heart failure stage

Background Myocardial fibrosis (MF) in noninfarcted myocardium may be an interstitial disease pathway that confers vulnerability to hospitalization for heart failure, death, or both across the spectrum of heart failure and ejection fraction. Hospitalization for heart failure is an epidemic that is difficult to predict and prevent and requires potential therapeutic targets associated with outcomes. Method and Results We quantified MF with cardiovascular magnetic resonance extracellular volume fraction (ECV) measures in 1172 consecutive patients without amyloidosis or hypertrophic or stress cardiomyopathy and assessed associations with outcomes using Cox regression. ECV ranged from 16.6% to 47.8%. Over a median of 1.7 years, 111 patients experienced events after cardiovascular magnetic resonance, 55 had hospitalization for heart failure events, and there were 74 deaths. ECV was more strongly associated with outcomes than “nonischemic” MF observed with late gadolinium enhancement, thus ECV quantified MF in multivariable models. Adjusting for age, sex, renal function, myocardial infarction size, ejection fraction, hospitalization status, and heart failure stage, higher ECV was associated with hospitalization for heart failure (hazard ratio 1.77; 95% CI 1.32 to 2.36 for every 5% increase in ECV), death (hazard ratio 1.87 95% CI 1.45 to 2.40) or both (hazard ratio 1.85, 95% CI 1.50 to 2.27). ECV improved classification of persons at risk and improved model discrimination for outcomes (eg, hospitalization for heart failure: continuous net reclassification improvement 0.33, 95% CI 0.05 to 0.66; P=0.02; 0.16, 95% CI 0.01 to 0.33; P=0.02; integrated discrimination improvement 0.037, 95% CI 0.008 to 0.073; P<0.01). Conclusion MF measured by ECV is associated with hospitalization for heart failure, death, or both. MF may represent a principal phenotype of cardiac vulnerability that improves risk stratification. Because MF can be reversible, cells and enzymes regulating collagen could be potential therapeutic targets.

Free-Breathing, Motion-Corrected Late Gadolinium Enhancement Is Robust and Extends Risk Stratification to Vulnerable Patients

Background— Routine clinical use of novel free-breathing, motion-corrected, averaged late-gadolinium-enhancement (moco-LGE) cardiovascular MR may have advantages over conventional breath-held LGE (bh-LGE), especially in vulnerable patients. Methods and Results— In 390 consecutive patients, we collected bh-LGE and moco-LGE with identical image matrix parameters. In 41 patients, bh-LGE was abandoned because of image quality issues, including 10 with myocardial infarction. When both were acquired, myocardial infarction detection was similar (McNemar test, P=0.4) with high agreement (&kgr;=0.95). With artifact-free bh-LGE images, pixelwise myocardial infarction measures correlated highly (R 2=0.96) without bias. Moco-LGE was faster, and image quality and diagnostic confidence were higher on blinded review (P<0.001 for all). During a median of 1.2 years, 20 heart failure hospitalizations and 18 deaths occurred. For bh-LGE, but not moco-LGE, inferior image quality and bh-LGE nonacquisition were linked to patient vulnerability confirmed by adverse outcomes (log-rank P<0.001). Moco-LGE significantly stratified risk in the full cohort (log-rank P<0.001), but bh-LGE did not (log-rank P=0.056) because a significant number of vulnerable patients did not receive bh-LGE (because of arrhythmia or inability to hold breath). Conclusions— Myocardial infarction detection and quantification are similar between moco-LGE and bh-LGE when bh-LGE can be acquired well, but bh-LGE quality deteriorates with patient vulnerability. Acquisition time, image quality, diagnostic confidence, and the number of successfully scanned patients are superior with moco-LGE, which extends LGE-based risk stratification to include patients with vulnerability confirmed by outcomes. Moco-LGE may be suitable for routine clinical use.

Myocardial Damage Detected by Late Gadolinium Enhancement Cardiovascular Magnetic Resonance Is Associated With Subsequent Hospitalization for Heart Failure

Background Hospitalization for heart failure (HHF) is among the most important problems confronting medicine. Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) robustly identifies intrinsic myocardial damage. LGE may indicate inherent vulnerability to HHF, regardless of etiology, across the spectrum of heart failure stage or left ventricular ejection fraction (LVEF). Methods and Results We enrolled 1068 consecutive patients referred for CMR where 448 (42%) exhibited LGE. After a median of 1.4 years (Q1 to Q3: 0.9 to 2.0 years), 57 HHF events occurred, 15 deaths followed HHF, and 43 deaths occurred without antecedent HHF (58 total deaths). Using multivariable Cox regression adjusting for LVEF, heart failure stage, and other covariates, LGE was associated with first HHF after CMR (HR: 2.70, 95% CI: 1.32 to 5.50), death (HR: 2.13, 95% CI: 1.08 to 4.21), or either death or HHF (HR: 2.52, 95% CI: 1.49 to 4.25). Quantifying LGE extent yielded similar results; more LGE equated higher risks. LGE improved model discrimination (IDI: 0.016, 95% CI: 0.005 to 0.028, P=0.002) and reclassification of individuals at risk (continuous NRI: 0.40, 95% CI: 0.05 to 0.70, P=0.024). Adjustment for competing risks of death that shares common risk factors with HHF strengthened the LGE and HHF association (HR: 4.85, 95% CI: 1.40 to 16.9). Conclusions The presence and extent of LGE is associated with vulnerability for HHF, including higher risks of HHF across the spectrum of heart failure stage and LVEF. Even when LVEF is severely decreased, those without LGE appear to fare reasonably well. LGE may enhance risk stratification for HHF and may enhance both clinical and research efforts to reduce HHF through targeted treatment.

Temporal relation between myocardial fibrosis and heart failure with preserved ejection fraction: Association with baseline disease severity and subsequent outcome

Importance Among myriad changes occurring during the evolution of heart failure with preserved ejection fraction (HFpEF), cardiomyocyte–extracellular matrix interactions from excess collagen may affect microvascular, mechanical, and electrical function. Objective To investigate whether myocardial fibrosis (MF) is similarly prevalent both in those with HFpEF and those at risk for HFpEF, similarly associating with disease severity and outcomes. Design, Setting, and Participants Observational cohort study from June 1, 2010, to September 17, 2015, with follow-up until December 14, 2015, at a cardiovascular magnetic resonance (CMR) center serving an integrated health system. Consecutive patients with preserved systolic function referred for CMR were eligible. Cardiovascular magnetic resonance was used to exclude patients with cardiac amyloidosis (n = 19). Exposures Myocardial fibrosis quantified by extracellular volume (ECV) CMR measures. Main Outcome and Measures Baseline BNP; subsequent hospitalization for heart failure or death. Results Of 1174 patients identified (537 [46%] female; median [interquartile range {IQR}] age, 56 [44-66] years), 250 were “at risk” for HFpEF given elevated brain-type natriuretic peptide (BNP) level; 160 had HFpEF by documented clinical diagnosis, and 745 did not have HFpEF. Patients either at risk for HFpEF or with HFpEF demonstrated similarly higher prevalence/extent of MF and worse prognosis compared with patients with no HFpEF. Among those at risk for HFpEF or with HFpEF, the actual diagnosis of HFpEF was not associated with significant differences in MF (median ECV, 28.2%; IQR, 26.2%-30.7% vs 28.3%; IQR, 25.5%-31.4%; P = .60) or prognosis (log-rank 0.8; P = .38). Over a median of 1.9 years, 61 patients at risk for HFpEF or with HFpEF experienced adverse events (19 hospitalization for heart failure, 48 deaths, 6 with both). In those with HFpEF, ECV was associated with baseline log BNP (disease severity surrogate) in multivariable linear regression models, and was associated with outcomes in multivariable Cox regression models (eg, hazard ratio 1.75 per 5% increase in ECV, 95% CI, 1.25-2.45; P = .001 in stepwise model) whether grouped with patients at risk for HFpEF or not. Conclusions and Relevance Among myriad changes occurring during the apparent evolution of HFpEF where elevated BNP is prevalent, MF was similarly prevalent in those with or at risk for HFpEF. Conceivably, MF might precede clinical HFpEF diagnosis. Regardless, MF was associated with disease severity (ie, BNP) and outcomes. Whether cells and secretomes mediating MF represent therapeutic targets in HFpEF warrants further evaluation.

Effectiveness of late gadolinium enhancement to improve outcomes prediction in patients referred for cardiovascular magnetic resonance after echocardiography

BackgroundEchocardiography (echo) is a first line test to assess cardiac structure and function. It is not known if cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) ordered during routine clinical practice in selected patients can add additional prognostic information after routine echo. We assessed whether CMR improves outcomes prediction after contemporaneous echo, which may have implications for efforts to optimize processes of care, assess effectiveness, and allocate limited health care resources.Methods and resultsWe prospectively enrolled 1044 consecutive patients referred for CMR. There were 38 deaths and 3 cardiac transplants over a median follow-up of 1.0 years (IQR 0.4-1.5). We first reproduced previous survival curve strata (presence of LGE and ejection fraction (EF) < 50%) for transplant free survival, to support generalizability of any findings. Then, in a subset (n = 444) with contemporaneous echo (median 3 days apart, IQR 1–9), EF by echo (assessed visually) or CMR were modestly correlated (R2 = 0.66, p < 0.001), and 30 deaths and 3 transplants occurred over a median follow-up of 0.83 years (IQR 0.29-1.40). CMR EF predicted mortality better than echo EF in univariable Cox models (Integrated Discrimination Improvement (IDI) 0.018, 95% CI 0.008-0.034; Net Reclassification Improvement (NRI) 0.51, 95% CI 0.11-0.85). Finally, LGE further improved prediction beyond EF as determined by hazard ratios, NRI, and IDI in all Cox models predicting mortality or transplant free survival, adjusting for age, gender, wall motion, and EF.ConclusionsAmong those referred for CMR after echocardiography, CMR with LGE further improves risk stratification of individuals at risk for death or death/cardiac transplant.

Myocardial fibrosis is associated with subsequent death and hospitalization for heart failure in obese adults

Cardiac imaging in obese adults poses significant technical challenges, yet the prognostic value of diffuse myocardial fibrosis in obese adults quantified with cardiovascular magnetic resonance (CMR) extracellular volume fraction (ECV) measures is unknown. This issue is important because obesity increases the risks of death and hospitalization for heart failure (HHF). Myocardial fibrosis measured in obese adults with ECV may indicate vulnerability to death and HHF.

MYOCARDIAL FIBROSIS QUANTIFIED BY CMR EXTRACELLULAR VOLUME FRACTION PREDICTS MORTALITY AND DETECTS RESPONSE TO THERAPY IN THE NONISCHEMIC PATIENT POPULATION

Myocardial fibrosis expands the extracellular matrix (ECM) adversely affecting mechanical, electrical, and vasomotor function. We quantified ECM expansion, evaluated its association with mortality in the non-ischemic patient population, and assessed the impact of renin angiotensin aldosterone system

Myocardial fibrosis quantified by the extracellular extravascular volume fraction is associated with the left ventricular sphericity index and the left atrial volume index

Summary The objective of this study is to test the hypothesis that quantitative measures of myocardial fibrosis such as the myocardial extravascular extracellular volume fraction (Ve) are associated with markers of adverse cardiac remodeling such as the left atrial volume index (LAVi) and left ventricular sphericity index (Si). Background LAVi and Si are intermediate phenotypes that precede adverse outcomes. Myocardial fibrosis is quantifiable with contemporary CMR techniques, is treatable, and may represent a therapeutic target when these intermediate phenotypes are present. Methods We measured myocardial Ve in 267 individuals referred for CMR without confounders such as myocardial infarction, where Ve= [ lr (1-Hct) - Vp]; the specific density of myocardial tissue, r=1.05; the myocardial plasma volume fraction, Vp=0.045, and l=ΔR1myocardium/ ΔR1blood. T1 was measured with an ECG-gated MOLLI sequence acquired before and 20 minutes after a gadolinium contrast bolus (0.2 mmol/kg). LAVi and Si were measured from standard SSFP cine images: LAVi = [8/3π [(A1)(A2)/L] where A1 and A2 are LA areas from end-systolic 2-chamber and 4-chamber views, L represents the shortest anteroposterior LA dimension from either view, and Si =EDV/[LAX^3 π /6), where EDV is the end-diastolic volume measured from short axis stacks and LAX^3 is the cube of the long axis diastolic dimension from a 4 chamber view. Multivariable linear regression models quantified the association of Ve with LAVi and Si, adjusting for key characteristics identified by stepwise selection. Results Ve was associated with LAVi (t value 4.5, p<0.001), and this association remained after adjusting for age, ejection fraction, EDV index, and left ventricular mass index (t value 2.8, p=0.005). Ve was also associated with Si (t value 5.6, p<0.001), and this association remained after adjusting for age, gender, EDV index, body mass index, and left ventricular mass index (t value 2.18, p=0.036). Conclusions Ve is associated with key intermediate phenotypes that indicate adverse cardiac remodeling such as LAVi and Si.