Background
Extracellular matrix (ECM) expansion may be a fundamental feature of adverse myocardial remodeling, appears to be treatable, and its measurement may improve risk stratification. Yet, the relationship between mortality and ECM is not clear due to difficulties with its measurement. To assess its relationship with outcomes, we used novel, validated cardiovascular magnetic resonance (CMR) techniques to quantify the full spectrum of ECM expansion not readily detectable by conventional CMR.
Methods and Results
We recruited 793 consecutive patients at the time of CMR without amyloidosis or hypertrophic cardiomyopathy as well as 9 healthy volunteers (ages 20–50). We measured the extracellular volume fraction (ECV) to quantify the extracellular matrix expansion in myocardium without myocardial infarction (MI). ECV employs gadolinium contrast (Gd) as an extracellular space marker based on T1 measures of blood and myocardium pre-/post-Gd and hematocrit measurement. In volunteers, ECV ranged from 21.7–26.2%, but in patients, it ranged from 21.0–45.8%, indicating considerable burden. There were 39 deaths over a median follow-up of 0.8 years (IQR 0.5–1.2 years), and 43 individuals who experienced the composite endpoint of death/cardiac transplant/left ventricular assist device (LVAD) implantation. In Cox regression models, ECV related to all-cause mortality and the composite endpoint (HR 1.55; 95% CI 1.27–1.88 and HR 1.48; 95% CI 1.23–1.78, respectively, for every 3% increase in ECV), adjusting for age, left ventricular ejection fraction, and MI size.
Conclusions
ECV measures of extracellular matrix expansion may predict mortality as well as other composite endpoints (death/cardiac transplant/LVAD).
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.
BackgroundMyocardial extravascular extracellular volume fraction (Ve) measures quantify diffuse fibrosis not readily detectable by conventional late gadolinium (Gd) enhancement (LGE). Ve measurement requires steady state equilibrium between plasma and interstitial Gd contrast. While a constant infusion produces steady state, it is unclear whether a simple bolus can do the same. Given the relatively slow clearance of Gd, we hypothesized that a bolus technique accurately measures Ve, thus facilitating integration of myocardial fibrosis quantification into cardiovascular magnetic resonance (CMR) workflow routines. Assuming equivalence between techniques, we further hypothesized that Ve measures would be reproducible across scans.MethodsIn 10 volunteers (ages 20-81, median 33 yr, 3 females), we compared serial Ve measures from a single short axis slice from two scans: first, during a constant infusion, and second, 12-50 min after a bolus (0.2 mmol/kg gadoteridol) on another day. Steady state during infusion was defined when serial blood and myocardial T1 data varied <5%. We measured T1 on a 1.5 T Siemens scanner using a single-shot modified Look Locker inversion recovery sequence (MOLLI) with balanced SSFP. To shorten breath hold times, T1 values were measured with a shorter sampling scheme that was validated with spin echo relaxometry (TR = 15 sec) in CuSO4-Agar phantoms. Serial infusion vs. bolus Ve measures (n = 205) from the 10 subjects were compared with generalized estimating equations (GEE) with exchangeable correlation matrices. LGE images were also acquired 12-30 minutes after the bolus.ResultsNo subject exhibited LGE near the short axis slices where Ve was measured. The Ve range was 19.3-29.2% and 18.4-29.1% by constant infusion and bolus, respectively. In GEE models, serial Ve measures by constant infusion and bolus did not differ significantly (difference = 0.1%, p = 0.38). For both techniques, Ve was strongly related to age (p < 0.01 for both) in GEE models, even after adjusting for heart rate. Both techniques identically sorted older individuals with higher mean Ve values.ConclusionMyocardial Ve can be measured reliably and accurately 12-50 minutes after a simple bolus. Ve measures are also reproducible across CMR scans. Ve estimation can be integrated into CMR workflow easily, which may simplify research applications involving the quantification of myocardial fibrosis.
RMVT can arise from the outflow tract of both the right and left ventricles. RMVTs with a precordial R wave transition at or before lead V2 are consistent with a left ventricular origin.
Multidetector helical computed tomography images of the LA and PVs are accurate and provide detailed anatomic information. Significant differences in dimensions but not morphologic detail were apparent between groups.
Rationale
Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensive patients and has been correlated to enhanced atrial fibrosis. Despite a lack of direct evidence that fibrosis causes AF, reversal of fibrosis is considered as a plausible therapy.
Objective
To evaluate the efficacy of the anti-fibrotic hormone relaxin (RLX) at suppressing AF in spontaneously hypertensive rats (SHR).
Methods and Results
Normotensive Wistar Kyoto (WKY) and SHR were treated for 2-weeks with vehicle (WKY+V and SHR+V), or RLX (0.4mg/kg/day, SHR+RLX) using implantable mini-pumps. Hearts were perfused, mapped optically to analyze action potential durations (APDs), intracellular Ca2+-transients, restitution kinetics (RK) and tested for AF vulnerability. SHR hearts had slower conduction velocity (CV) (p< 0.01 vs. WKY), steeper CV RKs, greater collagen deposition, higher levels of transcripts for TGFβ, metalloproteinase-2, metalloproteinase-9, collagen I/III and reduced connexin-43 phosphorylation (p< 0.05 vs. WKY). Programmed stimulation triggered sustained AF in SHR (n=5/5), SHR+V (n=4/4) but not in WKY (n=0/5) and SHR+RLX (n=1/8, p<0.01). RLX treatment reversed the transcripts for fibrosis, flattened CV-RK, reduced APD90, increased CV (p<0.01) and reversed atrial hypertrophy (p<0.05). Independent of anti-fibrotic actions, RLX (0.1µM) increased Na+-current density, INa (~2-fold in 48-hours) in human cardiomyocytes derived from iPSCs (n=18/18, p<0.01).
Conclusions
RLX-treatment suppressed AF in SHR hearts by increasing CV from a combination of reversal of fibrosis and hypertrophy and increasing INa. The study provides compelling evidence that RLX may provide a novel therapy to manage AF in humans by reversing fibrosis, and hypertrophy and modulating cardiac ionic currents.
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