Objectives The aim of the study was to determine whether longitudinal left ventricular (LV) function provides prognostic information in a large cohort of patients with systemic light-chain (AL) ...amyloidosis. Background AL amyloidosis is associated with a high incidence of cardiovascular events. Reduced myocardial longitudinal function is one of the hallmarks of myocardial involvement in this rare disease. Methods Two hundred six consecutive patients with biopsy-proven AL amyloidosis were investigated in this prospective observational study. Echocardiographic imaging parameters, mean tissue Doppler-derived longitudinal strain (LS), and two-dimensional global longitudinal strain (2D-GLS) of the LV, cardiac serological biomarkers, and comprehensive clinical disease characteristics were assessed. The primary endpoint was all-cause mortality or heart transplantation. Results After a median follow-up of 1207 days, LS and 2D-GLS were significant predictors of survival in AL amyloidosis. The cutoff values discriminating survivors from nonsurvivors were −10.65% for LS and −11.78% for 2D-GLS. In a multivariable echocardiographic Cox model, only diastolic dysfunction and 2D-GLS remained as independent predictors of survival. In comprehensive clinical models, 2D-GLS (p < 0.0001), diastolic dysfunction (p < 0.01), the pathologic free light chains (p < 0.05), cardiac troponin-T (cTnT) (p < 0.01), and the Karnofsky index (p < 0.001) remained as independent predictors. 2D-GLS delineated a superior prognostic value compared with that derived from pathologic free light chains or cTnT in patients evaluated before firstline chemotherapy (n = 113; p < 0.0001), and remained the only independent predictor besides the Karnofsky index in subjects with preserved LV ejection fraction (≥50%; n = 127; p < 0.01). LS and 2D-GLS both offered significant incremental information (p < 0.001) for the assessment of outcome compared with clinical variables (age, Karnofsky index, and New York Heart Association functional class) and serological biomarkers. Conclusions In the largest serial investigation reported so far, reduced LV longitudinal function served as an independent predictor of survival in AL amyloidosis and offered incremental information beyond standard clinical and serological parameters.
Objectives The extent of adverse myocardial remodeling contributes essentially to the prognosis after myocardial infarction (MI). In this study we investigated whether inhibition of “mammalian target ...of rapamycin” (mTOR) attenuates left ventricular (LV) remodeling after MI. Background Therapeutic strategies to inhibit remodeling are currently limited to inhibition of neurohumoral activation. The mTOR-dependent signaling mechanisms are centrally involved in remodeling processes and provide new therapeutic opportunities. Methods Everolimus (RAD) treatment was initiated on the day after or 3 days after induction of myocardial infarction (MI) in rats. Results After 28 days, RAD-treated animals had reduced post-MI remodeling, with improved LV function and smaller LV end-diastolic diameters (8.9 ± 0.3 mm vs. 11.4 ± 0.2 mm, p < 0.05), end-diastolic volumes (304 ± 30 μl vs. 414 ± 16 μl, p < 0.05), and cardiac myocyte size (−40% vs. vehicle, p < 0.05). Infarct size was significantly reduced compared with vehicle-treated animals. The mTOR inhibition increased autophagy and concomitantly decreased proteasome activity in the border zone of the infarcted myocardium. Measurement of autophagic flux demonstrated that RAD did not decrease autophagosome clearance. When RAD treatment was initiated 3 days after MI, adverse remodeling was still attenuated and increased autophagy was still present. Sustained improvement of LV function was observed 3 months after MI, even when RAD treatment was discontinued after 1 month. Conclusions Inhibition of mTOR is a potential therapeutic strategy to limit infarct size and to attenuate adverse LV remodeling after MI.
Abstract Background Inherited arrhythmias were originally considered isolated electrical defects. There is growing evidence that ion channel dysfunction also contributes to myocardial disorders, but ...genetic overlap has not been reported for sinus node dysfunction (SND) and noncompaction cardiomyopathy (NCCM). Objectives The study sought to investigate a familial electromechanical disorder characterized by SND and NCCM, and to identify the underlying genetic basis. Methods The index family and a cohort of unrelated probands with sinus bradycardia were examined by electrocardiography, Holter recording, exercise stress test, echocardiography, and/or cardiac magnetic resonance imaging. Targeted next-generation and direct sequencing were used for candidate gene analysis and mutation scanning. Ion channels were expressed in HEK293 cells and studied using patch-clamp recordings. Results SND and biventricular NCCM were diagnosed in multiple members of a German family. Segregation analysis suggested autosomal-dominant inheritance of the combined phenotype. When looking for potentially disease-causing gene variants with cosegregation, a novel hyperpolarization-activated cyclic nucleotide channel 4 ( HCN4 )-G482R mutation and a common cysteine and glycine-rich protein 3 ( CSRP3 )-W4R variant were identified. HCN4 -G482R is located in the highly conserved channel pore domain. Mutant subunits were nonfunctional and exerted dominant-negative effects on wild-type current. CSRP3 -W4R has previously been linked to dilated and hypertrophic cardiomyopathy, but was also found in healthy subjects. Moreover, different truncation (695X) and missense (P883R) HCN4 mutations segregated with a similar combined phenotype in an additional, unrelated family and a single unrelated proband respectively, which both lacked CSRP3 -W4R. Conclusions The symptom complex of SND and NCCM is associated with heritable HCN4 defects. The NCCM phenotype may be aggravated by a common CSRP3 variant in one of the families.
Purpose:
Low plasma concentrations of the amino acid homoarginine (HA) have been shown to correlate with adverse cardiovascular outcome, particularly in patients with chronic kidney disease. The ...present study sought to investigate the effect of HA treatment on cardiac remodeling in rats undergoing artificially induced renal insufficiency by 5/6 nephrectomy (5/6 Nx).
Methods:
A total of 33 male Wistar rats were randomly divided into sham and 5/6 Nx groups, receiving either placebo treatment or 400 mg·kg−1·day−1 HA over a 4-week period.
Results:
5/6 Nx per se resulted in adverse myocardial remodeling with aggravated cardiac function and associated cardiac overload as the most obvious alteration (−23% ejection fraction, P < 0.0001), as well as increased myocardial fibrosis (+80%, P = 0.0005) compared to placebo treated sham animals. HA treatment of 5/6 Nx rats has led to an improvement of ejection fraction (+24%, P = 0.0003) and fractional shortening (+21%, P = 0.0126), as well as a decrease of collagen deposition (−32%, P = 0.0041), left ventricular weight (−14%, P = 0.0468), and myocyte cross-sectional area (−12%, P < 0.0001). These changes were accompanied by a downregulation of atrial natriuretic factor (−65% P < 0.0001) and collagen type V alpha 1 chain (−44%, P = 0.0006). Sham animals revealed no significant changes in cardiac function, myocardial fibrosis, or any of the aforementioned molecular changes after drug treatment.
Conclusion:
Dietary HA supplementation appears to have the potential of preventing cardiac remodeling and improving heart function in the setting of chronic kidney disease. Our findings shed new light on HA as a possible new therapeutic agent for patients at high cardiovascular risk.
Routine quantitative assessment of left ventricular (LV) volumes with echocardiography is hindered by time-consuming methods requiring a manual trace of the LV cavity from two apical two-dimensional ...planes. Thus, the aim of this study was to evaluate faster new semiautomatic echocardiographic methods that could represent a feasible alternative for the assessment of LV volumes and ejection fraction (EF) in clinical practice.
Two semiautomatic methods, the automated EF (Auto-EF) for two-dimensional echocardiography and the 4D Auto LVQ tool for three-dimensional echocardiography (3DE), were compared with the biplane modified Simpson's method and cardiac magnetic resonance (CMR) imaging in 47 patients. To evaluate the accuracy of volumetry, additional in vitro measurements using water-filled latex balloons were performed with both modalities.
Results of balloon volumetry by echocardiography and CMR measurements were in good agreement with real balloon volumes. The mean LV EF was 45 ± 11% by Auto-EF, 45 ± 11% by 3DE, 48 ± 11% by Simpson's method, and 54 ± 12% by CMR. Linear regression and Bland-Altman analyses showed good associations for semiautomatic methods with Simpson's method (Auto-EF, r = 0.85, bias = 3%, limits of agreement LOA = 12%; 3DE, r = 0.79, bias = 3%, LOA = 14%), as well as with CMR (Auto-EF, r = 0.74, bias = 9%, LOA = 17%; 3DE, r = 0.73, bias = 9%, LOA = 17%). Intra- and interobserver variability were 6% and 12% with Auto-EF and 8% and 11% with 3DE, respectively.
Good correlations between semiautomatic echocardiographic parameters for assessment of LV volumes and EF could be observed when compared with Simpson's method or CMR. However, intertechnique agreement analysis of absolute LV volumes revealed considerable differences, with significant underestimation of volumes and EF with respect to CMR.
Abstract Objectives This study sought to evaluate myocardial perfusion reserve index (MPRI) and diastolic strain rate, both assessed by cardiac magnetic resonance (CMR) as a noninvasive tool for the ...detection of microvasculopathy. Background Long-term survival of cardiac allograft recipients is limited primarily by cancer and cardiac allograft vasculopathy (CAV). Besides epicardial CAV, diagnosed by coronary angiography, stenotic microvasculopathy was found to be an additional independent risk factor for survival after heart transplantation. Methods Sixty-three consecutive heart transplant recipients who underwent CMR, coronary angiography, and myocardial biopsy were enrolled. Stenotic vasculopathy in microvessels was considered in myocardial biopsies by immunohistochemistry and CAV was graded during coronary angiography according to International Society of Heart and Lung Transplantation criteria. In addition, by CMR microvasculopathy was assessed by myocardial perfusion reserve during pharmacologic hyperemia with adenosine and strain-encoded magnetic resonance using a modified spatial modulation of magnetization tagging pulse sequence in all patients. Results Decreasing MPRI and diastolic strain rates were observed in patients with decreasing microvessel luminal radius to wall thickness ratio and decreasing capillary density ( r = 0.45 and r = 0.61 for MPRI and r = 0.50 and r = 0.38 for diastolic strain rate, respectively; p < 0.005 for all). Using multivariable analysis, both MPRI and diastolic strain rate were robust predictors of stenotic microvasculopathy, independent of age, organ age, and CAV by International Society of Heart and Lung Transplantation criteria (hazard ratio: 0.07, p = 0.006 for MPRI; hazard ratio: 0.91, p = 0.002 for diastolic strain rate). Patients without stenotic microvasculopathy in the presence of no or mild CAV (n = 36) exhibited significantly higher median survival free of events, compared with patients with stenotic microvasculopathy in the presence of no or mild CAV (n = 18; p = 0.04 by log rank). Conclusions CMR represents a valuable noninvasive diagnostic tool, which may be used for the early detection of transplant microvasculopathy before the manifestation of CAV during surveillance coronary angiographic procedures.
To the Editor: In the present study we sought to investigate the predictive value of resting and inducible wall motion abnormalities (WMA) and of late gadolinium enhancement (LGE) for hard cardiac ...outcomes and for revascularization procedures in 3,138 patients undergoing dobutamine cardiac magnetic resonance (DCMR) in 2 tertiary centers (University Hospital Heidelberg; and German Heart Institute, Berlin) and during a long-term follow-up. Other events included clinically indicated revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). Because the results of the magnetic resonance examination might have triggered revascularization procedures, patients with "early" revascularization procedures within 3 months after DCMR were censored.
Objectives The purpose of this study was to determine the prognostic value of strain-encoded magnetic resonance imaging (SENC) during high-dose dobutamine stress cardiac magnetic resonance imaging ...(DS-MRI) compared with conventional wall motion readings. Background Detection of inducible ischemia by DS-MRI on the basis of assessing cine images is subjective and depends on the experience of the readers, which may influence not only the diagnostic classification but also the risk stratification of patients with ischemic heart disease. Methods In all, 320 consecutive patients with suspected or known coronary artery disease underwent DS-MRI, using a standard protocol in a 1.5T MR scanner. Wall motion abnormalities (WMA) and myocardial strain were assessed at baseline and during stress, and outcome data including cardiac deaths, nonfatal myocardial infarctions (“hard events”), and revascularization procedures performed >90 days after the MR scans were collected. Results Thirty-five hard events occurred during a 28 ± 9 month follow-up period, including 10 cardiac deaths and 25 nonfatal myocardial infarctions, and 32 patients underwent coronary revascularization. Using a series of Cox proportional-hazards models, both resting and inducible WMA offered incremental information for the assessment of hard cardiac events compared to clinical variables (chi-square = 13.0 for clinical vs. chi-square = 26.1 by adding resting WMA, p < 0.001, vs. chi-square = 39.3 by adding inducible WMA, p < 0.001). Adding visual SENC or quantitative strain rate reserve to this model further improved the prediction of outcome (chi-square = 50.7 vs. chi-square = 52.5, p < 0.001 for both). In a subset of patients (n = 175) who underwent coronary angiography, SENC yielded significantly higher sensitivity for coronary artery disease detection (96% vs. 84%, p < 0.02), whereas specificity and accuracy were not significantly different (88% vs. 94% and 93% vs. 88%, p = NS for both). Conclusions Strain-encoded MRI aids the accurate identification of patients at high risk for future cardiac events and revascularization procedures, beyond the assessment of conventional atherogenic risk factors and resting or inducible WMA on cine images. (Strain-Encoded Cardiac Magnetic Resonance Imaging as an Adjunct for Dobutamine Stress Testing; NCT00758654 )
Objectives The aim of our study was to investigate whether echocardiographic phase imaging (EPI) can predict response in patients who are considered for cardiac resynchronization therapy (CRT). ...Background CRT improves quality of life, exercise capacity, and outcome in patients with bundle-branch block and advanced heart failure. Previous studies used QRS duration to select patients for CRT; the accuracy of this parameter to predict functional recovery, however, is controversial. Methods We examined 42 patients with advanced heart failure (New York Heart Association NYHA functional class III to IV, QRS duration >130 ms, and ejection fraction <35%) before and 6 to 8 months after CRT. Left ventricular (LV) dyssynchrony was estimated by calculating the SD of time to peak velocities (Ts-SD) by conventional tissue Doppler imaging (TDI), and the mean phase index (mean EPI-Index) was calculated by EPI in 12 mid-ventricular and basal segments. Patients who were alive and had significant relative decrease in end-systolic LV volume of ΔESV ≥15% at 6 to 8 months of follow-up were defined as responders. All others were classified as nonresponders. Results The Ts-SD and the mean EPI-Index were related to ΔESV (r = 0.43 for Ts-SD and r = 0.67 for mean EPI-Index, p < 0.01 for both), and both parameters yielded similar accuracy for the prediction of LV remodeling (area under the curve of 0.87 for TDI vs. 0.90 for EPI, difference between areas = 0.03, p = NS) and ejection fraction (EF) improvement (area under the curve of 0.87 for TDI vs. 0.93 for EPI, difference between areas = 0.06, p = NS). Furthermore, patients classified as responders by EPI (mean EPI-Index ≤59%) showed significant improvement in NYHA functional class and in 6-min walk test (409 ± 88 m at follow-up vs. 312 ± 86 m initially, p < 0.001). Conclusion Echocardiographic phase imaging can predict functional recovery, reverse LV remodeling, and clinical outcomes in patients who undergo CRT. EPI is a method that objectively and accurately quantifies LV dyssynchrony and seems to be noninferior to TDI for the prediction of reverse LV remodeling and functional recovery.
Dilation of the ascending aorta was detected in 20 of 26 (77%) HCN4 mutation-positive patients in whom we could obtain images with diagnostic quality sufficient to assess the ascending aorta. Because ...our data suggested that dilation of the aorta in HCN4 mutation carriers displays an age-dependent penetrance, this was subsequently tested. Because aortic diameter is correlated with age in the general population (where the aortic diameter increases with 0.19 mm/year; p < 2e-16) (4) we used a multiple regression model to assess whether there was an additive effect of HCN4 mutation carriership on increase in aortic dilation with increasing age. ...we here report on multiple families harboring HCN4 mutations, who show significant dilation of the aorta ascendens, besides the recently established combined phenotype of bradycardia, NCCM, and mitral valve disease.
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