Hypertrophy Regression with N-AcetyLcysTeine in Hypertrophic CardioMyopathy (HALT-HCM): A Randomized Placebo Controlled Double Blind Pilot Study

RATIONALE: Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy and interstitial fibrosis are important risk factors for sudden death and morbidity in HCM. Oxidative stress is implicated in the pathogenesis of cardiac hypertrophy and fibrosis. Treatment with anti-oxidant N-acetylcysteine (NAC) reverses cardiac hypertrophy and fibrosis in animal models of HCM. OBJECTIVE: To determine effect sizes of NAC on indices of cardiac hypertrophy and fibrosis in patients with established HCM. METHODS AND RESULTS: Regression with N-AcetyLcysTeine in Hypertrophic CardioMyopathy (HALT-HCM) is a double blind randomized, sex-matched, placebo-control single center pilot study in patients with HCM. HCM patients, who had a left ventricular wall thickness of ≥15 mm, were randomized either to a placebo or to NAC (1:2 ratio, respectively). NAC was titrated up to 2.4 g per day. Clinical evaluation, blood chemistry, and six-minute walk test were performed every 3 months, and electrocardiography, echocardiography, and cardiac magnetic resonance imaging (CMR), the latter whenever not contraindicated, before and after 12 months of treatment. 85 out of 232 screened patients met the eligibility criteria, 42 agreed to participate; 29 were randomized to NAC and 13 to placebo groups. Demographics, echocardiographic, and CMR phenotypes at the baseline between the two groups were similar. Whole exome sequencing in 38 patients identified a spectrum of 42 pathogenic variants in genes implicated in HCM in 26 participants. Twenty-four patients in the NAC and eleven in the placebo groups completed the study. Six severe adverse events occurred in the NAC group but were considered unrelated to NAC. The effect sizes of NAC on the clinical phenotype, echocardiographic, and CMR indices of cardiac hypertrophy, function, and extent of late gadolinium enhancement, a surrogate for fibrosis, were small. CONCLUSIONS: Treatment with NAC for 12-months had small effect sizes on indices of cardiac hypertrophy or fibrosis. The small sample size of the HALT-HCM study hinders from making firm conclusions about efficacy of NAC in HCM

Optical phase conjugation for turbidity suppression in biological samples

Elastic optical scattering, the dominant light-interaction process in biological tissues, prevents tissues from being transparent. Although scattering may appear stochastic, it is in fact deterministic in nature. We show that, despite experimental imperfections, optical phase conjugation (λ = 532 nm) can force a transmitted light field to retrace its trajectory through a biological target and recover the original light field. For a 0.69-mm-thick chicken breast tissue section, we can enhance point-source light return by a factor of ~5 x 10^3 and achieve a light transmission enhancement factor of 3.8 within a collection angle of 29°. Additionally, we find that the reconstruction's quality, measured by the width of the reconstructed point source, is independent of tissue thickness (up to a thickness of 0.69 mm). This phenomenon may be used to enhance light transmission through tissue, enable measurement of small tissue movements, and form the basis of new tissue imaging techniques

The role of dobutamine stress cardiovascular magnetic resonance in the clinical management of patients with suspected and known coronary artery disease

BACKGROUND: Recent studies have demonstrated the consistently high diagnostic and prognostic value of dobutamine stress cardiovascular magnetic resonance (DCMR). The value of DCMR for clinical decision making still needs to be defined. Hence, the purpose of this study was to assess the utility of DCMR regarding clinical management of patients with suspected and known coronary artery disease (CAD) in a routine setting. METHODS AND RESULTS: We prospectively performed a standard DCMR examination in 1532 consecutive patients with suspected and known CAD. Patients were stratified according to the results of DCMR: DCMR-positive patients were recommended to undergo invasive coronary angiography and DCMR-negative patients received optimal medical treatment. Of 609 (40%) DCMR-positive patients coronary angiography was performed in 478 (78%) within 90 days. In 409 of these patients significant coronary stenoses ≥ 50% were present (positive predictive value 86%). Of 923 (60%) DCMR-negative patients 833 (90%) received optimal medical therapy. During a mean follow-up period of 2.1 ± 0.8 years (median: 2.1 years, interquartile range 1.5 to 2.7 years) 8 DCMR-negative patients (0.96%) sustained a cardiac event.In 131 DCMR-positive patients who did not undergo invasive angiography, 20 patients (15%) suffered cardiac events. In 90 DCMR-negative patients (10%) invasive angiography was performed within 2 years (range 0.01 to 2.0 years) with 56 patients having coronary stenoses ≥ 50%. CONCLUSION: In a routine setting DCMR proved a useful arbiter for clinical decision making and exhibited high utility for stratification and clinical management of patients with suspected and known CAD

Mutations in Protein-Binding Hot-Spots on the Hub Protein Smad3 Differentially Affect Its Protein Interactions and Smad3-Regulated Gene Expression

Hub proteins are connected through binding interactions to many other proteins. Smad3, a mediator of signal transduction induced by transforming growth factor beta (TGF-β), serves as a hub protein for over 50 protein-protein interactions. Different cellular responses mediated by Smad3 are the product of cell-type and context dependent Smad3-nucleated protein complexes acting in concert. Our hypothesis is that perturbation of this spectrum of protein complexes by mutation of single protein-binding hot-spots on Smad3 will have distinct consequences on Smad3-mediated responses.We mutated 28 amino acids on the surface of the Smad3 MH2 domain and identified 22 Smad3 variants with reduced binding to subsets of 17 Smad3-binding proteins including Smad4, SARA, Ski, Smurf2 and SIP1. Mutations defective in binding to Smad4, e.g., D408H, or defective in nucleocytoplasmic shuttling, e.g., W406A, were compromised in modulating the expression levels of a Smad3-dependent reporter gene or six endogenous Smad3-responsive genes: Mmp9, IL11, Tnfaip6, Fermt1, Olfm2 and Wnt11. However, the Smad3 mutants Y226A, Y297A, W326A, K341A, and E267A had distinct differences on TGF-β signaling. For example, K341A and Y226A both reduced the Smad3-mediated activation of the reporter gene by ∼50% but K341A only reduced the TGF-β inducibilty of Olfm2 in contrast to Y226A which reduced the TGF-β inducibility of all six endogenous genes as severely as the W406A mutation. E267A had increased protein binding but reduced TGF-β inducibility because it caused higher basal levels of expression. Y297A had increased TGF-β inducibility because it caused lower Smad3-induced basal levels of gene expression.Mutations in protein binding hot-spots on Smad3 reduced the binding to different subsets of interacting proteins and caused a range of quantitative changes in the expression of genes induced by Smad3. This approach should be useful for unraveling which Smad3 protein complexes are critical for specific biological responses

Defining left ventricular remodeling following acute ST-segment elevation myocardial infarction using cardiovascular magnetic resonance.

The assessment of post-myocardial infarction (MI) left ventricular (LV) remodeling by cardiovascular magnetic resonance (CMR) currently uses criteria defined by echocardiography. Our aim was to provide CMR criteria for assessing LV remodeling following acute MI.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site