Background Heart failure (HF) remains a complex syndrome with high morbidity and mortality, despite recent advancements in treatment. This persistent burden highlights the need for the discovery of novel therapeutic strategies. The natriuretic peptide (NP) system, through guanylyl cyclase receptors GC-A and GC-B, exhibits established protective actions mediated by the second messenger cGMP, offering a unique approach to addressing HF’s complex pathophysiology. Activation of GC-A by atrial and B-type NP leads to arterial vasodilation, natriuresis, anti-hypertrophic effects and inhibition of the renin angiotensin aldosterone system. Meanwhile, GC-B activation by C-type NP promotes anti-fibrotic, lusitropic and venodilatory actions. Several therapeutics are in clinical trials in HF that target either GC-A or GC-B, but not both. Furthermore, no endogenous NP can activate both receptor pathways. Therefore, our objective was to engineer a novel unimolecular peptide capable of dual activation of GC-A and GC-B receptors, leveraging their combined benefits. Hypothesis We hypothesized that combining key receptor-activating and peptide-stabilizing amino acids from GC-B and GC-A peptide activators would yield a dual-acting NP capable of activating both receptors, generating cGMP-mediated actions in vitro and in vivo. Methods RT-A1 was engineered using a rational drug design approach. In vitro, HEK 293 cells selectively expressing human GC-A or GC-B, human cardiac myocytes (HCMs) and fibroblasts (HCFs), were stimulated with RT-A1 at doses of 10-7 and 10-8 M for 10 minutes and intracellular cGMP was measured. In vivo, RT-A1 (50 pmol/kg/min) or vehicle was administered subcutaneously (SQ) via osmotic minipumps in normal mice (n=3-4/group) for 28 days. Plasma cGMP, blood pressure (BP) and cardiac size were assessed. Data are mean±SE, *p<0.05. Results RT-A1 dose-dependently increased cGMP in HEK GC-A and GC-B cells, confirming RT-A1 can engage both receptors. In HCMs and HCFs, RT-A1 significantly increased cGMP. Chronic SQ infusion of RT-A1 for 28 days in normal mice significantly reduced left ventricular to body weight ratio (2.7±0.04 vs.3.1±0.02 mg/g*) and increased plasma cGMP (61±7 vs. 29±4 pmol/mL*) compared to vehicle, confirming target engagement in vivo. There was no change in BP with RT-A1. Conclusions These findings demonstrate the successful engineering of RT-A1, a novel peptide-based dual GC-A and GC-B activator that generates cGMP in HCMs and HCFs. Notably, chronic SQ RT-A1 infusion significantly elevated plasma cGMP levels, which were coupled with anti-hypertrophic effects, without inducing tachyphylaxis or altering BP. RT-A1 may represent a first-in-class dual GC-A and GC-B peptide agonist with significant therapeutic potential for HF, warranting further investigation.

AIMS:Atherosclerotic carotid plaque assessments have not been integrated into routine clinical practice due to the time-consuming nature of both imaging and measurements. Plaque score, Rotterdam method, is simple, quick, and only requires 4-6 B-mode ultrasound images. The aim was to assess the benefit of plaque score in a community cardiology clinic to identify patients at risk for major adverse cardiovascular events (MACE). METHODS AND RESULTS:Patients ≥ 40 years presenting for risk assessment were given a carotid ultrasound. Exclusions included a history of vascular disease or MACE and being >75 years. Kaplan-Meier curves and hazard ratios were performed. The left and right common carotid artery (CCA), bulb, and internal carotid artery were given 1 point per segment if plaque was present (plaque scores 0-6). Administrative data holdings at ICES were used for 10-year event follow-up. Of 8472 patients, 60% were females (n = 5121). Plaque was more prevalent in males (64% vs. 53.9%; P < 0.0001). The 10-year MACE cumulative incidence estimate was 6.37% with 276 events (males 6.9% vs. females 6.0%; P = 0.004). Having both maximal CCA intima media thickness < 1.00 mm and plaque score = 0 was associated with less events. A plaque score < 2 was associated with a low 10-year event rate (4.1%) compared with 2-4 (8.7%) and 5-6 (20%). CONCLUSION:A plaque score ≥ 2 can re-stratify low-intermediate risk patients to a higher risk for events. Plaque score may be used as a quick assessment in a cardiology office to guide treatment management of patients.

Background:Obesity is an important risk factor in heart failure with preserved ejection fraction (HFpEF), but the precise mechanisms that drive obesity-associated cardiac remodeling are not well understood. Our previous work has shown that increased expression of the natriuretic peptide clearance receptor (Nprc) may drive cardiac remodeling in response to high fat diet. In this study, we hypothesized that Nprc plays a central role in preventing and reversing experimental HFpEF. Methods:Nprc knockout mice were generated to induce global, cardiomyocyte-specific, or adipocyte-specific disruption of the Nprc (Npr3) gene. HFpEF was induced by the 2-hit stress of L-NAME and high fat diet. Outcomes measured included echocardiography, exercise endurance, invasive catheterization, and histologic assessment. Differential gene expression in adipocyte Nprc knockout visceral adipose tissue was investigated via bulk RNA sequencing and validated by RT-qPCR and culture of H9C2 cells with or without Wnt5a treatment. Adipocyte-mediated Wnt ligand release was interrupted in vivo via LGK974 injection in mice subjected to HFpEF conditions. Results:Global inducible Nprc knockout prevented and reversed structural, hemodynamic, echocardiographic, and exercise tolerance features of HFpEF. This effect was found to be driven by adipocyte-specific, not cardiomyocyte-specific Nprc expression. Bulk RNA sequencing of adipocyte-specific Nprc knockout in peri-gonadal visceral adipose tissue identified downregulation of several secretory pathways, including Wnt pathways. Wnt5a was identified as one of the most downregulated genes by RNA sequencing and specifically validated by qPCR. Wnt5a exposure increased cardiomyocyte hypertrophy in vitro, and LGK974 (PORCN inhibitor) treatment in vivo decreased circulating Wnt5a levels and improved cardiac remodeling in HFpEF. Conclusions:Our study identifies a novel crosstalk mechanism between cardiomyocytes and adipocytes in obesity-associated HFpEF driven by natriuretic peptide-mediated inhibition of release of Wnt5a from adipocytes.

BACKGROUND:Cardiac sarcomeres generate the fundamental forces of each heartbeat. Cardiac myocytes (CMs) express nonmuscle versions of muscle-specific sarcomere proteins, which have unknown relevance to sarcomere function or heart physiology. METHODS:Expression levels of nonmuscle cytoskeletal proteins versus muscle-specific counterparts in CMs were directly compared. Function and subcellular localization of the nonmuscle protein ACTN4 (alpha-actinin-4) in induced pluripotent stem cell-derived CMs were determined using small interfering RNA-mediated knockdown, overexpression, and pharmacological perturbation. Impacts of ACTN4 depletion or knockout on cardiac structure function were evaluated in zebrafish embryos. Left ventricular Actn4 expression was evaluated in a mouse model of chronic pressure overload. Human ACTN4 gene variants were tested for association with heart failure with preserved ejection fraction using the BioVU biobank. A meta-analysis was conducted on ventricular data sets of human cardiomyopathies. RESULTS:ACTN4 expression in human CMs met or exceeded some muscle-specific genes (eg, MYH6). Anti-ACTN4 antibodies colocalized with anti-ACTN2 (alpha-actinin-2) at the sarcomere Z-disc in human, mouse, and zebrafish ventricular tissue. Coimmunoprecipitation and structural modeling suggest a Z-disc ACTN4:ACTN2 complex. ACTN4 depletion from induced pluripotent stem cell-derived CMs resulted in increased sarcomere assembly, decreased sarcomere component turnover, elevated contractile force, and contractility-dependent cellular hypertrophy. Overexpression of an ACTN4 actin-binding chimera suppressed sarcomere assembly. In zebrafish embryos, ACTN4 depletion/knockout induced ventricular hypercontractility and atrial enlargement. Selective modulation of ventricular contractility was sufficient to prevent or phenocopy atrial remodeling. In mice, Actn4, but not Actn2, was upregulated in the left ventricular following pressure overload. One of 14 ACTN4 single-nucleotide polymorphisms was associated with reduced heart failure with preserved ejection fraction risk in humans, and prepublished studies suggest a pattern of ventricular ACTN4 upregulation in certain human cardiomyopathies. CONCLUSIONS:A nonmuscle actinin (ACTN4) populates the cardiac Z-disc. ACTN4 regulates sarcomeric architecture in CMs. ACTN4 influences fractional shortening at the cell level and contractility at the tissue level. Changes in ventricular ACTN4 levels are associated with remodeling and may influence clinical outcomes related to heart failure.

Aims:Stress echocardiography (SE), though widely accessible, has some limitations in its diagnostic test characteristics for predicting major adverse cardiovascular events (MACEs). Carotid plaque score provides direct detection of subclinical atherosclerosis and can be integrated into the stress protocol. The aim of our study was to assess the value of adding a carotid plaque score to SE to enhance the test diagnostics for predicting MACE in low-intermediate-risk patients. Methods and results:Patients aged 40-75 years referred for SE received a carotid ultrasound and were followed for 5-year MACE. Hard MACE was defined as a composite of cardiovascular death, non-fatal stroke or myocardial infarction, and emergency coronary revascularization. Soft MACE included non-emergency coronary revascularization. Patients aged >75 years, on a statin, with previously known vascular disease, a history of stroke, myocardial infarction, vascular intervention, or a resting wall motion abnormality on a baseline echo were excluded. Administrative data holdings housed at the Institute of Clinical Evaluative Sciences, ICES, were used for event follow-up. Of the 2588 patients, there were 49 cumulative incidence hard MACE and 119 soft MACE. Carotid plaque score improved the sensitivity of SE for predicting 1- and 5-year MACE. A plaque score threshold value of ≥2 provided clear differentiation of patients who experienced MACE in both positive and non-positive (negative/inconclusive for ischaemia) SE results. Conclusion:Plaque score enhances diagnostic test characteristics of SE. The combination of carotid ultrasound with SE is an important new tool for cardiovascular risk assessment. This simple tool may help differentiate risk in patients with non-positive SE results.

HomeCirculationVol. 148, No. 2Myocardial Neprilysin Is Increased in Hypertrophic Cardiomyopathy Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBMyocardial Neprilysin Is Increased in Hypertrophic Cardiomyopathy David W.J. Armstrong, Lance A. Riley, Yan Ru Su, Ashish S. Shah, Tarek Absi, Deepak K. Gupta, Quinn S. Wells, D. Marshall Brinkley, Lynne W. Stevenson and W. David Merryman David W.J. ArmstrongDavid W.J. Armstrong Correspondence to: David W.J. Armstrong, MD, PhD, Room 9445, MRB4, 2213 Garland Ave, Nashville, TN 37232. Email E-mail Address: [email protected] https://orcid.org/0000-0003-3198-7277 From the Division of Cardiovascular Medicine (D.W.J.A., Y.R.S., D.K.G., Q.S.W., D.M.B., L.W.S.), Vanderbilt University, Nashville, TN. , Lance A. RileyLance A. Riley Departments of Biomedical Engineering (L.A.R., W.D.M.), Vanderbilt University, Nashville, TN. Foresight Diagnostics Inc., Aurora, CO (L.A.R.). , Yan Ru SuYan Ru Su From the Division of Cardiovascular Medicine (D.W.J.A., Y.R.S., D.K.G., Q.S.W., D.M.B., L.W.S.), Vanderbilt University, Nashville, TN. , Ashish S. ShahAshish S. Shah Cardiac Surgery (A.S.S., T.A.), Vanderbilt University, Nashville, TN. , Tarek AbsiTarek Absi Cardiac Surgery (A.S.S., T.A.), Vanderbilt University, Nashville, TN. , Deepak K. GuptaDeepak K. Gupta https://orcid.org/0000-0003-2191-3485 From the Division of Cardiovascular Medicine (D.W.J.A., Y.R.S., D.K.G., Q.S.W., D.M.B., L.W.S.), Vanderbilt University, Nashville, TN. , Quinn S. WellsQuinn S. Wells https://orcid.org/0000-0003-3899-0313 From the Division of Cardiovascular Medicine (D.W.J.A., Y.R.S., D.K.G., Q.S.W., D.M.B., L.W.S.), Vanderbilt University, Nashville, TN. Biomedical Informatics (Q.S.W.), Vanderbilt University, Nashville, TN. Pharmacology (Q.S.W.), Vanderbilt University, Nashville, TN. , D. Marshall BrinkleyD. Marshall Brinkley https://orcid.org/0000-0002-9511-7767 From the Division of Cardiovascular Medicine (D.W.J.A., Y.R.S., D.K.G., Q.S.W., D.M.B., L.W.S.), Vanderbilt University, Nashville, TN. , Lynne W. StevensonLynne W. Stevenson https://orcid.org/0000-0002-8626-5258 From the Division of Cardiovascular Medicine (D.W.J.A., Y.R.S., D.K.G., Q.S.W., D.M.B., L.W.S.), Vanderbilt University, Nashville, TN. and W. David MerrymanW. David Merryman https://orcid.org/0000-0001-9662-1503 Departments of Biomedical Engineering (L.A.R., W.D.M.), Vanderbilt University, Nashville, TN. Originally published10 Jul 2023https://doi.org/10.1161/CIRCULATIONAHA.123.064153Circulation. 2023;148:167–169A frequent narrative is that no medical therapy modifies the natural history of hypertrophic cardiomyopathy (HCM), but evidence shows valsartan and mavacamten modify disease progression in HCM. Yet, no medical therapy has been shown to modify fibrosis in HCM. Given the role of fibrosis in the risk of adverse outcomes, there is a need to identify pathways that may influence HCM development and progression.Neprilysin (NEP) is the primary enzyme that degrades natriuretic peptides. Myocardial expression and activity of NEP is elevated in dilated cardiomyopathy,1 and NEP inhibition with the angiotensin receptor blocker/neprilysin inhibitor (ARNi) sacubitril/valsartan reduces the risk of heart failure (HF) hospitalization and death in patients with HF with reduced ejection fraction (HFrEF). However, in patients with HF with preserved EF (HFpEF), there was no reduction in death. Patients with HCM were excluded from trials evaluating ARNi in HF, pointing to an unmet clinical need to determine the efficacy of ARNi in HCM. Further, myocardial expression of NEP in patients with HCM has not been previously described. Herein, we examine myocardial expression of NEP in HCM.We extracted publicly available gene expression data from 3 independent cohorts of patients with HCM. In all 3 cohorts, the expression of MME (membrane metalloendopeptidase), the gene encoding NEP, was significantly higher in patients with HCM versus controls (unused healthy donor hearts).2–4MME expression was higher in obstructive HCM (oHCM) versus controls using both microarray2 (Figure [A]) and RNA sequencing3 (Figure [B]). In patients with end-stage nonobstructive HCM and dilated cardiomyopathy at the time of transplant, single nucleus RNA sequencing revealed higher MME expression only in fibroblasts, and the degree of MME elevation was not significantly different in end-stage nonobstructive HCM versus dilated cardiomyopathy (Figure [C]). A previous report demonstrated higher myocardial MME expression and NEP activity in the setting of severe aortic senosis.1 To further determine whether MME expression is altered in myocardial hypertrophy that is not due to HCM, we examined patients with HFpEF and mild to moderate hypertrophy without HCM. MME expression was also slightly higher versus controls but significantly lower compared with patients having HFrEF at transplant. (Figure [D]).5 Of note, the latter study analyzed right ventricular septal samples, but gene expression profiles strongly correlated between right and left ventricular tissue.5 Collectively, these data suggest that convergence of MME transcription is a feature of cardiomyopathy independent of etiology.Download figureDownload PowerPointFigure. Myocardial neprilysin expression in hypertrophic cardiomyopathy. Myocardial MME is higher in patients with oHCM at septal myectomy vs control using microarray (oHCM n=106; control n=39; A) and RNAseq (oHCM n=18; control n=5; B). C, Higher myocardial MME gene expression is specific to fibroblasts in patients with end-stage nHCM (n=15) and DCM (n=11) at the time of transplant compared with controls (n=16). D, Higher myocardial MME expression in patients who have HFpEF (n=41) and HFrEF (n=30) compared with controls (n=30), with MME expression being significantly higher in HFrEF compared with HFpEF (P=4.88E-7). Note: the data in B through D are presented as Log2 fold change compared with controls; therefore, there are no bars for control groups. In the Vanderbilt University Medical Center cohort of patients with oHCM (n=36), MME expression is higher using quantitative polymerase chain reaction (E) compared with controls (n=8). The increase in MME expression parallels higher neprilysin concentration (using AlphaLISA; PerkinElmer) and activity (using solid-phase activity assay) compared with controls (E through G). Collectively, these data indicate that convergence of MME transcription is a feature of cardiomyopathy independent of etiology, and neprilysin may be a viable therapeutic target in patients with HCM. In A and E through G, t test or Mann-Whitney U test were used when appropriate. Details regarding statistical analyses for B through D can be found in Marron et al,3 Chaffin et al,4 and Hahn et al.5 Data are presented as mean±SD where error bars are present.DCM indicates dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy MME, membrane metalloendopeptidase; nHCM, nonobstructive hypertrophic cardiomyopathy; oHCM, obstructive hypertrophic cardiomyopathy; RNAseq, RNA sequencing; snRNAseq, single nucleus RNA sequencing.Next, we tested whether higher MME transcription was associated with higher myocardial NEP expression and activity in patients with oHCM. Myocardial tissue was obtained from the Vanderbilt University Medical Center Cardiovascular Core Laboratory, consisting of 36 patients with oHCM at myectomy and 8 nontransplanted healthy donor hearts. This study was approved by the Vanderbilt University Medical Center institutional review board, and all participants gave informed consent. Among patients with oHCM, the mean age was 51±15 years, and 23 (64%) were women, with a mean resting left ventricular outflow tract gradient of 54±49 mm Hg, mean provocable peak gradient of 106±70 mm Hg, mean septal thickness of 2.2±0.5 cm, and mean left ventricular EF of 65±10% (range, 53–88). Among 15 patients who underwent genetic screening, 7 (46%) had a pathogenic sarcomere mutation. A defibrillator was present in 10 (27%) at the time of surgery. Cardiac magnetic resonance imaging was performed in 25 (69%) before surgery, of whom 20 (80%) had late gadolinium enhancement; none were on mavacamten. Consistent with the aforementioned data, MME expression was significantly higher in patients with oHCM versus controls using quantitative polymerase chain reaction (Figure [D]). Myocardial NEP protein expression and activity were also significantly higher in patients with oHCM versus controls (Figure [E and F]).Future studies are required to define the mechanism of NEP elevation in HCM. Higher myocardial NEP may degrade natriuretic peptides, which exert antihypertrophic and antifibrotic effects that would be favorable in HCM. Future studies are required to determine whether increased NEP contributes to natriuretic peptide deficiency and whether ARNi modifies myocyte and fibroblast biology in HCM. Alternatively, ARNi may prevent degradation of other substrates with favorable biologic actions such as adrenomedullin and glucagon-like peptide-1. Conversely, ARNi may increase endothelin, which would be deleterious in HCM. These data also suggest that innovative natriuretic peptide-based therapies for HCM may require analogs with resistance to enzymatic degradation by NEP. The efficacy of ARNi in HCM has been demonstrated in 2 case reports in patients with HCM who progressed to develop systolic dysfunction. The phase II SILICOFCM trial (Sacubitril/Valsartan vs Lifestyle in Hypertrophic Cardiomyopathy; NCT03832660) will evaluate the effect of ANRi in HCM with change in peak oxygen consumption as the primary outcome.Limitations of our study include exclusion of patients with end-stage nonobstructive HCM in evaluating NEP protein expression and activity, exclusion of patients with less severe disease or symptomatic burden, and lack of samples available to examine systemic NEP concentration and activity, which may be altered in HCM.Overall, we report that HCM is associated with elevation of myocardial NEP. These data provide insight into the potential role of NEP in the pathophysiology of HCM.The data that support the findings of this study are available from the corresponding author upon reasonable request.Article InformationAcknowledgmentsThe authors thank Julie A. Bastarache, MD (Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center) for use of the BioTek plate reader; Ashish Chougule, PhD (PerkinElmer), Tim Prickett, PhD (Christchurch Heart Institute, University of Otago), and Oi Wah Liew, PhD (Department of Medicine, National University of Singapore) for helpful discussions regarding the AlphaLISA assay; and J. Scott Miners, PhD (Institute of Clinical Neurosciences, University of Bristol), for helpful discussion regarding the solid-phase neprilysin activity assay.Sources of FundingThis work was supported by a grant from the Vanderbilt Institute for Clinical and Translational Research (VR55836) and support from the National Institutes of Health (grant F32HL165917 to D.W.J.A. and grant R35HL135790 to W.D.M.).Nonstandard Abbreviations and AcronymsARNiangiotensin receptor blocker/neprilysin inhibitorEFejection fractionHCMhypertrophic cardiomyopathyHFheart failureMMEmembrane metalloendopeptidaseNEPneprilysinoHCMobstructive hypertrophic cardiomyopathyDisclosures Dr Gupta has received research support from Imara, Inc. The other authors report no relevant disclosures.FootnotesFor Sources of Funding and Disclosures, see page 169.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: David W.J. Armstrong, MD, PhD, Room 9445, MRB4, 2213 Garland Ave, Nashville, TN 37232. Email david.w.armstrong@vumc.orgReferences1. Fielitz J, Dendorfer A, Pregla R, Ehler E, Zurbrügg HR, Bartunek J, Hetzer R, Regitz-Zagrosek V. Neutral endopeptidase is activated in cardiomyocytes in human aortic valve stenosis and heart failure.Circulation. 2002; 105:286–289. doi: 10.1161/hc0302.103593LinkGoogle Scholar2. Bos JM, Hebl VB, Oberg AL, Sun Z, Herman DS, Teekakirikul P, Seidman JG, Seidman CE, Dos Remedios CG, Maleszewski JJ, et al. Marked up-regulation of ACE2 in hearts of patients with obstructive hypertrophic cardiomyopathy: implications for SARS-CoV-2–mediated COVID-19.Mayo Clin Proc. 2020; 95:1354–1368. doi: 10.1016/j.mayocp.2020.04.028CrossrefMedlineGoogle Scholar3. Maron BA, Wang R-S, Shevtsov S, Drakos SG, Arons E, Wever-Pinzon O, Huggins GS, Samokhin AO, Oldham WM, Aguib Y, et al. Individualized interactomes for network-based precision medicine in hypertrophic cardiomyopathy with implications for other clinical pathophenotypes.Nat Commun. 2021; 12:873. doi: 10.1038/s41467-021-21146-yCrossrefMedlineGoogle Scholar4. Chaffin M, Papangeli I, Simonson B, Akkad A-D, Hill MC, Arduini A, Fleming SJ, Melanson M, Hayat S, Kost-Alimova M, et al. Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy.Nature. 2022; 608:174–180. doi: 10.1038/s41586-022-04817-8CrossrefMedlineGoogle Scholar5. Hahn VS, Knutsdottir H, Luo X, Bedi K, Margulies KB, Haldar SM, Stolina M, Yin J, Khakoo AY, Vaishnav J, et al. Myocardial gene expression signatures in human heart failure with preserved ejection fraction.Circulation. 2021; 143:120–134. doi: 10.1161/CIRCULATIONAHA.120.050498LinkGoogle Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. 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Background High-sensitivity cardiac troponin (hs-cTn) assays enhance detection of lower circulating troponin concentrations, but the impact on outcomes in clinical practice is unclear. Our objective was to compare outcomes of chest pain patients discharged from emergency departments (EDs) using hs-cTn and conventional troponin (cTn) assays. Methods We conducted an observational study of chest pain patients aged 40-105 years who presented to an ED from April 1, 2013, to March 31, 2017, and were discharged home. We compared 30-day and 1-year outcomes of EDs that used hs-cTn versus cTn assays. The primary outcome was a composite of all-cause death, myocardial infarction or unstable angina. Comparisons were conducted with (1) no adjustment; (2) adjustment for demographic, socioeconomic, and hospital characteristics; and (3) full clinical adjustment. Results Among the 394,910 patients, 62,138 (15.7%) were evaluated at hs-cTn EDs and 332,772 (84.3%) were evaluated at cTn EDs. Patients discharged from hs-cTn EDs were less likely to have diabetes, hypertension, or prior heart disease. At 30 days, the unadjusted primary outcome rate was lower in hs-cTn EDs (0.9% vs 1.0%, P < .001). The 30-day hazard ratios for the primary outcome were 0.84 (95% CI 0.77-0.92) for no adjustment and 0.98 (95% CI 0.88-1.08) for full adjustment. Over 1 year, patients discharged from hs-cTn EDs had significantly fewer primary outcomes (3.7% vs 4.1%, P < .001) and lower hazard ratio (0.93; 95% CI 0.89-0.98) even after full adjustment. Conclusions Hs-cTn testing was associated with a significantly lower adjusted hazard of myocardial infarction, angina, and all-cause hospitalization at 1 year but not 30 days.

Atrial fibrillation (AF) is a frequent complication of acute coronary syndromes (ACS) and is associated with an increased risk of in-hospital and long-term mortality. Our objective was to determine whether patients with previous AF and those who presented with or developed AF during their ACS hospitalization (new onset) have an associated increased risk of short- and mid-term cardiovascular events, death, or a composite. We included 7,228 patients from the Global Registry of Acute Coronary Events electrocardiogram core laboratory substudy, who presented with an ACS. Associated multivariable-adjusted risk of death and major adverse cardiovascular events (MACE) of death, re-infarction, or stroke in-hospital and at 6 months were estimated. New-onset AF and previous AF patients had higher rates of in-hospital mortality (14.9% and 10.9%, respectively) compared with patients without AF (3.8%; both p < 0.001). New-onset AF and previous AF patients had higher rates of 6-month mortality (22.3% and 21.3%, respectively) compared with patients without AF (7.0%; both p <0.001). After adjustment for clinical prognosticators, including those in the Global Registry of Acute Coronary Events risk model, new-onset AF was associated with higher mortality in-hospital (ORadj 1.87, 95% CI 1.30 to 2.70) and at 6 months (ORadj 1.75, 95% CI 1.29 to 2.39) as well as MACE at 6 months (ORadj 1.43, 95% CI 1.12 to 1.81) compared with patients without AF, but were at similar risk compared to those with previous AF (all p > 0.40). In conclusion, the risk of death and MACE after ACS in patients with new-onset and previous AF appears similar and significantly increased compared with patients without AF.

BackgroundThe postexercise ankle-brachial index (ABI) is useful in patients with suspected peripheral arterial disease (PAD) and a normal resting ABI. Our objective was to determine the independent predictors of an abnormal postexercise ABI. HypothesisWe hypothesized that the lowest ankle systolic pressure to calculate the resting ABI would be associated with an abnormal post-exercise ABI. MethodsAmong 619 consecutive patients referred for suspected PAD, we calculated the postexercise ABI in patients with a normal resting ABI. An ABI <0.90 at rest was considered abnormal. We investigated 3 definitions of an abnormal postexercise ABI, defined as either <0.90, or >5% or >20% reduction compared with rest. ResultsUsing multivariate analysis, the lowest ABI (calculated using the lowest and not the highest ankle systolic pressure) was consistently the most powerful independent predictor of an abnormal postexercise ABI. Patients with an abnormal lowest resting ABI were significantly more likely to have an abnormal postexercise ABI, as well as a significantly greater reduction in the ABI compared with rest. The lowest ABI had a high specificity (95%) but low sensitivity (82%) for a postexercise ABI <0.90. ConclusionsAn abnormal lowest ABI (calculated with the lowest ankle systolic pressure) is the most important independent predictor of an abnormal ABI response to exercise in patients with a conventionally normal ABI. All such patients should be exercised and their ABI measured postexercise.

A 63-year-old female with no significant past medical history was presented with a 5-day history of progressive opsoclonus-myoclonus, headaches, and fevers. Her workup was significant only for positive West-Nile Virus serum serologies. She received a 2-day course of intravenous immunoglobulin (IvIG). At an 8-week follow up, she had a complete neurological remission. Adult-onset opsoclonus-myoclonus syndrome is a rare condition for which paraneoplastic and infectious causes have been attributed. To our knowledge, this is the first case reported of opsoclonus-myoclonus secondary to West-Nile Virus treated with intravenous immunoglobulin monotherapy.

ObjectiveMeasurement of office blood pressure using a fully automated sphygmomanometer that takes multiple readings with the patient resting quietly alone has been called automated office blood pressure (AOBP). Almost all AOBP research has involved the patient resting alone in an examining room, which is often impractical in a clinical setting. The possibility that valid AOBP readings can be obtained with the patient resting quietly in a waiting room was examined. MethodsAOBP readings using the BpTRU device recorded with the patient resting quietly in the waiting room were obtained in patients referred for ambulatory BP monitoring. The relationship between the AOBP and the awake ambulatory blood pressure (AABP) (mmHg) was examined. ResultsIn 422 patients, the mean (±SD) AABP (139.4±13.4/80.7±10.6) was similar to the mean AOBP recorded in the waiting room (140.5±19.8/83.1±11.2), with both values being significantly lower than a single office BP (155.1±18.7/90.2±12.7) taken by a nurse. In the 178 untreated patients, the mean systolic AOBP and AABP were almost identical, with the diastolic AOBP being 1.5 mmHg higher. Bland–Altman plots for systolic BP showed a relatively consistent relationship for AOBP versus the AABP over the range of BPs recorded. The sensitivity, specificity, and accuracy for AOBP versus AABP were comparable with the values obtained with AOBP recorded previously in an examining room. ConclusionAOBP readings recorded in a waiting room are comparable with the AABP, making it possible to obtain AOBP in clinical practice without the need to occupy an examining room.

The developmental origins of health and disease refer to the theory that adverse maternal environments influence fetal development and the risk of cardiovascular disease in adulthood. We used the chronically hypertensive atrial natriuretic peptide knockout (ANP-/-) mouse as a model of gestational hypertension, and attempted to determine the effect of gestational hypertension on left ventricular (LV) structure and function in adult offspring. We crossed normotensive ANP+/+ females with ANP-/- males (yielding ANP+/-(WT) offspring) and hypertensive ANP-/- females with ANP+/+ males (yielding ANP+/-(KO) offspring). Cardiac gene expression was measured using real-time quantitative PCR. Cardiac function was assessed using echocardiography. Daily injections of isoproterenol (ISO) were used to induce cardiac stress. Collagen deposition was assessed using picrosirius red staining. All mice were 10 weeks of age. Gestational hypertension resulted in significant LV hypertrophy in offspring, with no change in LV function. Treatment with ISO resulted in significant LV diastolic dysfunction with a restrictive filling pattern (increased E/A ratio and E/e') and interstitial myocardial fibrosis only in ANP+/-(KO) and not ANP+/-(WT) offspring. Gestational hypertension programs adverse LV structural and functional remodeling in offspring. These data suggest that adverse maternal environments may increase the risk of heart failure in offspring later in life.

Objective: To determine the effect of gestational hypertension on the developmental origins of blood pressure (BP), altered kidney gene expression, salt-sensitivity and cardiac hypertrophy (CH) in adult offspring.Methods: Female mice lacking atrial natriuretic peptide (ANP-/-) were used as a model of gestational hypertension. Heterozygous ANP+/- offspring was bred from crossing either ANP+/+ females with ANP-/- males yielding ANP+/-(WT) offspring, or from ANP-/- females with ANP+/+ males yielding ANP+/-(KO) offspring. Maternal BP during pregnancy was measured using radiotelemetry. At 14 weeks of age, offspring BP, gene and protein expression were measured in the kidney with real-time quantitative PCR, receptor binding assay and ELISA.Results: ANP+/-(KO) offspring exhibited normal BP at 14 weeks of age, but displayed significant CH (P < 0.001) as compared to ANP+/-(WT) offspring. ANP+/-(KO) offspring exhibited significantly increased gene expression of natriuretic peptide receptor A (NPR-A) (P < 0.001) and radioligand binding studies demonstrated significantly reduced NPR-C binding (P = 0.01) in the kidney. Treatment with high salt diet increased BP (P < 0.01) and caused LV hypertrophy (P < 0.001) and interstitial myocardial fibrosis only in ANP+/-(WT) and not ANP+/-(KO) offspring, suggesting gestational hypertension programs the offspring to show resistance to salt-induced hypertension and LV remodeling. Our data demonstrate that altered maternal environments can determine the salt-sensitive phenotype of offspring. (C) 2013 Elsevier B.V. All rights reserved.

Sex-specific differences in hormone-mediated gene regulation may influence susceptibility to cardiac hypertrophy, a primary risk factor for cardiovascular disease. Under hormonal influence, natriuretic peptide (NP) and nitric oxide synthase (NOS) systems modulate cardio-protective gene programs through common downstream production of cyclic guanosine 3′–5′ monophosphate (cGMP). Ablation of either system can adversely affect cardiac adaptation to stresses and insults. This study elucidates sex-specific differences in cardiac NP and NOS system gene expression and assesses the impact of the estrous cycle on these systems using the atrial natriuretic peptide gene-disrupted (ANP −/− ) mouse model. Left ventricular expression of the NP and NOS systems was analyzed using real-time quantitative polymerase chain reaction in 13- to 16-week-old male, proestrous and estrous female ANP +/+ and ANP −/− mice. Left ventricular and plasma cGMP levels were measured to assess the convergent downstream effects of the NP and NOS systems. Regardless of genotype, males had higher expression of the NP system while females had higher expression of the NOS system. In females, transition from proestrus to estrus lowered NOS system expression in ANP +/+ mice while the opposite was observed in ANP −/− mice. No significant changes in left ventricular cGMP levels across gender and genotype were observed. Significantly lower plasma cGMP levels were observed in ANP −/− mice compared to ANP +/+ mice. Regardless of genotype, sex-specific differences in cardiac NP and NOS system expression exist, each sex enlisting a predominant system to conserve downstream cGMP. Estrous cycle-mediated alterations in NOS system expression suggests additional hormone-mediated gene regulation in females.

Background: Sex dimorphism in the prevalence, onset, development and progression of cardiovascular disease (CVD) is well recognized, but the mechanisms whereby sex hormones are believed to confer cardioprotection are still not fully understood. Objective: This study more closely delineates the effect of 17β-Estradiol (E2) on the expression and signaling of the cardiac NP and NOS systems, well-known cardioprotective modulators of the cardiac hypertrophy (CH) response, that both contribute to downstream production of cyclic guanosine 3’,5’-monophosphate (cGMP). Materials and Methods: Ovariectomized (OVX) female ANP+/+ and ANP-/- mice, 6 - 7 weeks old, were subjected to a five-week treatment with E2 (100 μg/100 μL/day) or vehicle (VEH). Left ventricle from these treatment groups, along with that from age-matched male ANP+/+ and ANP-/- mice was used to assess expression of these systems by real-time quantitative PCR (qPCR). Left ventricle tissue and plasma cGMP were measured by enzyme immunoassay to assess alterations in resultant downstream signaling. Results: NP system expression was unchanged across genotype, sex and E2 treatment. Sex-specific differences in NOS system expression were observed; female mice showed an increased expression of NOS system genes that were significantly elevated in all but one of the E2 treatment groups. Left ventricle tissue cGMP remained unchanged across genotype, sex and E2 treatment. Plasma cGMP levels were unchanged in ANP+/+ treatment groups. In ANP-/- treatment groups, plasma cGMP in the female OVX-E2 mice was significantly higher compared to male and female OVX-VEH mice. Conclusion: These findings demonstrate that in the absence of ANP, E2 upregulates cardiac NOS system expression to produce cGMP. This study confirms the importance of the cardiac NOS system in females; this particular system may be a promising future target for sex-specific treatments and therapies for CVD in women.