Highlights From the Circulation Family of Journals
2017; Lippincott Williams & Wilkins; Volume: 135; Issue: 22 Linguagem: Inglês
10.1161/circulationaha.117.029235
ISSN1524-4539
AutoresZhenjiang Yang, Joseph K. Prinsen, Kevin Bersell, Wangzhen Shen, Liudmila V. Yermalitskaya, Tatiana N. Sidorova, Paula B. Luis, Lynn Hall, Wei Zhang, Liping Du, Ginger L. Milne, Patrick S. Tucker, Alfred L. George, Courtney Campbell, Robert Pickett, Christian M. Shaffer, Nagesh Chopra, Tao Yang, Björn C. Knollmann, Dan M. Roden, Katherine T. Murray, Dana Fourey, Melanie Care, Katherine A. Siminovitch, Adaya Weissler‐Snir, Waseem Hindieh, Raymond H. Chan, Michael H. Gollob, Harry Rakowski, Arnon Adler, Philipp Lurz, Maximilian von Roeder, Karl‐Philipp Rommel, Johannes T. Kowallick, Stephan Blazek, Christian Besler, Karl Fengler, Joachim Lotz, Gerd Hasenfuß, Christian Lücke, Matthias Gutberlet, Gerhard Schüler, Andreas Schuster, Jacob Lønborg, Khurram Nasir,
Tópico(s)Receptor Mechanisms and Signaling
ResumoHomeCirculationVol. 135, No. 22Highlights From the Circulation Family of Journals Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBHighlights From the Circulation Family of Journals Originally published30 May 2017https://doi.org/10.1161/CIRCULATIONAHA.117.029235Circulation. 2017;135:2196–2201Circulation: Arrhythmia and ElectrophysiologyAzithromycin is a commonly used antibiotic and is known to increase the risk of cardiovascular and sudden cardiac death; however, the underlying mechanisms are unclear. This study finds that the antibiotic acutely causes diffuse depression and prolongation of the cardiac conduction system and ion channel block. Azithromycin potentiates cardiac sodium current over the long term to promote intracellular sodium loading. These results provide a mechanistic basis for the novel form of proarrhythmia and increased risk of sudden cardiac death seen with azithromycin.Azithromycin Causes a Novel Proarrhythmic SyndromeZhenjiang Yang, MD, PhD, Joseph K. Prinsen, DO, PhD, Kevin R. Bersell, PhD, Wangzhen Shen, MD, Liudmila Yermalitskaya, PhD, Tatiana Sidorova, PhD, Paula B. Luis, PhD, Lynn Hall, BA, Wei Zhang, MS, Liping Du, PhD, Ginger Milne, PhD, Patrick Tucker, PhD, Alfred L. George Jr, MD, Courtney M. Campbell, MD, PhD, Robert A. Pickett, MD, Christian M. Shaffer, BS, Nagesh Chopra, MD, Tao Yang, MD, PhD, Bjorn C. Knollmann, MD, PhD, Dan M. Roden, MD, Katherine T. Murray, MDCorrespondence to: Katherine T. Murray, MD, Division of Clinical Pharmacology, Room 559 Preston Research Bldg, Vanderbilt University School of Medicine, 2220 Pierce Ave, Nashville, TN 37232. E-mail [email protected]BACKGROUND: The widely used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including the one we document here, demonstrate that azithromycin can cause rapid, polymorphic ventricular tachycardia in the absence of QT prolongation, indicating a novel proarrhythmic syndrome. We investigated the electrophysiological effects of azithromycin in vivo and in vitro using mice, cardiomyocytes, and human ion channels heterologously expressed in human embryonic kidney (HEK 293) and Chinese hamster ovary (CHO) cells.METHODS AND RESULTS: In conscious telemetered mice, acute intraperitoneal and oral administration of azithromycin caused effects consistent with multi-ion channel block, with significant sinus slowing and increased PR, QRS, QT, and QTc intervals, as seen with azithromycin overdose. Similarly, in HL-1 cardiomyocytes, the drug slowed sinus automaticity, reduced phase 0 upstroke slope, and prolonged action potential duration. Acute exposure to azithromycin reduced peak SCN5A currents in HEK cells (IC50=110±3 μmol/L) and Na+ current in mouse ventricular myocytes. However, with chronic (24 hour) exposure, azithromycin caused a ≈2-fold increase in both peak and late SCN5A currents, with findings confirmed for INa in cardiomyocytes. Mild block occurred for K+ currents representing IKr(CHO cells expressing hERG; IC50=219±21 μmol/L) and IKs (CHO cells expressing KCNQ1+KCNE1; IC50=184±12 μmol/L), whereas azithromycin suppressed L-type Ca++currents (rabbit ventricular myocytes, IC50=66.5±4 μmol/L) and IK1 (HEK cells expressing Kir2.1, IC50=44±3 μmol/L).CONCLUSIONS: Chronic exposure to azithromycin increases cardiac Na+ current to promote intracellular Na+ loading, providing a potential mechanistic basis for the novel form of proarrhythmia seen with this macrolide antibiotic.Circ Arrhythm Electrophysiol. 2017;10:e003560. DOI: 10.1161/CIRCEP.115.003560.Circulation: Cardiovascular GeneticsThis study reanalyzes classification of genetic variants according to current guidelines, demonstrating that double mutations in patients with hypertrophic cardiomyopathy are less common than previously estimated. The study found that with the use of contemporary methods of classification, there is virtually no evidence to support double mutations as an independent risk factor for sudden cardiac death. Double heterozygote mutations in hypertrophic cardiomyopathy are uncommon, and clinical data are scarce, with the exception of the particularly malignant double radical MYBPC3 mutations.Prevalence and Clinical Implication of Double Mutations in Hypertrophic CardiomyopathyRevisiting the Gene-Dose EffectDana Fourey, MD, Melanie Care, MSc, Katherine A. Siminovitch, MD, Adaya Weissler-Snir, MD, Waseem Hindieh, MD, Raymond H. Chan, MD, MPH, Michael H. Gollob, MD, Harry Rakowski, MD, Arnon Adler, MDCorrespondence to: Arnon Adler, MD, Division of Cardiology, Toronto General Hospital, University of Toronto, 200 Elizabeth St, Toronto, Ontario, Canada, M5G 2C4. E-mail [email protected]BACKGROUND: Available data suggests that double mutations in patients with hypertrophic cardiomyopathy are not rare and are associated with a more severe phenotype. Most of this data, however, is based on noncontemporary variant classification.METHODS AND RESULTS: Clinical data of all hypertrophic cardiomyopathy patients with 2 rare genetic variants were retrospectively reviewed and compared with a group of patients with a single disease-causing variant. Furthermore, a literature search was performed for all studies with information on prevalence and outcome of patients with double mutations. Classification of genetic variants was reanalyzed according to current guidelines. In our cohort (n=1411), 9% of gene-positive patients had 2 rare variants in sarcomeric genes but only in 1 case (0.4%) were both variants classified as pathogenic. Patients with 2 rare variants had a trend toward younger age at presentation when compared with patients with a single mutation. All other clinical variables were similar. In data pooled from cohort studies in the literature, 8% of gene-positive patients were published to have double mutations. However, after reanalysis of reported variants, this prevalence diminished to 0.4%. All patients with 2 radical mutations in MYBPC3 in the literature had severe disease with death or heart transplant during the first year of life. Data on other specific genotype–phenotype correlations were scarce.CONCLUSIONS: Double mutations in patients with hypertrophic cardiomyopathy are much less common than previously estimated. With the exception of double radical MYBPC3 mutations, there is little data to guide clinical decision making in cases with double mutations.Circ Cardiovasc Genet. 2017;10:e001685. DOI: 10.1161/CIRCGENETICS.116.001685.Circulation: Cardiovascular ImagingThe study aimed to further characterize left atrial function in patients with heart failure with preserved ejection fraction (HFpEF) independently of left ventricular pathology. Cardiac magnetic resonance myocardial feature tracking was performed in patients with HFpEF and without HFpEF. Left atrial conduit strain is significantly impaired in HFpEF, associated with exercise intolerance, and represents a distinct feature of HFpEF, independently of left ventricular stiffness and relaxation.Influence of Left Atrial Function on Exercise Capacity and Left Ventricular Function in Patients With Heart Failure and Preserved Ejection FractionMaximilian von Roeder, MD, Karl-Philipp Rommel, MD, Johannes Tammo Kowallick, MD, Stephan Blazek, MD, Christian Besler, MD, Karl Fengler, MD, Joachim Lotz, MD, Gerd Hasenfuß, MD, Christian Lücke, MD, Matthias Gutberlet, MD, Gerhard Schuler, MD, Andreas Schuster, MD, PhD, MBA, Philipp Lurz, MD, PhDCorrespondence to: Philipp Lurz, MD, PhD, Department of Internal Medicine/Cardiology, University of Leipzig, Heart Center, Struempellstrasse 39, 04289 Leipzig, Germany. E-mail [email protected]BACKGROUND: Although left atrial (LA) dysfunction is common in heart failure with preserved ejection fraction (HFpEF), its functional implications beyond the reflection of left ventricular (LV) pathology are not well understood. The aim of this study was to further characterize LA function in HFpEF patients.METHODS AND RESULTS: We performed cardiac magnetic resonance myocardial feature tracking in 22 patients with HFpEF and 12 patients without HFpEF. LA reservoir strain, LA conduit strain, and LA booster pump strain were quantified. Peak oxygen uptake (VO2max) was determined. Invasive pressure–volume loops were obtained to evaluate LV diastolic properties. LV early filling was determined from LV volume–time curves as derived from cardiac magnetic resonance. LA reservoir and conduit strain were significantly lower in HFpEF (LA reservoir strain, 22±7% versus 29±6%, P=0.04; LA conduit strain, −9±5% versus −15±4%, P<0.01). Patients with HFpEF showed lower oxygen uptake (17±6 versus 29±8 mL/(kg min); P<0.01). Strain measurement for LA conduit function was strongly associated with VO2max (r=0.80; P<0.01). On multivariable regression analysis, LA conduit strain emerged as strongest predictor for VO2max even after inclusion of LV stiffness and relaxation time (β=0.80; P<0.01). LA conduit strain correlated with the volume of early ventricular filling (r=0.67; P 132 to <145 versus ≥145 mm Hg).METHODS AND RESULTS: ADHF was defined as hospitalization for ADHF, confirmed and formally adjudicated by a blinded events committee using standardized protocols. At 3.29 years follow-up, there were 103 ADHF events (2.2%) among 4683 standard arm participants and 65 ADHF events (1.4%) among 4678 intensive arm participants (Cox proportional hazards ratio, 0.63; 95% confidence interval, 0.46–0.85; P value =0.003). In multivariable analyses, including treatment arm, baseline covariates that were significant predictors for ADHF included chronic kidney disease, cardiovascular disease, age≥75 years, body mass index, and higher systolic BP. The beneficial effect of the intervention on incident ADHF was consistent across all prespecified subgroups. Participants who had incident ADHF had markedly increased risk of subsequent cardiovascular events, including a 27-fold increase (P<0.001) in cardiovascular death.CONCLUSIONS: Targeting a systolic BP<120 mm Hg, compared with <140 mm Hg, significantly reduced ADHF events, and the benefit was similar across all key, prespecified subgroups. Participants who developed ADHF had markedly increased risk for subsequent cardiovascular events and death, highlighting the importance of strategies aimed at prevention of ADHF, especially intensive BP reduction.CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.Circ Heart Fail. 2017;10:e003613. DOI: 10.1161/CIRCHEARTFAILURE.116.003613.FootnotesCirculation is available at http://circ.ahajournals.org. Previous Back to top Next FiguresReferencesRelatedDetails May 30, 2017Vol 135, Issue 22 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.029235PMID: 28559497 Originally publishedMay 30, 2017 PDF download Advertisement
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