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Pacemaker-induced transient asynchrony suppresses heart failure progression.

ABSTRACT: Uncoordinated contraction from electromechanical delay worsens heart failure pathophysiology and prognosis, but restoring coordination with biventricular pacing, known as cardiac resynchronization therapy (CRT), improves both. However, not every patient qualifies for CRT. We show that heart failure with synchronous contraction is improved by inducing dyssynchrony for 6 hours daily by right ventricular pacing using an intracardiac pacing device, in a process we call pacemaker-induced transient asynchrony (PITA). In dogs with heart failure induced by 6 weeks of atrial tachypacing, PITA (starting on week 3) suppressed progressive cardiac dilation as well as chamber and myocyte dysfunction. PITA enhanced ?-adrenergic responsiveness in vivo and normalized it in myocytes. Myofilament calcium response declined in dogs with synchronous heart failure, which was accompanied by sarcomere disarray and generation of myofibers with severely reduced function, and these changes were absent in PITA-treated hearts. The benefits of PITA were not replicated when the same number of right ventricular paced beats was randomly distributed throughout the day, indicating that continuity of dyssynchrony exposure is necessary to trigger the beneficial biological response upon resynchronization. These results suggest that PITA could bring the benefits of CRT to the many heart failure patients with synchronous contraction who are not CRT candidates.

SUBMITTER: Kirk JA

PROVIDER: S-EPMC4858435 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Project description:ImportanceTimely and complete disclosure of medical device defects is necessary to manage patient care safely and effectively.ObjectivesTo determine if the manufacturer's recommendations following the recall of a medical device were timely and complete, the follow-up information and data provided to patients and physicians were adequate for managing patient care, and the actions taken by the US Food and Drug Administration (FDA) regarding the recall were appropriate.Design, setting, and participantsThis single-center retrospective case series included 90 of 448 patients who were implanted with a cardiac resynchronization therapy pacemaker at the Minneapolis Heart Institute from May 2003 through January 2011; this pacemaker was recalled in November 2015. In addition, returned product reports submitted by the manufacturer to the FDA via the Manufacturer and User Facility Device Experience (MAUDE) database from January 2008 through December 2018 were analyzed.Main outcomes and measuresClinical outcomes were serious adverse clinical events that occurred before and after the November 2015 recall notifying physicians and patients that the device's battery could fail unexpectedly because of high internal impedance. Technical outcomes were signs and causes of failure.ResultsFive of 90 patients observed during 2015 experienced syncope when their pacemakers stopped pacing owing to battery or wire connection defects prior to the recall. Of the 90 patients, 37 (41%) were men, and the median (interquartile range) age at implantation was 71.3 (66.1-78.2) years. Analysis of the MAUDE data revealed that battery failures prior to the recall were associated with serious adverse events that included 1 death, 1 cardiac arrest, 5 syncopal attacks, and 6 heart failure exacerbations; 3 additional prerecall syncopal events were caused by wire connection defects. The manufacturer and the FDA were aware of the battery and wire connection defects for 19 months before issuing the recall, yet the wire connection problem was not included in the advisory and physicians were not informed that interrogating the pacemaker could result in loss of pacing. The FDA classified the recall as class II rather than the more critical class I.Conclusions and relevanceThis case series study of patients implanted with a defective pacemaker found that the pacemaker recall was delayed and that subsequent communications did not include all critical information needed for safe and effective patient care. These findings should prompt reforms in how the medical device industry and the FDA manage future medical device recalls.

Project description:Although p38 MAP Kinase α (p38 MAPKα) is generally accepted to play a central role in the cardiac stress response, to date its function in maladaptive cardiac hypertrophy is still not unambiguously defined. To induce a pathological type of cardiac hypertrophy we infused angiotensin II (AngII) for 2 days via osmotic mini pumps in control and tamoxifen-inducible, cardiomyocyte (CM)-specific p38 MAPKα KO mice (iCMp38αKO) and assessed cardiac function by echocardiography, complemented by transcriptomic, histological, and immune cell analysis. AngII treatment after inactivation of p38 MAPKα in CM results in left ventricular (LV) dilatation within 48 h (EDV: BL: 83.8 ± 22.5 µl, 48 h AngII: 109.7 ± 14.6 µl) and an ectopic lipid deposition in cardiomyocytes, reflecting a metabolic dysfunction in pressure overload (PO). This was accompanied by a concerted downregulation of transcripts for oxidative phosphorylation, TCA cycle, and fatty acid metabolism. Cardiac inflammation involving neutrophils, macrophages, B- and T-cells was significantly enhanced. Inhibition of adipose tissue lipolysis by the small molecule inhibitor of adipocytetriglyceride lipase (ATGL) Atglistatin reduced cardiac lipid accumulation by 70% and neutrophil infiltration by 30% and went along with an improved cardiac function. Direct targeting of neutrophils by means of anti Ly6G-antibody administration in vivo led to a reduced LV dilation in iCMp38αKO mice and an improved systolic function (EF: 39.27 ± 14%). Thus, adipose tissue lipolysis and CM lipid accumulation augmented cardiac inflammation in iCMp38αKO mice. Neutrophils, in particular, triggered the rapid left ventricular dilatation. We provide the first evidence that p38 MAPKα acts as an essential switch in cardiac adaptation to PO by mitigating metabolic dysfunction and inflammation. Moreover, we identified a heart-adipose tissue-immune cell crosstalk, which might serve as new therapeutic target in cardiac pathologies.

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Pacemaker-induced transient asynchrony suppresses heart failure progression.

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