Pacemaker Induced Transient Assynchrony (PITA) staves off Heart Failure | 12/23/2015Healthy and the majority of failing hearts beat synchronously. However, some hearts contract with poor coordination and if they are weak, this worsens clinical outcomes. Pacemakers used to reset a heart's rhythm can also change the synchrony of contraction, making it better or worse, and current therapy called resynchronization makes it better. Perhaps counterintuitively, we now show that that using a pacemaker to purposely induce dyssynchrony--but only for part of each day--makes the synchronous failing heart better. In our process, pacemaker-induced transient asynchrony (PITA), the heart's right ventricle is paced to induce a 6-hour period of dyssynchrony each day, followed by atrial pacing to resynchronize the heart for the remaining 18 hours. In dogs with heart failure, PITA halted chamber dilation and negative remodeling of the heart tissue, improved cellular signaling and force generation, and resulted in normal muscle fiber structure and function, similar to healthy controls. PITA may help the majority of patients with heart failure who have synchronous contraction and thus are not treated with standard resynchronization pacemakers. PKG Oxidation Worsens Heart Disease | 05/01/2015PKG1a is a kinase activated by cyclic GMP, and it plays a protective role as a brake against maladaptive cardiac stress. However, it can be oxidized at Cys42, and this alters it activation. Here we reveal this suppresses its capacity to protect the pressure-overloaded heart. Oxidation of the kinase alters its intracellular localization, preventing it from targeting plasma membrane proteins such as transient receptor potential canonical-6 (Trpc6). This enhances the maladaptive response to stress. Keeping PKG1a in a reduced state should improve its ability to counter adverse signaling with heart disease.PDE9A controls Natriuretic Peptide cGMP signaling in the Heart and Contributes to Heart Disease | 05/01/2015The highly selective cGMP-hydrolyzing PDE9A is found in heart muscle, specifically in myocytes. It is upregulated in human heart failure, particularly HF with a preserved ejection fraction, and in animal models of heart disease. Mice genetically lacking PDE9A or with the enzyme pharmacologically blocked are protected from pressure overload stress. PDE9A, unlike PDE5A, targets cGMP generated by natriuretic peptide signaling, and its inhibition remains protective in vivo even if the alternative pathway linked to nitric oxide synthase is blocked. Cardiac Resynchronization is a Calcium Sensitizer - in study highlighted by NEJM | 03/01/2014New research shows that failing hearts with dyssynchronous contraction have markedly depressed myofilament calcium sensitivity and maximal activated force. CRT reverses both dramatically. Using a canine model, we show that the decline in sensitivity is related to a fall in GSK3b activation, and that CRT reactivates the kinase. Proteomic analysis identified ~10 different myofilament proteins modified by CRT, and bio-informatics identified GSK3b as a likely targeting kinase. This was further confirmed by incubation of myocytes from dyssynchronous hearts with GSK3b.