Tachycardia‐induced ventricular dysfunction jigsaw: do all pieces now fit?

Persistent tachycardia, in humans and in animals, is a well-known and time-dependent cause for reversible ventricular dysfunction, cardiomyopathy and progressive systolic heart failure (Nerheim et al. 2004, Gopinathanair et al. 2015). In early phases of the process, contractile function declines, the left ventricle dilates and the left ventricular ejection fraction decreases (Spinale et al. 1990). This is accompanied by depletion of high-energy stores, changes in the sympathetics and the renin–angiotensin system activation, myocyte and extracellular remodelling and defects in calcium handling. Ultimately, there is myocyte loss, elongation and misalignment, disruption in extracellular matrix architecture and alterations in the myocyte basement membrane associated with an increase in β-actin, γ-actin, α-tubulin and matrix metalloproteinases and a decrease in laminin attachment, fibronectin, type IV collagen and sarcolemma festoons. Normally, increased contraction frequency improves contractile performance and calcium handling but rapid, persistent tachycardia interferes with this response creating defects in calcium cycling and prolongation of calcium transients (Cory et al. 1993, Eising et al. 1994) causing impairment in contractility and relaxation at the cellular level. What is behind this? In this issue of the journal, de Pauw and associates (De Pauw et al. 2016) addressed this question in a series of interesting, elaborate and elegant experiments involving a total of 53 dogs (although controls not well described) that the evaluated effects of short-term (48 h) rapid ventricular pacing on attenuation of the contractile response as measured by several key physiological parameters. These data provide new insights into pathophysiological mechanisms responsible for pacing-induced heart failure. Left ventricular pressure, left ventricular fractional shortening, regional wall thickening, coronary blood flow and ‘contractile reserve’ were evaluated in select animals. In a subset, exercise testing was performed at baseline and after rapid pacing. Left ventricular contractility decreased with pacing. Upon pacing cessation, contractility improved over time. Left ventricular fractional shortening was reduced independent of coronary blood flow and myocardial oxygen consumption. LV dP/dTmax decreased at all loading conditions. Catecholamine levels increased; ATP and ADP levels decreased slightly. With exercise, ‘contractile reserve’ was reduced and was independent of heart rate and unrelated to coronary blood flow. The ‘contractile reserve’ and heart rate response were blunted to isoproterenol even though the response to incremental calcium administration was preserved and tested in a subgroup with autonomic blockade. There was an apparent change in myocardial sensitivity to calcium independent of autonomic activation. The calcium dose–response curve shifted to the right suggesting decreased calcium availability or reduced calcium sensitivity. There was no direct assessment of calcium sensitivity or measurement of intracellular calcium, and the utility of administering calcium this way to test myocardial sensitivity has some deficiencies. Oxygen consumption at rest and during exercise was unchanged but reduced performance suggested reduced mechanical efficiency at a wide range of loading conditions. Mechanisms responsible remain uncertain. To evaluate sarcoplasmic reticulum function, post-extrasystolic potentiation and calcium uptake were measured. Post-extrasystolic potentiation increased slightly, but the maximal velocity of sarcoplasmic reticulum calcium uptake was unchanged. There was also no difference in ryanodine-sensitive calcium uptake in paced vs. controls (not well described). Electron microscopy evaluated calcium deposition and assessed ultrastructural evidence for ischaemia. The latter was not observed. However, excessive calcium handling at the level of the sarcolemma was concluded to be present with dense deposits along the sarcolemma, T-tubules and crista of the mitochondria in select cases. Findings suggested were mild calcium overload and increased sodium–calcium exchange. Other abnormalities of the mitochondria nuclei and sarcomeres were present. These complex and involved series of experiments in limited numbers of animals provide fascinating data. The question is: Are all the parts of the jig puzzle of acute pacing-induced left ventricular dysfunction now pieced together? These data do augment our knowledge regarding what is initially occurring with calcium handling during rapid pacing-induced left ventricular dysfunction. These findings build on previous data but are not totally unique. Many investigations have evaluated pacing-induced heart failure and have considered mechanisms responsible. The consistency of information between this and prior studies may be good (indicating that the proper mechanism is in sight or may be bad (since what is found is only what is being sought after). DePauw and colleagues are likely on the right track and their data provide new insights into calcium handling. However, only a few animals were utilized for each experiment. This may be acceptable provided that experimental conditions remain stable and that these experimental finding apply to other models and in other conditions. Is calcium infusion in seven dogs, for example, all it takes to determine sarcoplasmic reticulum calcium handling? Probably not. Can anything be stated about calcium transients? Probably not. Regarding electron microscopy findings, the cause for the abnormalities observed is not clear. DePauw et al. elaborate a unified mechanistic hypothesis. However, a new mechanism is not shown. There appears to be calcium overload, preserved sarcoplasmic reticulum function, contractile dysfunction with preserved calcium reserve and a blunted response to isoproterenol and exercise. Reduced calcium sensitivity may cause contractile dysfunction but how does it lead to reduced mechanical efficacy? Are more calcium transients and is more oxygen consumption needed for the same contractile force? There appears to be a defect in calcium handling but mechanisms responsible on ultrastructural and biochemical levels remain uncertain. Calcium binding to calmodulin and accompanying activation of calcium calmodulin kinase II (CAMKII) could be responsible in the process of modulating excitation–contraction coupling by a series of complex steps. While observations indicate intracellular remodelling counteracts deleterious calcium overload during tachycardia, and these data may fit with other experiments, the exact mechanisms responsible for the observations remain uncertain. DePauw and colleagues are a long way from showing that there is a central role for CAMKII as a target for future heart failure treatment as they conclude. While these data add to our understanding of the initial ventricular dysfunction that occurs with rapid pacing, we are no closer to a unified concept of the mechanism responsible for acute ventricular dysfunction related to calcium handling, no closer to a better understanding of how acute ventricular dysfunction leads to more long-standing ventricular dysfunction and no better positioned to understand the basic mechanisms, including the role of CAMKII (if there is one) in the development of this process. The jigsaw puzzle of tachycardia-induced ventricular dysfunction remains incomplete. More than one piece of the puzzle is missing. BioControl, Boston Scientific, Biotronik, Amarin, Amgen, Boehringer Ingelheim, On-X, Lundbeck, Daiichi Sankyo (consultant for all and speaker for Lundeck and Daiichi Sankyo and all unrelated to this particular editorial).