When electrical signals go awry in heart tissue, the ultimate cause is molecular, which suggests that molecular-scale interventions—drugs—would be favored means of correcting arrhythmias. Yet drug therapies have fallen out of favor because of side effects. Although safe and effective drugs would surely benefit many of the 2.7 million Americans who live with arrhythmias, other therapies—pacemakers, implantable defibrillators, or cardiac ablations—must often suffice.

If only the molecular mechanisms underpinning arrhythmias were better understood, it would be possible to develop more targeted drugs. To study these mechanisms, and hopefully direct research to more effective anti-arrhythmia drugs, researchers at NYU Langone Medical Center decided to take a close look at a protein known as Pcp4, a known regulator of the heart’s rhythm. The researchers found that when Pcp4 is relatively scarce, as it is when expression of the Pcp4 gene is disrupted, ventricular arrhythmias may result.

The results of this investigation into Pcp4’s functions appeared October 8 in The Journal of Clinical Investigation, in an article entitled, “PCP4 regulates Purkinje cell excitability and cardiac rhythmicity.” In this article, the researchers described how they were able to isolate cardiac Purkinje cells in a mouse model of cardiomyopathy and show that Pcp4 expression was down-regulated in the diseased hearts.

“Through transcriptional profiling of genetically labeled cardiomyocytes, we identified expression of Purkinje cell protein-4 (Pcp4), a putative regulator of calmodulin and Ca2+/calmodulin-dependent kinase II (CaMKII) signaling, exclusively within the His-Purkinje network,” wrote the authors. “Using Pcp4-null mice and acquired cardiomyopathy models, we determined that reduced expression of PCP4 is associated with CaMKII activation, abnormal electrophysiology, dysregulated intracellular calcium handling, and proarrhythmic behavior in isolated Purkinje cells.”

In other words, down-regulated Pcp4 expression led to electrical abnormalities that increased the susceptibility to arrhythmias. The investigators also found Pcp4 in cardiac ganglia, where it also influences the heart’s rhythm and modulates heart rate control.

“This study demonstrates that Purkinje cell protein-4 (Pcp4) is not only important in maintaining the heart’s normal rhythmic behavior, but that when Pcp4 expression is reduced, it short-circuits electrical activity in a small but critical population of cells in the heart muscle, leading to cardiac arrhythmias,” said Glenn I. Fishman, M.D., William Goldring Professor of Medicine and Director of the Leon H. Charney Division of Cardiology at NYU Langone, and the study’s senior author. “We see increased morbidity and mortality when Pcp4 expression is abnormal in our animal models, including ventricular arrhythmias and sudden cardiac death.”

With Pcp4 revealed as an important regulator of the heart’s rhythm, it may serve, in the words of the NYU study’s authors, as “a potential arrhythmia-susceptibility candidate.” Dr. Fishman emphasized this point in a release issued by NYU: “Although much work remains to be done, our data suggest that drugs that mimic Pcp4’s action in the heart could potentially stabilize the heart’s rhythm.”

The development of Pcp4-mimicking drugs could be hastened by yet greater scrutiny of the molecular basis for altered Purkinje electrophysiology and calcium homeostasis. According to the authors of the NYU study, the gene that expresses Pcp4 modulates CaMKII signaling, regulating cardiac excitability through both Purkinje cell-autonomous and central mechanisms.

“Surprisingly, the effect of PCP4 on cardiac rhythmicity appears quite complex and mediated by PC-autonomous as well as autonomically mediated effects,” explained the authors. “While Pcp4-null mice showed a greater burden of ventricular arrhythmias and aberrant ventricular conduction consistent with the proarrhythmic cellular remodeling seen in isolated cells, our telemetric recordings also suggested that PCP4 influences cardiac rhythmicity through a non–cell autonomous mechanism involving modulation of autonomic tone.”

Besides summarizing the results of their investigation, the authors speculated about where related research might go next. “Pcp4 is unique to date in that expression within the cardiomyocyte lineage appears restricted to the ventricular conduction system, that is, the His-Purkinje network, with no detectable expression more proximally in the SA or AV nodes,” the authors explained. “The mechanisms that facilitate this highly circumscribed expression pattern are unknown; however, a combination of in silico and direct experimental strategies should begin to unravel the relevant transcriptional circuitry.”

Regardless of underlying mechanisms, the authors added, genetically engineered models utilizing Pcp4 regulatory elements should be useful in examining ventricular conduction system development and function in health and disease. The authors even speculated the Pcp4 could be relevant to neurological disorders.

“PCP4 is reportedly downregulated in selected brain regions in a number of neurologic syndromes, including Parkinson disease, Huntington disease, and chronic alcoholism. Moreover, a genetic mouse model of Huntington disease phenocopies the autonomic dysregulation seen in the Pcp4-null animals,” they noted. “It is tantalizing to speculate that PCP4 downregulation may play a mechanistic role in the autonomic dysregulation observed in selected neurologic syndromes.”

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