Sinus Node Dysfunction.

Sinus node dysfunction (SND) is a multifaceted disorder most prevalent in older individuals, but may also occur at an earlier age. In most cases, the SND diagnosis is ultimately established by documenting its ECG manifestations. EPS has limited utility. The treatment strategy is largely dictated by symptoms and ECG manifestations. Not infrequently, both bradycardia and tachycardia coexist in the same patients, along with other diseases common in the elderly (e.g., hypertension, coronary artery disease), thereby complicating treatment strategy. Prevention of the adverse consequences of both bradyarrhythmia and tachyarrhythmia is important to reduce susceptibility to syncope, falls, and thromboembolic complications.

Sinus Node Dysfunction.

Sinus node dysfunction (SND) is a multifaceted disorder most prevalent in older individuals, but may also occur at an earlier age. In most cases, the SND diagnosis is ultimately established by documenting its ECG manifestations. EPS has limited utility. The treatment strategy is largely dictated by symptoms and ECG manifestations. Not infrequently, both bradycardia and tachycardia coexist in the same patients, along with other diseases common in the elderly (e.g., hypertension, coronary artery disease), thereby complicating treatment strategy. Prevention of the adverse consequences of both bradyarrhythmia and tachyarrhythmia is important to reduce susceptibility to syncope, falls, and thromboembolic complications.

Hypothesis: Paroxetine, a G Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor Reduces Morbidity and Mortality in Patients With Heart Failure.

The hypothesis that paroxetine decreases morbidity and mortality in patients with heart failure (HF) is plausible but unproven. Basic research demonstrates that inhibition of G protein-coupled receptor kinase 2 (GRK2) both in vitro and in vivo in the myocardium may be beneficial. G protein-coupled receptor kinase 2 antagonism is purported to exert cardioprotective effects immediately following myocardial injury by blunting toxic overstimulation on a recently injured heart. In addition, chronic overexpression of GRK2 inhibits catecholamine induction of vital positive chronotropic and ionotropic effects required to preserve cardiac output leading to worsening of congestive HF. In cardiac-specific GRK2 conditional knockout mice, there is significant improvement in left ventricular wall thickness, left ventricular end-diastolic diameter (LVEDD), and ejection fraction (EF) compared to controls. Paroxetine is a selective serotonin reuptake inhibitor which was recently shown to have the ability to directly inhibit GRK2 both in vitro and in vivo. At physiologic temperatures, paroxetine inhibits GRK2-dependent phosphorylation of an activated G-protein-coupled receptor with a half maximal inhibitory concentration of 35 micromoles, a substantially greater affinity than for other G protein-coupled receptor kinases. In a randomized trial in mice with systolic HF and depressed EF postmyocardial infarction, those treated with paroxetine had a 30% increase in EF, improved contractility, and LVEDD and wall thickness compared to those treated with medical therapy alone. While further basic research may continue to elucidate plausible mechanisms of benefit and observational studies will contribute important relevant information, large scale randomized trials designed a priori to do so are necessary to test the hypothesis.