Use of a leadless pacemaker in the management of swallow syncope: A case report.

A 41-year-old male presented with syncope whilst eating and was subsequently demonstrated to have recurrent symptomatic sinus pauses whilst swallowing. Following the exclusion of structural heart disease, he was diagnosed with swallow syncope, an uncommon variant of neurocardiogenic syncope. To avoid long-term complications of a transvenous pacemaker, the case was managed with a leadless pacemaker which resulted in complete resolution of symptoms.

Electrocardiographic QRS duration is influenced by body mass index and sex.

BACKGROUND: Electrocardiogram (ECG) measured QRS duration has been shown to influence cardiovascular outcomes. However, there is paucity of data on whether ECG QRS duration is influenced by obesity and sex in large populations. METHODS: All ECGs performed by a pathology provider over a 2-year period were included. ECGs with confounding factors and those not in sinus rhythm were excluded from the primary analysis. RESULTS: Of the 76,220 who met the inclusion criteria, 41,685 (55%) were females. The median age of the study cohort was 61 years (interquartile [IQR] range 48-71 years). The median QRS duration was 86 ms (IQR 80-94 ms). The median BMI was 27.6 kg/m2 (IQR 24.2-31.8 kg/m2). When stratified according to the World Health Organization classification of BMI < 18.50 kg/m2, 18.50-24.99 kg/m2, 25.00-29.99 kg/m2, and ≥ 30.00 kg/m2, the median QRS durations were 82 ms (IQR 76-88 ms), 86 ms (IQR 80-92 ms), 88 ms (IQR 80-94 ms) and 88 ms (IQR 82-94 ms), respectively (p < 0.001 for linear trend). Median QRS duration for females was 84 ms (IQR 78-88 ms); for males, it was 92 ms (IQR 86-98 ms), p < 0.001. Compared to males, females had narrower QRS complexes at similar age and similar BMI. In multiple linear regression analysis, BMI correlated positively with QRS duration (standardized beta 0.095, p < 0.001) independent of age, sex, and heart rate. CONCLUSIONS: In this large cohort there was a positive association between increasing BMI and QRS duration. Females had narrower QRS duration than males at similar age and similar BMI.

Pharmacological Therapy for Ventricular Arrhythmias: A State-of-the Art Review.

While implantable cardioverter defibrillators decrease mortality in high risk groups of patients who have ventricular arrhythmias, antiarrhythmic drugs are still required to reduce the burden of both benign and life-threatening arrhythmias. This review will address the available medical therapy for ventricular arrhythmias in Australia and their use in different clinical situations.

Ventricular Tachycardia in Ischemic Heart Disease.

Ventricular arrhythmias are a significant cause of morbidity and mortality in patients with ischemic structural heart disease. Endocardial and epicardial mapping strategies include scar characterization channel identification, and recording and ablation of late potentials and local abnormal ventricular activities. Catheter ablation along with new technology and techniques of bipolar ablation, needle catheter, and autonomic modulation may increase efficacy in difficult to ablate ventricular arrhythmias. Catheter ablation of ventricular arrhythmias seem to confer mortality and morbidity benefits in patients with ischemic heart disease.

Stimulation of the cardiac myocyte Na+-K+ pump due to reversal of its constitutive oxidative inhibition.

Protein kinase C can activate NADPH oxidase and induce glutathionylation of the ß1-Na(+)-K(+) pump subunit, inhibiting activity of the catalytic α-subunit. To examine if signaling of nitric oxide-induced soluble guanylyl cyclase (sGC)/cGMP/protein kinase G can cause Na(+)-K(+) pump stimulation by counteracting PKC/NADPH oxidase-dependent inhibition, cardiac myocytes were exposed to ANG II to activate NADPH oxidase and inhibit Na(+)-K(+) pump current (Ip). Coexposure to 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) to stimulate sGC prevented the decrease of Ip. Prevention of the decrease was abolished by inhibition of protein phosphatases (PP) 2A but not by inhibition of PP1, and it was reproduced by an activator of PP2A. Consistent with a reciprocal relationship between ß1-Na(+)-K(+) pump subunit glutathionylation and pump activity, YC-1 decreased ANG II-induced ß1-subunit glutathionylation. The decrease induced by YC-1 was abolished by a PP2A inhibitor. YC-1 decreased phosphorylation of the cytosolic p47(phox) NADPH oxidase subunit and its coimmunoprecipitation with the membranous p22(phox) subunit, and it decreased O2 (·-)-sensitive dihydroethidium fluorescence of myocytes. Addition of recombinant PP2A to myocyte lysate decreased phosphorylation of p47(phox) indicating the subunit could be a substrate for PP2A. The effects of YC-1 to decrease coimmunoprecipitation of p22(phox) and p47(phox) NADPH oxidase subunits and decrease ß1-Na(+)-K(+) pump subunit glutathionylation were reproduced by activation of nitric oxide-dependent receptor signaling. We conclude that sGC activation in cardiac myocytes causes a PP2A-dependent decrease in NADPH oxidase activity and a decrease in ß1 pump subunit glutathionylation. This could account for pump stimulation with neurohormonal oxidative stress expected in vivo.

Redox-dependent regulation of the Na⁺-K⁺ pump: new twists to an old target for treatment of heart failure.

By the time it was appreciated that the positive inotropic effect of cardiac glycosides is due to inhibition of the membrane Na(+)-K(+) pump, glycosides had been used for treatment of heart failure on an empiric basis for ~200 years. The subsequent documentation of their lack of clinical efficacy and possible harmful effect largely coincided with the discovery that a raised Na(+) concentration in cardiac myocytes plays an important role in the electromechanical phenotype of heart failure syndromes. Consistent with this, efficacious pharmacological treatments for heart failure have been found to stimulate the Na(+)-K(+) pump, effectively the only export route for intracellular Na(+) in the heart failure. A paradigm has emerged that implicates pump inhibition in the raised Na(+) levels in heart failure. It invokes protein kinase-dependent activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and glutathionylation, a reversible oxidative modification, of the Na(+)-K(+) pump molecular complex that inhibits its activity. Since treatments of proven efficacy reverse the oxidative Na(+)-K(+) pump inhibition, the pump retains its status as a key pharmacological target in heart failure. Its role as a target is well integrated with the paradigms of neurohormonal abnormalities, raised myocardial oxidative stress and energy deficiency implicated in the pathophysiology of the failing heart. We propose that targeting oxidative inhibition of the pump is useful for the exploration of future treatment strategies. This article is part of a Special Issue entitled "Na(+)Regulation in Cardiac Myocytes".

ß(3) adrenergic stimulation of the cardiac Na+-K+ pump by reversal of an inhibitory oxidative modification.

BACKGROUND: inhibition of L-type Ca(2+) current contributes to negative inotropy of ß(3) adrenergic receptor (ß(3) AR) activation, but effects on other determinants of excitation-contraction coupling are not known. Of these, the Na(+)-K(+) pump is of particular interest because of adverse effects attributed to high cardiac myocyte Na(+) levels and upregulation of the ß(3) AR in heart failure. METHODS AND RESULTS: we voltage clamped rabbit ventricular myocytes and identified electrogenic Na(+)-K(+) pump current (I(p)) as the shift in holding current induced by ouabain. The synthetic ß(3) AR agonists BRL37344 and CL316,243 and the natural agonist norepinephrine increased I(p). Pump stimulation was insensitive to the ß(1)/ß(2) AR antagonist nadolol and the protein kinase A inhibitor H-89 but sensitive to the ß(3) AR antagonist L-748,337. Blockade of nitric oxide synthase abolished pump stimulation and an increase in fluorescence of myocytes loaded with a nitric oxide-sensitive dye. Exposure of myocytes to ß(3) AR agonists decreased ß(1) Na(+)-K(+) pump subunit glutathionylation, an oxidative modification that causes pump inhibition. The in vivo relevance of this was indicated by an increase in myocardial ß(1) pump subunit glutathionylation with elimination of ß(3) AR-mediated signaling in ß(3) AR(-/-) mice. The in vivo effect of BRL37344 on contractility of the nonfailing and failing heart in sheep was consistent with a beneficial effect of Na(+)-K(+) pump stimulation in heart failure. CONCLUSIONS: the ß(3) AR mediates decreased ß(1) subunit glutathionylation and Na(+)-K(+) pump stimulation in the heart. Upregulation of the receptor in heart failure may be a beneficial mechanism that facilitates the export of excess Na(+).

Frequency of late drug-eluting stent thrombosis with non-cardiac surgery.

Drug-eluting stents (DES) are highly effective in reducing restenosis but have a small but significant risk for late stent thrombosis (LAST). Cessation of antiplatelet drugs for noncardiac surgery has been implicated in precipitating LAST, prompting surgery to be done on antiplatelet therapy, with all the attendant bleeding risks, or deferred until 12 months after DES implantation, despite limited data defining the risk for LAST. Using billing data from 2 large health funds, members who had DES insertion (n = 9,321) with subsequent noncardiac surgery (n = 4,126) were mailed a questionnaire regarding their noncardiac procedures, antiplatelet use, and subsequent coronary events. From 1,086 returned, 710 were suitable for inclusion, identifying 11 patients (1.5%) with perioperative myocardial infarctions confirmed by medical records. Angiography showed that only 2 had stent thromboses, while 7 had new culprit lesion (2 patients did not undergo angiography). Before their noncoronary procedures, 66% were receiving dual-antiplatelet therapy, and 30% were taking single agents. Surgery was performed on dual therapy in 18%, on single agents in 23%, and with no antiplatelet therapy in 59%. The mean time to surgery from stent implantation was 348 days, with 56% <12 months. In conclusion, noncardiac surgery after DES implantation is frequent and appears to have low cardiac morbidity despite variable antiplatelet cessation. Perioperative myocardial infarctions occur because of narrowings in nonstented coronary arteries rather than from LASTs.

Activation of cAMP-dependent signaling induces oxidative modification of the cardiac Na+-K+ pump and inhibits its activity.

Cellular signaling can inhibit the membrane Na(+)-K(+) pump via protein kinase C (PKC)-dependent activation of NADPH oxidase and a downstream oxidative modification, glutathionylation, of the beta(1) subunit of the pump alpha/beta heterodimer. It is firmly established that cAMP-dependent signaling also regulates the pump, and we have now examined the hypothesis that such regulation can be mediated by glutathionylation. Exposure of rabbit cardiac myocytes to the adenylyl cyclase activator forskolin increased the co-immunoprecipitation of NADPH oxidase subunits p47(phox) and p22(phox), required for its activation, and increased superoxide-sensitive fluorescence. Forskolin also increased glutathionylation of the Na(+)-K(+) pump beta(1) subunit and decreased its co-immunoprecipitation with the alpha(1) subunit, findings similar to those already established for PKC-dependent signaling. The decrease in co-immunoprecipitation indicates a decrease in the alpha(1)/beta(1) subunit interaction known to be critical for pump function. In agreement with this, forskolin decreased ouabain-sensitive electrogenic Na(+)-K(+) pump current (arising from the 3:2 Na(+):K(+) exchange ratio) of voltage-clamped, internally perfused myocytes. The decrease was abolished by the inclusion of superoxide dismutase, the inhibitory peptide for the epsilon-isoform of PKC or inhibitory peptide for NADPH oxidase in patch pipette solutions that perfuse the intracellular compartment. Pump inhibition was also abolished by inhibitors of protein kinase A and phospholipase C. We conclude that cAMP- and PKC-dependent inhibition of the cardiac Na(+)-K(+) pump occurs via a shared downstream oxidative signaling pathway involving NADPH oxidase activation and glutathionylation of the pump beta(1) subunit.

Reversible oxidative modification: a key mechanism of Na+-K+ pump regulation.

Angiotensin II (Ang II) inhibits the cardiac sarcolemmal Na(+)-K(+) pump via protein kinase (PK)C-dependent activation of NADPH oxidase. We examined whether this is mediated by oxidative modification of the pump subunits. We detected glutathionylation of beta(1), but not alpha(1), subunits in rabbit ventricular myocytes at baseline. beta(1) Subunit glutathionylation was increased by peroxynitrite (ONOO(-)), paraquat, or activation of NADPH oxidase by Ang II. Increased glutathionylation was associated with decreased alpha(1)/beta(1) subunit coimmunoprecipitation. Glutathionylation was reversed after addition of superoxide dismutase. Glutaredoxin 1, which catalyzes deglutathionylation, coimmunoprecipitated with beta(1) subunit and, when included in patch pipette solutions, abolished paraquat-induced inhibition of myocyte Na(+)-K(+) pump current (I(p)). Cysteine (Cys46) of the beta(1) subunit was the likely candidate for glutathionylation. We expressed Na(+)-K(+) pump alpha(1) subunits with wild-type or Cys46-mutated beta(1) subunits in Xenopus oocytes. ONOO(-) induced glutathionylation of beta(1) subunit and a decrease in Na(+)-K(+) pump turnover number. This was eliminated by mutation of Cys46. ONOO(-) also induced glutathionylation of the Na(+)-K(+) ATPase beta(1) subunit from pig kidney. This was associated with a approximately 2-fold decrease in the rate-limiting E(2)-->E(1) conformational change of the pump, as determined by RH421 fluorescence. We propose that kinase-dependent regulation of the Na(+)-K(+) pump occurs via glutathionylation of its beta(1) subunit at Cys46. These findings have implications for pathophysiological conditions characterized by neurohormonal dysregulation, myocardial oxidative stress and raised myocyte Na(+) levels.

Angiotensin II inhibits the Na+-K+ pump via PKC-dependent activation of NADPH oxidase.

The sarcolemmal Na(+)-K(+) pump, pivotal in cardiac myocyte function, is inhibited by angiotensin II (ANG II). Since ANG II activates NADPH oxidase, we tested the hypothesis that NADPH oxidase mediates the pump inhibition. Exposure to 100 nmol/l ANG II increased superoxide-sensitive fluorescence of isolated rabbit ventricular myocytes. The increase was abolished by pegylated superoxide dismutase (SOD), by the NADPH oxidase inhibitor apocynin, and by myristolated inhibitory peptide to epsilon-protein kinase C (epsilonPKC), previously implicated in ANG II-induced Na(+)-K(+) pump inhibition. A role for epsilonPKC was also supported by an ANG II-induced increase in coimmunoprecipitation of epsilonPKC with the receptor for the activated kinase and with the cytosolic p47(phox) subunit of NADPH oxidase. ANG II decreased electrogenic Na(+)-K(+) pump current in voltage-clamped myocytes. The decrease was abolished by SOD, by the gp91ds inhibitory peptide that blocks assembly and activation of NADPH oxidase, and by epsilonPKC inhibitory peptide. Since colocalization should facilitate NADPH oxidase-dependent regulation of the Na(+)-K(+) pump, we examined whether there is physical association between the pump subunits and NADPH oxidase. The alpha(1)-subunit coimmunoprecipitated with caveolin 3 and with membrane-associated p22(phox) and cytosolic p47(phox) NADPH oxidase subunits at baseline. ANG II had no effect on alpha(1)/caveolin 3 or alpha(1)/p22(phox) interaction, but it increased alpha(1)/p47(phox) coimmunoprecipitation. We conclude that ANG II inhibits the Na(+)-K(+) pump via PKC-dependent NADPH oxidase activation.

Viability of hypokinetic segments: influence of tethering from adjacent segments: influence of tethering from adjacent segments.

Hypokinetic myocardium is presumed to be reversibly dysfunctional. However, hypokinetic segments do not necessarily improve after revascularization since their outcome can be influenced by tethering effects of adjacent myocardium. To assess whether hypokinetic segments improve following revascularization, 24 patients underwent resting and dobutamine stress echocardiography (DSE), with a total of 420 (20 per patient) myocardial segments studied pre- and postrevascularization. One hundred fifty-five hypokinetic segments were identified prerevascularization. Postrevascularization, only 57% of these segments improved in wall motion, while 43% showed no improvement or worsening of wall motion. Low dose (5-10 microg/kg/min) DSE identified correctly 57 (65%) of 88 segments that improved, and falsely predicted improvement in 26 (39%) of 67 segments that ultimately did not improve postrevascularization. Of the hypokinetic segments that did not improve, 90% were adjacent to at least one severely hypokinetic or akinetic segment as compared with 73% of the segments that improved following revascularization (P = 0.009). Sixty-five percent of all true positive DSE responses were adjacent to at least one akinetic or severely hypokinetic segment, while 87% of all false negative DSE responses were adjacent to at least one akinetic or severely hypokinetic segment (P = 0.03). In conclusion, myocardial segments found to be hypokinetic do not necessarily improve after revascularization. This may be related to tethering influences of adjacent segments, which have a contrasting level of function.