Markus Stühlinger

Endothelial Dysfunction Induced by Hyperhomocyst(e)inemia Role of Asymmetric Dimethylarginine

Background—Endothelial function is impaired by hyperhomocyst(e)inemia. We have previously shown that homocyst(e)ine (Hcy) inhibits NO production by cultured endothelial cells by causing the accumulation of asymmetric dimethylarginine (ADMA). The present study was designed to determine if the same mechanism is operative in humans. Methods and Results—We studied 9 patients with documented peripheral arterial disease (6 men; 3 women; age, 64±3 years), 9 age-matched individuals at risk for atherosclerosis (older adults; 9 men; age, 65±1 years), and 5 young control subjects (younger adults; 5 men; age, 31±1 years) without evidence of or risk factors for atherosclerosis. Endothelial function was measured by flow-mediated vasodilatation of the brachial artery before and 4 hours after a methionine-loading test (100 mg/kg body weight, administered orally). In addition, blood was drawn at both time points for measurements of Hcy and ADMA concentrations. Plasma Hcy increased after the methionine-loading test in each group (all, P <0.001). Plasma ADMA levels rose in all subjects, from 0.9±0.2 to 1.6±0.2 &mgr;mol/L in younger adults, from 1.5±0.2 to 3.0±0.4 &mgr;mol/L in older adults, and from 1.8±0.1 to 3.9±0.3 &mgr;mol/L in peripheral arterial disease patients (all, P <0.001). Flow-mediated vasodilatation was reduced from 13±2% to 10±1% in younger adults, from 6±1% to 5±1% in older adults, and from 7±1% to 3±1% in peripheral arterial disease patients (all, P <0.001). Furthermore, we found positive correlations between plasma Hcy and ADMA concentrations (P =0.03, r =0.450), as well as ADMA and flow-mediated vasodilatation (P =0.002, r =0.623). Conclusions—Our results suggest that experimental hyperhomocyst(e)inemia leads to accumulation of the endogenous NO synthase inhibitor ADMA, accompanied by varying degrees of endothelial dysfunction according to the preexisting state of cardiovascular health.

Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine.

OBJECTIVES The aim of this study was to investigate endothelial function and common carotid intima-media thickness (IMT) in healthy young men with mild-to-moderate hypertriglyceridemia. Plasma asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, was measured to further elucidate the mechanisms involved. BACKGROUND Hypertriglyceridemia is a risk factor for coronary heart disease although the mechanisms behind the increased risk remain to be defined. Acute elevation of plasma triglycerides induced by an intravenous fat load is associated with impaired endothelial function. The results of studies examining acute effects induced by a high-fat meal or effects of chronic hypertriglyceridemia on endothelial function are more inconsistent. METHODS Flow-mediated vasodilation and nitroglycerin-induced vasodilation of the brachial artery and common carotid IMT were measured noninvasively by ultrasound technique in 15 hypertriglyceridemic (HTG) subjects and 15 matched controls, mean age 34 years. Plasma concentrations of ADMA were measured by high-performance liquid chromatography. RESULTS Flow-mediated vasodilation was decreased in the HTG group (p < 0.0001), whereas nitroglycerin-induced vasodilation and carotid IMT did not differ significantly. Asymmetric dimethylarginine concentrations were higher in the HTG group (p < 0.05). CONCLUSIONS Hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentration of ADMA but not with increased IMT of the common carotid artery. The corollary is that chronic hypertriglyceridemia results in endothelial dysfunction, possibly due to increased ADMA concentration, and that endothelial dysfunction might precede increased IMT among the early manifestations of atherosclerosis.

Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure

AIMS We performed a randomized, double blind, crossover study of cardiac contractility modulation (CCM) signals in heart failure patients. METHODS AND RESULTS One hundred and sixty-four subjects with ejection fraction (EF) < 35% and NYHA Class II (24%) or III (76%) symptoms received a CCM pulse generator. Patients were randomly assigned to Group 1 (n = 80, CCM treatment 3 months, sham treatment second 3 months) or Group 2 (n = 84, sham treatment 3 months, CCM treatment second 3 months). The co-primary endpoints were changes in peak oxygen consumption (VO2,peak) and Minnesota Living with Heart Failure Questionnaire (MLWHFQ). Baseline EF (29.3 +/- 6.7% vs. 29.8 +/- 7.8%), VO2,peak (14.1 +/- 3.0 vs. 13.6 +/- 2.7 mL/kg/min), and MLWHFQ (38.9 +/- 27.4 vs. 36.5 +/- 27.1) were similar between the groups. VO2,peak increased similarly in both groups during the first 3 months (0.40 +/- 3.0 vs. 0.37 +/- 3.3 mL/kg/min, placebo effect). During the next 3 months, VO2,peak decreased in the group switched to sham (-0.86 +/- 3.06 mL/kg/min) and increased in patients switched to active treatment (0.16 +/- 2.50 mL/kg/min). MLWHFQ trended better with treatment (-12.06 +/- 15.33 vs. -9.70 +/- 16.71) during the first 3 months, increased during the second 3 months in the group switched to sham (+4.70 +/- 16.57), and decreased further in patients switched to active treatment (-0.70 +/- 15.13). A comparison of values at the end of active treatment periods vs. end of sham treatment periods indicates statistically significantly improved VO2,peak and MLWHFQ (P = 0.03 for each parameter). CONCLUSION In patients with heart failure and left ventricular dysfunction, CCM signals appear safe; exercise tolerance and quality of life (MLWHFQ) were significantly better while patients were receiving active treatment with CCM for a 3-month period.

Low apolipoprotein A-IV plasma concentrations in men with coronary artery disease

OBJECTIVES The objective of this study was to evaluate the relation between apolipoprotein A-IV (apoA-IV) plasma concentrations and coronary artery disease (CAD). BACKGROUND Experimental in vitro and in vivo studies favor apoA-IV to be protective against the development of atherosclerosis. Mice that overexpress either human or mouse apoA-IV demonstrated a significant reduction of aortic atherosclerotic lesions compared with control mice. Data on apoA-IV plasma concentrations and CAD in humans are lacking. METHODS We determined in two independent case-control studies of a Caucasian and an Asian Indian population whether apoA-IV plasma concentrations are related to the presence of angiographically assessed CAD. RESULTS Plasma apoA-IV levels were significantly lower in 114 male Caucasian subjects with angiographically defined CAD when compared with 114 age-adjusted male controls (10.2 +/-3.8 mg/dL vs. 15.1 +/- 4.0 mg/dL, p < 0.001). Logistic regression analysis indicated that the association between apoA-IV levels and CAD was independent of the high-density lipoprotein cholesterol and triglyceride concentrations. The inverse relationship between plasma levels of apoA-IV and the presence of CAD was confirmed in an independent sample of 68 male Asian Indians with angiographically documented CAD and 68 age-matched controls. CONCLUSIONS The results of this cross-sectional study demonstrate for the first time an association between low apoA-IV concentrations and CAD in humans and suggest that apoA-IV may play an antiatherogenic role in humans.

On Computing Dominant Frequency From Bipolar Intracardiac Electrograms

Dominant frequency (DF) computed from action potentials is a key parameter for investigating atrial fibrillation in animal studies and computer models. A recent clinical trial reported consistent results computing DF from 30 Hz to 400 Hz bandpass filtered bipolar electrograms in humans. The DF (<15 Hz and, thus, filtered out) was recovered by rectifying the signal, while the theoretical background of this approach was left uncommented. It is the focus of this paper to provide this background by a Fourier analysis. We demonstrate that it is mainly the timing of the narrow deflections (local activation at the catheter tip) which contribute to the DF peak in the frequency spectrum. Due to the typical signal morphology pronounced harmonic peaks occur in the spectrum. This is a disadvantage when computing the regularity index (RI) as a parameter for local organization and signal quality. It is demonstrated for synthetical and patient data that at low DF the RI is far below the optimal value one even for high underlying organization and good signal quality. The insight obtained promotes the development of better measures for organization. The finding that mainly timing of activation contributes to DF might promote the development of powerful realtime signal processing tools for computing DF

Appropriate Therapy But Not Inappropriate Shocks Predict Survival in Implantable Cardioverter Defibrillator Patients

Inappropriate implantable cardioverter defibrillator (ICD) shocks have been linked to a worse clinical outcome due to direct myocardial injury.

Homocysteine-induced vascular dysregulation is mediated by the NMDA receptor

Elevated plasma homocysteine accelerates myointimal hyperplasia and luminal narrowing after carotid endarterectomy. N-methyl D aspartate receptors (NMDAr) in rat cerebrovascular cells are involved in homocysteine uptake and receptor-mediated stimulation. In the vasculature, NMDAr subunits (NR1, 2A-2D) have been identified by sequence homology in rat aortic endothelial cells. Exposure of these cells to homocysteine increased expression of receptor subunits, an effect that was attenuated by dizocilpine (MK801), a noncompetitive NMDA inhibitor. The objective of this study was to investigate the existence of an NMDAr in rat vascular smooth muscle (A7r5) cells, and also the effect of homocysteine on vascular dysregulation as mediated by this receptor. Subunits of the NMDAr (NR1, 2A-2D) were detected in the A7r5 cells by using the reverse transcriptase polymerase chain reaction and Western blotting. Homocysteine induced an increase in A7r5 cell proliferation, which was blocked by MK801. Homocysteine, in a dose and time dependent manner, increased expression of matrix metallinoproteinase-9 and interleukin-1beta, which have been implicated in vascular smooth muscle cell migration and/or proliferation. Homocysteine reduced the vascular elaboration of nitric oxide and increased the elaboration of the nitric oxide synthase inhibitor, asymmetric dimethylarginine. All of these homocysteine mediated effects were inhibited by MK801. NMDAr exist in vascular smooth muscle cells and appear to mediate, at least in part, homocysteine-induced dysregulation of vascular smooth muscle cell functions.

Elevated γ-glutamyltransferase in implantable cardioverter defibrillator patients

ZusammenfassungHINTERGRUND: Erhöhte γ-Glutamyltransferase (GGT) Plasmaspiegel korrelieren mit kardiovaskulären Erkrankungen, aber nichts ist bekannt über eine mögliche Assoziation mit dem gehäuften Auftreten von ventrikulären Tachyarrhythmien. Weiters stellt sich die Frage, ob erhöhte GGT Werte auch bei ICD-Patienten mit einer erhöhten Sterblichkeit verbunden sind. METHODEN UND RESULTATE: Aufgrund der geschlechtsspezifischen Normalwerte von GGT wurden nur männliche Patienten in die Analyse eingeschlossen. In einer retrospektiven Studie an 743 Patienten konnte gezeigt werden, dass erhöhte GGT Werte mit einer signifikant erhöhten Gesamtmortalität, nicht aber mit einer gehäuften Notwendigkeit von appropriater ICD-Therapie (antitachykardes Pacing, Schockabgabe) assoziiert sind. In einer Cox Regressionsanalyse bestätigte sich ein erhöhter GGT Wert (>56 U/L) als unabhängiger Risikofaktor für erhöhte Sterblichkeit, vor allem wenn dieser in Kombination mit einer eingeschränkten Nierenfunktion (GFR <60 ml/min/1,73 m2) auftritt. ZUSAMMENFASSUNG: Erhöhte GGT Werte sind trotz ICD Therapie mit einer erhöhten Gesamtsterblichkeit assoziiert. Es bleibt zu überprüfen, ob dieser Routineparameter in der verbesserten Patientenselektion zur ICD Therapie eine Rolle spielen kann.SummaryBACKGROUND: Elevated γ-glutamyltransferase (GGT) is a new risk factor for cardiovascular diseases, but its impact on ventricular tachyarrhythmia occurrence and survival in patients with an implantable cardioverter defibrillator (ICD) is unknown. METHODS AND RESULTS: Considering that GGT levels are gender-dependent, female ICD recipients were excluded from our database because of the low incidence of events. In a retrospective analysis, appropriate ICD therapy (both shocks and antitachycardia pacing due to ventricular tachyarrhythmias) occurred in 31.9% of 320 male patients who had received an ICD for primary prevention (median follow-up of 2.3 years), and in 55.1% of 423 male patients who had received an ICD for secondary prevention (median follow-up of 3.9 years). Compared to normal low GGT plasma levels (below 28 U/L), total mortality but not risk for appropriate ICD therapy was elevated for higher GGT categories (p for trend = 0.004 in primary prevention and p for trend = 0.002 in secondary prevention, respectively). In Cox regression analysis, elevated GGT (>56 U/L) remained an independent predictor of death both in primary (p = 0.011) and in secondary prevention (p = 0.006). Patients with elevated GGT and renal insufficiency defined by an estimated glomerular filtration rate <60 ml/min/1.73 m2 suffered from excess total mortality jeopardizing the benefit of ICD therapy. CONCLUSION: Elevation of GGT is an important adverse prognostic parameter in ICD patients. A possible role of GGT for improved patient selection for ICD therapy deserves further investigation.

[Palpitations in competitive athletes. Risks from premature beats, nonsustained tachycardia and preexcitation].

Cardiovascular screening tests to prevent sudden cardiac death in athletes are discussed controversially, but they should include diligent patient history and physical examination as well as registration of an ECG. If palpitations or tachycardias are described or if preexcitation, supraventricular or ventricular arrhythmias are documented, further risk stratification is mandatory. Specifically the origin and the complexity of the arrhythmia need to be analyzed and any form of structural cardiac pathologies has to be ruled out. Sinus tachycardia, supraventricular and ventricular premature beats, atrial fibrillation as well as supraventricular and ventricular tachycardia may serve as substrate for palpitations. Each of these arrhythmias is associated with a different amount of cardiac risk and can be evidence for certain forms of structural cardiac disease. Recommendations to limit physical activity and specific treatment options depend on the type of the arrhythmia and the presence and the nature of underlying cardiac disease.ZusammenfassungKardiovaskuläre Screeninguntersuchungen zur Prävention des plötzlichen Herztods bei Leistungssportlern werden kontrovers diskutiert, sollten aber immer eine genaue Befragung und Untersuchung wie auch die Registrierung eines EKGs des Athleten beinhalten. Wenn bei der Anamnese des Sportlers Tachykardien oder Palpitationen geschildert werden oder im EKG eine Präexzitation oder supraventrikuläre oder ventrikuläre Rhythmusstörungen diagnostiziert werden, muss noch eine weitere Risikostratifizierung erfolgen. Diese umfasst einerseits eine genaue Analyse des Ursprungsorts und der Komplexität der Arrhythmie und andererseits den Ausschluss jeglicher struktureller Herzerkrankungen. Als Substrat von Palpitationen kommen Sinustachykardien, supraventrikuläre und ventrikuläre Extrasystolen, Vorhofflimmern und supraventrikuläre und ventrikuläre Tachykardien in Frage. Diese Rhythmusstörungen sind bei Sportlern mit einem unterschiedlichen Risiko verbunden und können jeweils Hinweise auf verschiedene strukturelle Herzerkrankungen sein. Empfehlungen zur Einschränkung sportlicher Tätigkeiten und zu einer spezifischen Therapie richten sich nach der Art der Arrhythmie und der Präsenz von kardialen Pathologien.AbstractCardiovascular screening tests to prevent sudden cardiac death in athletes are discussed controversially, but they should include diligent patient history and physical examination as well as registration of an ECG. If palpitations or tachycardias are described or if preexcitation, supraventricular or ventricular arrhythmias are documented, further risk stratification is mandatory. Specifically the origin and the complexity of the arrhythmia need to be analyzed and any form of structural cardiac pathologies has to be ruled out. Sinus tachycardia, supraventricular and ventricular premature beats, atrial fibrillation as well as supraventricular and ventricular tachycardia may serve as substrate for palpitations. Each of these arrhythmias is associated with a different amount of cardiac risk and can be evidence for certain forms of structural cardiac disease. Recommendations to limit physical activity and specific treatment options depend on the type of the arrhythmia and the presence and the nature of underlying cardiac disease.

Palpitationen beim Leistungssportler

Cardiovascular screening tests to prevent sudden cardiac death in athletes are discussed controversially, but they should include diligent patient history and physical examination as well as registration of an ECG. If palpitations or tachycardias are described or if preexcitation, supraventricular or ventricular arrhythmias are documented, further risk stratification is mandatory. Specifically the origin and the complexity of the arrhythmia need to be analyzed and any form of structural cardiac pathologies has to be ruled out. Sinus tachycardia, supraventricular and ventricular premature beats, atrial fibrillation as well as supraventricular and ventricular tachycardia may serve as substrate for palpitations. Each of these arrhythmias is associated with a different amount of cardiac risk and can be evidence for certain forms of structural cardiac disease. Recommendations to limit physical activity and specific treatment options depend on the type of the arrhythmia and the presence and the nature of underlying cardiac disease.ZusammenfassungKardiovaskuläre Screeninguntersuchungen zur Prävention des plötzlichen Herztods bei Leistungssportlern werden kontrovers diskutiert, sollten aber immer eine genaue Befragung und Untersuchung wie auch die Registrierung eines EKGs des Athleten beinhalten. Wenn bei der Anamnese des Sportlers Tachykardien oder Palpitationen geschildert werden oder im EKG eine Präexzitation oder supraventrikuläre oder ventrikuläre Rhythmusstörungen diagnostiziert werden, muss noch eine weitere Risikostratifizierung erfolgen. Diese umfasst einerseits eine genaue Analyse des Ursprungsorts und der Komplexität der Arrhythmie und andererseits den Ausschluss jeglicher struktureller Herzerkrankungen. Als Substrat von Palpitationen kommen Sinustachykardien, supraventrikuläre und ventrikuläre Extrasystolen, Vorhofflimmern und supraventrikuläre und ventrikuläre Tachykardien in Frage. Diese Rhythmusstörungen sind bei Sportlern mit einem unterschiedlichen Risiko verbunden und können jeweils Hinweise auf verschiedene strukturelle Herzerkrankungen sein. Empfehlungen zur Einschränkung sportlicher Tätigkeiten und zu einer spezifischen Therapie richten sich nach der Art der Arrhythmie und der Präsenz von kardialen Pathologien.AbstractCardiovascular screening tests to prevent sudden cardiac death in athletes are discussed controversially, but they should include diligent patient history and physical examination as well as registration of an ECG. If palpitations or tachycardias are described or if preexcitation, supraventricular or ventricular arrhythmias are documented, further risk stratification is mandatory. Specifically the origin and the complexity of the arrhythmia need to be analyzed and any form of structural cardiac pathologies has to be ruled out. Sinus tachycardia, supraventricular and ventricular premature beats, atrial fibrillation as well as supraventricular and ventricular tachycardia may serve as substrate for palpitations. Each of these arrhythmias is associated with a different amount of cardiac risk and can be evidence for certain forms of structural cardiac disease. Recommendations to limit physical activity and specific treatment options depend on the type of the arrhythmia and the presence and the nature of underlying cardiac disease.