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Biomedical subjects

Georg Noll

Publications and source records attributed to Georg Noll.

32 records · Page 2Linked to original sources
PubMed2003

Selective COX-2 inhibition improves endothelial function in coronary artery disease.

BACKGROUND: There is an ongoing debate as to whether the gastrointestinal safety of COX-2 inhibition compared with nonsteroidal antiinflammatory drugs (NSAIDs) may come at the cost of increased cardiovascular events. In view of the large number of patients at cardiovascular risk requiring chronic analgesic therapy with COX-2 inhibitors for arthritic and other inflammatory conditions, the effects of selective COX-2 inhibition on clinically useful surrogates for cardiovascular disease, particularly endothelial function, need to be determined. METHODS AND RESULTS: Fourteen male patients (mean age, 66+/-3 years) with severe coronary artery disease (average of 2.6 vessels with stenosis >75%) undergoing stable background therapy with aspirin and statins were included. The patients received celecoxib (200 mg BID) or placebo for a duration of 2 weeks in a double-blind, placebo-controlled, crossover fashion. After each treatment period, flow-mediated dilation of the brachial artery, high-sensitivity C-reactive protein, oxidized LDL, and prostaglandins were measured. Celecoxib significantly improved endothelium-dependent vasodilation compared with placebo (3.3+/-0.4% versus 2.0+/-0.5%, P=0.026), whereas endothelium-independent vasodilation, as assessed by nitroglycerin, remained unchanged (9.0+/-1.6% versus 9.5+/-1.3%, P=0.75). High-sensitivity C-reactive protein was significantly lower after celecoxib (1.3+/-0.4 mg/L) than after placebo (1.8+/-0.5 mg/L, P=0.019), as was oxidized LDL (43.6+/-2.4 versus 47.6+/-2.6 U/L, P=0.028), whereas prostaglandins did not change. CONCLUSIONS: This is the first study to demonstrate that selective COX-2 inhibition improves endothelium-dependent vasodilation and reduces low-grade chronic inflammation and oxidative stress in coronary artery disease. Thus, selective COX-2 inhibition holds the potential to beneficially impact outcome in patients with cardiovascular disease.

Aged↗
PubMed2003

ETA receptors mediate vasoconstriction of large conduit arteries during reduced flow in humans.

Vascular tone is regulated by endothelium-derived vasodilating and constricting substances, mainly nitric oxide and endothelin (ET)-1. These 2 mediators, which antagonize the actions of each other, are released in response to shear-stress produced by blood flow. The aim of this study was to delineate the contribution of endogenous ET-1 on vascular tone of a large conduit artery during reduced and hyperemic flow. Radial artery diameter was continuously measured with a high-resolution ultrasonic echo-tracking device in 8 healthy subjects. After establishing stable baseline conditions, a wrist cuff was inflated to suprasystolic pressure for 5 minutes. In another 5 subjects, measurements were obtained during intraarterial infusion of saline or an ETA receptor antagonist (BQ-123, 1 nmol/min) in a dosage not affecting basal radial diameter. Wrist occlusion caused a progressive vasoconstriction of the radial artery (P = 0.0001). Vasoconstriction of the radial artery during wrist occlusion was significantly attenuated by ETA receptor antagonism (-2.7% +/- 0.6% versus -6.8% +/- 0.6% during saline, P = 0.007). Flow-mediated vasodilation was not influenced by BQ-123 (7.5% +/- 0.8% versus 7.8% +/- 1.1%, P = NS). This study demonstrates active vasoconstriction of large conduit arteries during conditions of reduced blood flow via ETA receptoractivation. This may play an important role in disease states with reduced systemic or local blood flow and indicates the therapeutic potential of ETA receptor antagonism.

Adult↗
PubMed2003

Nasal oxygen and muscle sympathetic nerve activity in heart failure.

AIMS: To evaluate the effects of mild hyperoxia on sympathetic activity during quiet breathing in patients with chronic heart failure (CHF) and, hence, to investigate whether tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in these patients. Sympathetic activation in patients with CHF may result in part from increased chemoreflex sensitivity. Previous studies using microneurography did not demonstrate deactivation of the chemoreceptors while the patients were breathing 100% O(2). However, 100% O(2) may decrease cardiac output, thereby offsetting the effects on the chemoreflexes. SETTING: University hospital. PATIENTS AND INTERVENTIONS: Ten patients with moderate-to-severe CHF (mean [+/-SD] age, 53.9 +/- 9.2 years; mean ejection fraction, 21.3 +/- 4.7%) were assigned to breathing 20 min of O(2) as well as room air (3 L/min) applied by nasal prongs. Muscle sympathetic nerve activity (MSNA) was evaluated by microneurography of the peroneal nerve. RESULTS: The application of O(2) resulted in an increase of arterial O(2) saturation but no significant change in MSNA during resting ventilation. Although voluntary apneas were no longer with O(2) (25.3 +/- 5.8 vs 32.6 +/- 8.6 s, respectively; p = 0.014), MSNA during the last 10 s of voluntary apnea was lower while breathing O(2) (63.5 +/- 15.0 vs 59.9 +/- 13.9 bursts per minute, respectively; p = 0.02). CONCLUSIONS: The increased MSNA in the patients studied could not be reduced by mild hyperoxia, suggesting that the tonic activation of chemoreflex afferents is unlikely to contribute to the elevated sympathetic activity. That nasal O(2) reduces MSNA during apnea may explain the beneficial effects of nocturnal O(2) therapy in CHF patients with Cheyne-Stokes respiration.

Adult↗
PubMed2003

Detection of a novel exon 4 low-density lipoprotein receptor gene deletion in a swiss family with severe familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant disease which results in 2-3-fold elevated cholesterol levels and in accelerated atherosclerosis. FH is caused by small mutations or larger rearrangements in the low-density lipoprotein receptor (LDLR). Here, we report that screening the LDLR gene in a Swiss family (n = 15) with clinical symptoms of FH by combined single strand conformation polymorphism and long-distance PCR identified a novel 1.3 kb deletion in the LDLR. The deletion eliminated exon 4 of the LDLR presumably by recombination between two identical 25 bp repeats present in intron 3 and 4. The 25 bp sequence in intron 3 is part of an Alu repeat, whereas no homology to Alu repeats was found for the intron 4 region. This 1.3 kb LDLR deletion allele cosegregated with elevated cholesterol levels over three generations. Even on high-dose statin therapy, carriers of the deletion averaged 1.6 times higher cholesterol levels and 1.9 times higher apolipoprotein B-100 (apoB-100) levels than non-carriers who had lipid and apoB-100 levels within the range of the Swiss population. Most affected members of the first and second generation of this family had experienced a first myocardial infarction (MI) before the age of 55 years and most LDLR gene deletion carriers older than 40 years showed severe coronary artery disease (CAD). Hence, we conclude that deletion of exon 4 in the LDLR gene drastically decreases low-density lipoprotein binding leading to severe hypercholesterolemia.

Adult↗
PubMed2002

Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content: role of habitual versus nonhabitual drinking.

BACKGROUND: Coffee is the most abundantly consumed stimulant worldwide. However, its cardiovascular safety remains controversial. Possible health hazards have been related to its main ingredient, caffeine. Activation of the sympathetic nervous system by coffee may enhance cardiovascular risk; however, it is unclear whether this effect of coffee is related to caffeine or other substance(s) also contained in decaffeinated coffee. METHODS AND RESULTS: In 15 healthy volunteers (6 habitual and 9 nonhabitual coffee drinkers) arterial blood pressure (BP), heart rate, and muscle sympathetic nervous activity (MSA) were continuously recorded before and after drinking a triple espresso or a decaffeinated triple espresso or after intravenous administration of caffeine (250 mg) or placebo (saline) in the same subjects. There was a significant time x condition interaction for the intravenous caffeine and placebo conditions for MSA, with caffeine showing a significant increase in MSA at 60 minutes (53.2+/-14.1% total activity) and the placebo group showing no effect. A similar significant time effect was found for coffee drinking (54.1+/-22.5% total activity). Habitual and nonhabitual coffee drinkers demonstrated similar changes in MSA and BP after intravenous caffeine, whereas coffee drinking increased BP in nonhabitual drinkers only, despite comparable increases of MSA and plasma caffeine levels. Nonhabitual coffee drinkers showed similar activation of MSA and BP after caffeine infusion, coffee, or decaffeinated coffee. CONCLUSIONS: Acutely, coffee and caffeine induced comparable increases in MSA and BP in nonhabitual coffee drinkers, whereas habitual coffee drinkers exhibited lack of BP increase despite MSA activation to coffee. Because decaffeinated coffee also increases BP and MSA in nonhabitual drinkers, ingredients other than caffeine must be responsible for cardiovascular activation.

Administration, Oral↗
PubMed2002

Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT).

BACKGROUND: The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ET(A) antagonist darusentan in addition to modern standard therapy in patients with CHF. METHODS AND RESULTS: A total of 157 patients with CHF (present or recent NYHA class III of at least 3 months duration), pulmonary capillary wedge pressure > or =12 mm Hg, and a cardiac index < or =2.6 L x min(-1) x m(-2) were randomly assigned to double-blind treatment with placebo or darusentan (30, 100, or 300 mg/d) in addition to standard therapy. Short-term administration of darusentan increased the cardiac index, but this did not reach statistical significance compared with placebo. The increase in cardiac index was significantly more pronounced after 3 weeks of treatment (P<0.0001 versus placebo). Pulmonary capillary wedge pressure, pulmonary arterial pressure, pulmonary vascular resistance, and right atrial pressure remained unchanged. Heart rate, mean artery pressure, and plasma catecholamines remained unaltered, but systemic vascular resistance decreased significantly (P=0.0001). Higher dosages were associated with a trend to more adverse events (including death), particularly early exacerbation of CHF without further benefit on hemodynamics compared with moderate dosages. CONCLUSIONS: This study demonstrates for the first time in a large patient population that 3 weeks of selective ET(A) receptor blockade improves cardiac index in patients with CHF. However, long-term studies are needed to determine whether ET(A) blockade is beneficial in CHF.

Blood Pressure↗
PubMed2002

Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality. Striking similarities exist in the inflammatory and immunologic response in RA and atherosclerosis. Indeed, adhesion molecules and cytokines, tumor necrosis factor (TNF)-alpha in particular, are key mediators of joint inflammation and of vascular dysfunction and progression of atherosclerotic vascular disease. Hence, the aim of the present study was to assess the effect of chronic antiinflammatory treatment with the anti-TNF-alpha antibody infliximab on disease activity and endothelial function in patients with active RA. METHODS AND RESULTS: Eleven RA patients (mean age 46+/-5 years; disease duration 9+/-2 years) with high disease activity despite treatment with stable doses of methotrexate (<or=25 mg/wk) and prednisone (<or=10 mg/d) were investigated. Clinical status and endothelium-dependent and -independent vasodilation of the brachial artery as assessed by high-resolution ultrasound were measured before and after 12 weeks of infliximab therapy. Flow-mediated vasodilation improved from 3.2+/-0.4% to 4.1+/-0.5% (P=0.018), whereas endothelium-independent vasodilation with nitroglycerin and baseline diameter remained unchanged (13.6+/-1.2% versus 12.8+/-1.4%, P=0.98, and 3.74+/-0.15 versus 3.66+/-0.11 mm, P=0.54, respectively). Disease activity score (DAS28) was significantly reduced, from 5.6+/-0.3 to 3.5+/-0.6 (P=0.002). Erythrocyte sedimentation rate and C-reactive protein were lowered from 34+/-7 to 19+/-5 mm/h (P=0.04) and from 38+/-11 to 15+/-10 mg/L (P=0.08), respectively. CONCLUSIONS: This is the first study to show that anti-TNF-alpha treatment improves endothelial function in RA. The data suggest that in RA, endothelial dysfunction is part of the disease process and is mediated by TNF-alpha.

Antibodies, Monoclonal↗
PubMed2002

Mental stress induces prolonged endothelial dysfunction via endothelin-A receptors.

BACKGROUND: Mental stress is a risk factor for atherosclerosis and may precipitate myocardial ischemia and infarction. Because endothelial dysfunction is an early manifestation of atherosclerosis, we investigated the impact of mental stress on endothelial function. Methods and Results- The effects of a 3-minute mental stress task on endothelium-dependent vasodilation were studied in healthy subjects without cardiovascular risk factors. Flow-mediated (FMD) and nitroglycerin (0.4 mg sublingual)-induced vasodilation were studied before and after mental stress by high-resolution ultrasound of the radial artery. Additionally, FMD was assessed before and 10 to 45 minutes after mental stress during intraarterial infusion of a selective endothelin A receptor antagonist (BQ-123, 1 nmol/min) or saline, respectively. Endothelium-dependent vasodilation was reduced by half for about 45 minutes (8.0+/-1.1% versus 4.1+/-1.0%; P<0.002), whereas endothelium-independent vasodilation to nitroglycerin remained unaffected (15.6+/-1.6 versus 14.3+/-1.3%; NS). Intraarterial infusion of BQ-123, a selective endothelin-A receptor antagonist, but not saline prevented the impairment of endothelium-dependent vasodilation (8.6+/-1.2 versus 9.4+/-1.3%; NS). In contrast, intraarterial infusion of norepinephrine of similar duration as mental stress did not inhibit FMD. CONCLUSIONS: Mental stress induces prolonged endothelial dysfunction, which is prevented by selective endothelin-A receptor antagonism. This represents a novel and important link between mental stress and atherosclerotic vascular disease.

Adult↗
PubMed2002

High-density lipoprotein restores endothelial function in hypercholesterolemic men.

BACKGROUND: Hypercholesterolemia is a risk factor for atherosclerosis-causing endothelial dysfunction, an early event in the disease process. In contrast, high-density lipoprotein (HDL) cholesterol inversely correlates with morbidity and mortality representing a protective effect. Therefore, we investigated the effects of reconstituted HDL on endothelial function in hypercholesterolemic men. METHODS AND RESULTS: Endothelium-dependent and -independent vasodilation to intraarterial acetylcholine and sodium nitroprusside (SNP), respectively, was measured by forearm venous occlusion plethysmography in healthy normo- and hypercholesterolemic men. In hypercholesterolemics, the effects of reconstituted HDL (rHDL; 80 mg/kg IV over 4 hours) on acetylcholine- and SNP-induced changes in forearm blood flow were assessed in the presence or absence of the nitric oxide (NO) synthase inhibitor L-NMMA. Hypercholesterolemics showed reduced vasodilation to acetylcholine but not to SNP compared with normocholesterolemics (P<0.0001). rHDL infusion increased plasma HDL cholesterol from 1.3+/-0.1 to 2.2+/-0.1 mmol/L (P<0.0001, n=18) and significantly enhanced the acetylcholine-induced increase in forearm blood flow without affecting that induced by SNP. rHDL infusion also improved flow-mediated dilation of the brachial artery (to 4.5+/-0.9% from 2.7+/-0.6%, P=0.02). NO synthase inhibition prevented the improvement in acetylcholine-induced vasodilation while leaving the response to SNP unchanged. Albumin infusion in an equivalent protein dose had no effect on vasomotion or lipid levels. CONCLUSIONS: In hypercholesterolemic patients, intravenous rHDL infusion rapidly normalizes endothelium-dependent vasodilation by increasing NO bioavailability. This may in part explain the protective effect of HDL from coronary heart disease and illustrates the potential therapeutic benefit of increasing HDL in patients at risk from atherosclerosis.

Acetylcholine↗
PubMed2002

Endothelin antagonists and heart failure.

Chronic heart failure (CHF) is characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance, reduced exercise tolerance, and dyspnea. Despite considerable progress in the treatment of CHF, especially in targeting activated neurohumoral systems, mortality in these patients remains high. Therefore, new treatment approaches are warranted. Endothelin-1 (ET-1) plasma levels are elevated in CHF and correlate with both hemodynamic severity and symptoms. Plasma levels of ET-1 are strong independent predictors of mortality in CHF. Combined ET(A/B) selective ET(A) receptor antagonists have been evaluated in patients with CHF showing impressive hemodynamic improvements. These results indicate that ET receptor antagonists indeed have a potential to improve hemodynamics, symptoms, and potentially prognosis in patients with CHF, which still carries a high mortality.

Atrasentan↗
PubMed2002

Effects of chronic calcium channel blockade on sympathetic nerve activity in hypertension.

The sympathetic nervous system (SNS) is an important regulator of the circulation. Its activity is increased in hypertension and heart failure and adversely affects prognosis. Although certain drugs inhibit SNS, dihydropyridine calcium antagonists may stimulate the system. Phenylalkylamine calcium antagonists such as verapamil have a different pharmacological profile. We therefore tested the hypothesis of whether amlodipine, nifedipine, or verapamil differs in the effects on muscle sympathetic nerve activity (MSA). Forty-three patients (31 men, 12 women) with mild to moderate hypertension were randomly assigned to 1 drug for 8 weeks. Blood pressure, heart rate, and MSA (by microneurography) were measured at baseline and after 8 weeks of treatment. All calcium antagonists led to a similar decrease in blood pressure of 5.0+/-1.5 to 6.4+/-1.4 mm Hg at 8 weeks (P<0.001 versus baseline). There were no significant differences in MSA between groups. With amlodipine, MSA averaged 49+/-3 bursts/min (3 versus baseline); with nifedipine, 48+/-3 bursts/min (2 versus baseline); and with verapamil, 49+/-2 bursts/min (all, P=NS). With verapamil, norepinephrine decreased by 4% but tended to increase by about one third with amlodipine or nifedipine (P=NS). Thus, in hypertension slow release forms of verapamil, nifedipine, and amlodipine exert comparable antihypertensive effects and do not change MSA, although there was a trend toward decreased MSA and plasma norepinephrine with verapamil.

Amlodipine↗
PubMed2000

The Beauty and the Beast: Aspects of the Autonomic Nervous System.

Sympathetic nerve activity is altered and is a prognostic factor for many cardiovascular diseases such as hypertension, coronary syndromes, and congestive heart failure. Therefore, the selection of vasoactive drugs for the treatment of these diseases should also take into consideration their effects on the sympathetic nervous system.

Journal Article↗
PubMedDate not supplied

Lyme carditis: restitutio ad integrum documented by cardiac magnetic resonance imaging.

Lyme disease is a tickborne illness that could cause, weeks to months later, complications involving the joints, central nervous system, and cardiovascular system. We report a case of cardiac manifestation with transitory higher degree atrioventricular block and dysfunction of the left ventricle. Complete resolution without signs of myocardial scar is demonstrated by cardiac magnetic resonance imaging.

Adult↗