Acute and short-term effects of the nonpeptide endothelin-1 receptor antagonist bosentan in humans

Summary: In recent years, evidence from various animal experiments has accumulated that emphasizes the role of endothelin-1 in the pathophysiology of several cardiovascular diseases, including congestive heart failure. The recent advent of potent antagonists of this system now allows the assessment of the involvement of endothelin-1 in the maintenance of vascular tone in animals and humans. We report hemodynamic data from two trails in patients with chronic severe congestive heart failure (i.e., reduced left ventricular ejection fraction of 15 mmHg, and/or reduced cardiac index of 2.5 L/min/m2 or less) who were treated with the mixed endothelin-type A and type B-receptor antagonist bosentan. In the first study, the acute effect of bosentan (300 mg, intravenous) on hemodynamics and neurohormones was investigated. Bosentan was well tolerated and significantly improved impaired hemodynamics due to systemic and venous vasodilation. In the second trial, bosentan was given orally (0.5 g bid) for 14 days, in addition to conventional triple treatment for congestive heart failure, including digitalis, angiotensin-converting enzyme inhibitors, and diuretics. Cardiac hemodynamics were monitored during the first 24 hours of treatment, and measurements were repeated during the last day of bosentan therapy. Bosentan was well tolerated in these patients as well, and hemodynamic measures were compatible with an additional effect of bosentan after 2 weeks. However, there was a slight increase in heart rate as well. Our result underline the importance of endogenously generated endothelin-1 in congestive heart failure and suggest a potential benefit of endothelin antagonism in such patients. However, long-term studies are needed to establish whether chronic endothelin antagonism has beneficial clinical effects and is capable of improving survival and/or symptoms in severe heart failure patients who remain symptomatic despite standard triple therap

Effects of angiotensin converting enzyme inhibition on endothelial vasodilator function in primary human hypertension

Hypertension in animal models and in humans is associated with a decreased vasodilator response to acetylcholine which causes vascular relaxation by release of endothelium-derived relaxing factor from the endothelium. Since lowering of blood pressure, particularly with angiotensin converting enzyme inhibitors, improved the response to acetylcholine we investigated the effects of brachial artery infusions of ascending dosages of actetylcholine on forearm blood flow before and after 5 months of therapy with the angiotensin converting enzyme inhibitor, cilazapril, in 10 patients with mild to moderate primary hypertension. Cilazapril decreased blood pressure from 150.8 ± 14.4/98.9 ± 4.3 mmHg during placebo to 138.8 ± 15.6/88.6 ± 8.9 mmHg (P < 0.01). Brachial artery acetylcholine infusions increased forearm blood flow from 2.95 ± 1.5 to a maximum of 22.8 ± 11.5 ml.min−1.100 ml−1 forearm tissue and decreased forearm vascular resistance from 48.1 ± 34.1 to 6.9 ± 6.9 units before cilazapril. This response did not change after cilazapril therapy. Our findings in patients with primary hypertension, therefore, do not support the concept that angiotensin converting enzyme inhibition influences endothelium-dependent vascular relaxation to acetylcholine to a significant degree. Whether this lack of effect on endothelial vasodilator function is specific for the vascular bed chosen for study or whether it represents a fundamental difference between animal models and human hypertension remains an important issue to be clarifie

Treatment of mitral stenosis

In patients with mitral stenosis the need for therapeutic intervention can be assessed by clinical and non-invasive data. Mitral valve replacement is indicated when marked dyspnoea on mild exertion, dyspnoea at rest or pulmonray oedema, haemoptpis, atrial fibrillation, recurrent systemic emboli or right ventricular failure occur in a patient with a mitral valve area of <1·5cm2, as memured by Doppler echocardiography. This treatment will entail life-long anticoagulation in the majoriv of patients. Closed commissurotomy is no longer considered a valid therapeutic alternative due to its limited success rate but open cormmissurotomy and balloon valvotomy may be performed in patients with no significant calcification of valve cusps and no major concomitant mitral regurgitation. Preservation of the subvalvular apparatus and left ventricular geometry can be comidered the most important advantages of these techniques. More severe chronic symptom are generally required m indication for mitral valve replacement because of the additional long-term imponderabilities imposed by an implanted artrficial device. Therefore, in patienb with mitral stenosis different symptom and clinical findings will eventually lead to different intervention

Therapeutic benefits of increasing natriuretic peptide levels

Natriuretic peptides play an important role in water and salt homeostasis and in the regulation of the cardiovascular system. In recent years, exogenous administration of natriuretic peptides has primarily been used to improve our understanding of the role of natriuretic peptides. Also, it became evident that natriuretic peptides may be used therapeutically. Because of their peptide character, they cannot be administered orally and, therefore, may be used for short-term intravenous therapy only. In recent years, inhibitors of neutral endopeptidase, which degrades natriuretic peptides to inactive metabolites, have been investigated. This review focuses on the potential benefits of increasing natriuretic peptide levels, either through exogenous administration or inhibiting the degradation of endogenous natriuretic peptide

Pretransplant malignancy in candidates and posttransplant malignancy in recipients of cardiac transplantation

Background: Malignancy is generally considered a contraindication for cardiac transplantation, whereas secondary malignancy has been described under chronic immunosuppression. Patients and methods: We report here the frequency of malignancy encountered among the 495 patients evaluated at our cardiac transplant centre as well as the incidence and the course of post-transplant malignancy among 129 consecutive patients who underwent cardiac transplantation, with a subsequent minimum follow-up of 6 months. Results: A total of 10 out of 495 patients (2%) evaluated for heart transplantation presented with a history of previous malignancy: 3 of them underwent transplantation (2 survive, 1 died) whereas in the remaining 7 patients neoplasia was considered a contraindication for cardiac transplantation, and all 7 died (4 cardiac, 3 tumor-related deaths). Post-transplant malignancy was diagnosed in 10 of 129 patients (9%) 35 ± 15 months after transplantation (6 skin cancers, 1 lymphoproliferative disease, 3 solid tumors). No significant association was found between post-transplant malignancy and primary prophylaxis with antithymocyte globulin (ATG) or murine antihuman T-cell monoclonal antibodies (OKT3). Conclusions: These results confirm that pre-transplant malignancy is not an absolute contraindication for cardiac transplantation and that post-transplant follow-up must include careful monitoring of post-transplant malignanc

Calcium antagonist induced vasodilation in peripheral, coronary and cerebral vasculature as important factors in the treatment of elderly hypertensives

Increased arteriolar tone is the pathophysiological hallmark of essential hypertension and is determined by the intracellular free calcium concentration in the vascular smooth muscle cell. Calcium influx is an important determinant of vasoconstriction and excess calcium influx-dependent vasoconstriction has been shown by plethysmographical studies in patients with essential hypertension. Calcium antagonists acutely lower BP by reducing calcium influx, calcium concentration and peripheral resistance. The degree of the attendant sympathetic nerve reflex activation and counter-regulatory mechanisms determines the antihypertensive response of the individual. Chronic monotherapy with a calcium antagonist results in an antihypertensive response, which is directly related to the patient's age and pretreatment BP and indirectly related to plasma renin levels. The resulting reduction in after-load neither leads to reduced cerebral blood flow in hypertensive patients, nor aggravates congestive heart failure. Calcium antagonists are a useful alternative to diuretics, primarily in older patients with low renin levels, either alone or combined with any other antihypertensive drug, and provide effective and safe control of blood pressur

Spectroscopy of individual single-walled carbon nanotubes and their synthesis via chemical vapor deposition

Einzelmolekülspektroskopie an Kohlenstoffnanoröhren und deren Herstellung mittels chemischer Gasphasenabscheidung Im Rahmen dieser Arbeit wurde eine Apparatur zur chemischen Gasphasenabscheidung entwickelt, aufgebaut und dazu verwendet, vertikal und horizontal ausgerichtete Anordnungen aus Kohlenstoffnanoröhren wachsen zu lassen. So hergestellte, einzelne Nanoröhren wurden sowohl mittels eines Photolumineszenzmikroskops (PL Mikroskop), als auch mit Raman-, Rasterkraft- und Rasterelektronenmikroskopie untersucht. Für die Photolumineszenz-Anregungs-Spektroskopie (PLE Spektroskopie) an einwandigen Kohlenstoffnanoröhren (SWNTs) wurde ein PL Lasermikroskop konstruiert, das automatisierte Messungen in einem Anregungswellenlängenbereich von ~600 -1000nm (mittels 3 durchstimmbarer Laser) und die Aufnahme von PL Bildern mit einer räumlichen Auflösung von bis zu 400nm gestattete. Die PL von direkt gewachsenen, frei hängenden SWNTs wurde mit der von SWNTs in D2O/Tensid Dispersionen und ebenso mit der von SWNTs in organischen Lösungsmitteln verglichen. Die beobachteten Verschiebungen der charakteristischen optischen E11 Emissions- und E22 Anregungsenergien kommen durch Veränderungen in der Umgebung der Nanoröhren zustande. Dadurch ergibt sich eine unterschiedliche dielektrische Abschirmung der elektronischen Anregungen (Exzitonen). Ebenso wurde die PL von direkt gewachsenen SWNTs (frei hängend und auf der Oberfläche liegend) mit der von einzelnen, aus D2O/Tensid Dispersionen heraus auf einer Oberfläche abgeschiedenen SWNTs bei Temperaturen bis zu 4K verglichen. Nur letztere zeigen bei tiefen Temperaturen PL-Blinken und spektrale Diffusion. PLE Spektren von frei hängenden SWNTs und von Dispersionen, in denen einzelne Chiralitäten angereichert waren, ermöglichten die erste direkte Beobachtung von zwei tiefliegenden Exzitonenzuständen unterhalb des tiefsten optisch erlaubten E11 Exzitons. Die energetische Position dieser Zustände, sowie deren Intensität im Vergleich zu der E11 Emissionslinie werden diskutiert. Das PL Mikroskop war empfindlich genug, um die schwache PL von direkt gewachsenen SWNTs auf dielektrischen Oberflächen zu detektieren. Extrem lange, mittels CVD auf Si/SiO2 synthetisierte SWNTs konnten so abgebildet, ihre Chiralität bestimmt und die strukturelle Integrität entlang der Aufrollachse überprüft werden. Darüber hinaus wurden solche Nanoröhren mittels Rasterkraftmikroskopie manipuliert (verschoben, vebogen und zerrissen). Wir zeigen, dass PLE Mikroskopie eine leistungsstarke Methode ist, um noch vorhandene axiale uns torsionale Dehnung in SWNTs nachzuweisen. An gebrochenen Stellen wurde bei Nanoröhren ein auffälliges PL Verhalten gefunden. Schließlich wird ein neues Verfahren vorgestellt, mit dem relative Konzentrationen sowie Quantenausbeuten dispergierter, halbleitender SWNTs durch statistisches Zählen von PL Signalen bestimmt werden können

Spectroscopy of Individual Single-Walled Carbon Nanotubes and their Synthesis via Chemical Vapor Deposition

A chemical vapor deposition (CVD) reactor was designed, built and used to grow vertically and horizontally aligned carbon nanotube arrays. The as-grown nanotubes were investigated on a single tube level using nearinfrared photoluminescence (PL) microscopy as well as Raman, atomic force and scanning electron microscopy (SEM). For photoluminescence excitation (PLE) spectroscopy of individual, semiconducting single-walled carbon nanotubes (SWNTs), a specialized PL set-up was constructed

Effects of anti-ischaemic drug therapy in silent myocardial ischaemia type I: the Swiss Interventional Study on Silent Ischaemia type I (SWISSI I): a randomized, controlled pilot study

Aims To determine the effect of anti-ischaemic drug therapy on long-term outcomes of asymptomatic patients without coronary artery disease (CAD) history but silent exercise ST-depression. Methods and results In a randomized multicentre trial, 263 of 522 asymptomatic subjects without CAD but at least one CAD risk factor in whom silent ischaemia by exercise ECG was confirmed by stress imaging were asked to participate. The 54 (21%) consenting patients were randomized to anti-anginal drug therapy in addition to risk factor control (MED, n = 26) or risk factor control-only (RFC, n = 28). They were followed yearly for 11.2 ± 2.2 years. During 483 patient-years, cardiac death, non-fatal myocardial infarction, or acute coronary syndrome requiring hospitalization or revascularization occurred in 3 (12%) of MED vs. 17 (61%) of RFC patients (P < 0.001). In addition, MED patients had consistently lower rates of exercise-induced ischaemia during follow-up, and left ventricular ejection fraction remained unchanged (−0.7%, P = 0.597) in contrast to RFC patients in whom it decreased over time (−6.0%, P = 0.006). Conclusion Anti-ischaemic drug therapy and aspirin seem to reduce cardiac events in subjects with asymptomatic ischaemia type I. In such patients, exercise-induced ST-segment depression should be verified by stress imaging; if silent ischaemia is documented, anti-ischaemic drug therapy and aspirin should be considere