Instantaneous coronary collateral function during supine bicycle exercise

Aims The instantaneous response of the collateral circulation to isometric physical exercise in patients with non-occlusive coronary artery disease (CAD) is not known. Methods and results Thirty patients (age 59 ± 9 years) undergoing percutaneous coronary intervention because of stable CAD were included in the study. Collateral function was determined before and during the last minute of a 6 min protocol of supine bicycle exercise during radial artery access coronary angiography. Collateral flow index (CFI, no unit) was determined as the ratio of mean distal coronary occlusive to mean aortic pressure both subtracted by central venous pressure. To avoid confounding due to recruitment of coronary collaterals by repetitive balloon occlusions, patients were randomly assigned to a group ‘rest first' with CFI measurement during rest followed by CFI during exercise, and to a group ‘exercise first' with antecedent CFI measurement during exercise before CFI at rest. Simultaneously, coronary collateral conductance (occlusive myocardial blood flow per aorto-coronary pressure drop) was determined by myocardial contrast echocardiography in the last 10 consecutive patients. Overall, CFI increased from 0.168 ± 0.118 at rest to 0.262 ± 0.166 during exercise (P = 0.0002). The exercise-induced change in CFI did not differ statistically in the two study groups. Exercise-induced CFI reserve (CFI during exercise divided by CFI at rest) was 2.2 ± 1.8. Overall, rest to peak bicycle exercise change of coronary collateral conductance was from 0.010 ± 0.010 to 1.109 ± 0.139 mL/min/100 mmHg (P < 0.0001); the respective change was similar in both groups. Conclusion In patients with non-occlusive CAD, collateral flow instantaneously doubles during supine bicycle exercise as compared with the resting state. ClinicalTrials.gov Identifier: NCT0094705

Oversizing and Restenosis with Self-Expanding Stents in Iliofemoral Arteries

Purpose: Uncoated self-expanding nitinol stents (NS) are commonly oversized in peripheral arteries. In current practice, 1-mm oversizing is recommended. Yet, oversizing of NS may be associated with increased restenosis. To provide further evidence, NS were implanted in porcine iliofemoral arteries with a stent-to-artery-ratio between 1.0 and 2.3. Besides conventional uncoated NS, a novel self-expanding NS with an antiproliferative titanium-nitride-oxide (TiNOX) coating was tested for safety and efficacy. Methods: Ten uncoated NS and six TiNOX-coated NS (5-6mm) were implanted randomly in the iliofemoral artery of six mini-pigs. After implantation, quantitative angiography (QA) was performed for calculation of artery and minimal luminal diameter. Follow-up was performed by QA and histomorphometry after 5months. Results: Stent migration, stent fracture, or thrombus formation were not observed. All stents were patent at follow-up. Based on the location of the stent (iliac/femoral) and the stent-to-artery-ratio, stent segments were divided into "normal-sized” (stent-to-artery-ratio<1.4, n=12) and "oversized” (stent-to-artery-ratio≥1.4, n=9). All stent segments expanded to their near nominal diameter during follow-up. Normal-sized stent segments increased their diameter by 6% and oversized segments by 29%. A significant correlation between oversizing and restenosis by both angiography and histomorphometry was observed. Restenosis rates were similar for uncoated NS and TiNOX-coated NS. Conclusions: TiNOX-coated NS are as safe and effective as uncoated NS in the porcine iliofemoral artery. All stents further expand to near their nominal diameter during follow-up. Oversizing is linearly and positively correlated with neointimal proliferation and restenosis, which may not be reduced by TiNOX-coatin

Instantaneous coronary collateral function during supine bicycle exercise

The instantaneous response of the collateral circulation to isometric physical exercise in patients with non-occlusive coronary artery disease (CAD) is not known

Coronary collaterals and risk for restenosis after percutaneous coronary interventions: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>The benefit of the coronary collateral circulation (natural bypass network) on survival is well established. However, data derived from smaller studies indicates that coronary collaterals may increase the risk for restenosis after percutaneous coronary interventions. The purpose of this systematic review and meta-analysis of observational studies was to explore the impact of the collateral circulation on the risk for restenosis.</p> <p>Methods</p> <p>We searched the MEDLINE, EMBASE and ISI Web of Science databases (2001 to 15 July 2011). Random effects models were used to calculate summary risk ratios (RR) for restenosis. The primary endpoint was angiographic restenosis > 50%.</p> <p>Results</p> <p>A total of 7 studies enrolling 1,425 subjects were integrated in this analysis. On average across studies, the presence of a good collateralization was predictive for restenosis (risk ratio (RR) 1.40 (95% CI 1.09 to 1.80); <it>P </it>= 0.009). This risk ratio was consistent in the subgroup analyses where collateralization was assessed with intracoronary pressure measurements (RR 1.37 (95% CI 1.03 to 1.83); <it>P </it>= 0.038) versus visual assessment (RR 1.41 (95% CI 1.00 to 1.99); <it>P </it>= 0.049). For the subgroup of patients with stable coronary artery disease (CAD), the RR for restenosis with 'good collaterals' was 1.64 (95% CI 1.14 to 2.35) compared to 'poor collaterals' (<it>P </it>= 0.008). For patients with acute myocardial infarction, however, the RR for restenosis with 'good collateralization' was only 1.23 (95% CI 0.89 to 1.69); <it>P </it>= 0.212.</p> <p>Conclusions</p> <p>The risk of restenosis after percutaneous coronary intervention (PCI) is increased in patients with good coronary collateralization. Assessment of the coronary collateral circulation before PCI may be useful for risk stratification and for the choice of antiproliferative measures (drug-eluting stent instead bare-metal stent, cilostazol).</p

Effect of High-Cholesterol Diet and Endothelin ET(A) Receptor-Blockade on Vascular and Renal Function in Experimental Models of Hypertension

Titelblatt Inhaltsverzeichnis 1 Einleitung 5 2 Material und Methoden 10 2.1 Studienaufbau 10 2.2 Versuchstiere 10 2.3 Blutdruckmessung 12 2.4 Biochemische Urin- und Blutanalysen 13 2.5 Organentnahme 14 2.6 Organkammer-Experimente 15 2.6.1 Versuchsaufbau 15 2.6.2 Versuchsprotokolle 15 2.6.3 Substanzen 17 2.7 Statistische Auswertung 17 3 Ergebnisse 19 3.1 Studie A: Genetisch determinierte Hypertonie 19 3.1.1 Körper- und Organgewichte 19 3.1.2 Systolischer Blutdruck 19 3.1.3 Biochemische Urinanalysen 21 3.1.4 Biochemische Blutanalysen 21 3.1.5 Untersuchungen zur Gefäßfunktion 23 3.2 Studie B: Spontane Proteinurie bei Hypertonie 26 3.2.1 Körper- und Organgewichte 26 3.2.2 Systolischer Blutdruck 26 3.2.3 Biochemische Urinanalysen 27 3.2.4 Biochemische Blutanalysen 27 3.2.5 Untersuchungen zur Gefäßfunktion 29 3.3 Studie C: Salzsensitive Hypertonie 32 3.3.1 Körper- und Organgewichte 32 3.3.2 Systolischer Blutdruck 33 3.3.3 Biochemische Urinanalysen 33 3.3.4 Untersuchungen zur Gefäßfunktion 35 4 Diskussion 37 4.1 Genetisch determinierte Hypertonie 37 4.1.1 Wirkungen einer Cholesterinbehandlung auf renale Funktionsparameter 37 4.1.1 Wirkungen einer Cholesterinbehandlung auf vaskuläre Funktionsparameter 39 4.2 Spontane Proteinurie bei Hypertonie 41 4.2.1 Wirkungen einer Cholesterinbehandlung auf renale Funktionsparameter 41 4.2.2 Wirkungen einer Cholesterinbehandlung auf vaskuläre Funktionsparameter 43 4.3 Salzsensitive Hypertonie 44 4.3.1 Wirkungen einer Endothelinblockade auf renale Funktionsparameter 44 4.3.2 Wirkungen einer Endothelinblockade auf vaskuläre Funktionsparameter 46 5 Abkürzungen 50 6 Zusammenfassung 52 7 Literatur 54 8 Lebenslauf, Publikationen und Danksagung 66 9 Anhang 71 9.1 Materialliste 71 9.1.1 Laborgeräte 71 9.1.2 Laborzubehör 72 9.1.3 Substanzen 73Die arterielle Hypertonie ist ein wesentlicher Risikofaktor für die Entstehung der Atherosklerose, die für etwa die Hälfte der Morbidität und Mortalität in den Industrieländern verantwortlich ist. Im Rahmen hypertensiver Endorganschädigungen kommt es zu einer systemischen Dysfunktion des vaskulären Endothels und zu einer Mikroalbuminurie, die wichtige prognostische Marker bei Patienten mit kardiovaskulären Erkrankungen darstellen. In der vorliegenden Arbeit wurde daher untersucht, ob eine Cholesterindiät (ChD) zu einer verstärkten Endorganschädigung an Niere und Aorta bei der spontan hypertensiven Ratte (SHR) und der München Wistar Frömter (MWF)-Ratte führt. Weiterhin wurde untersucht, ob eine Behandlung mit einem Endothelin ET(A)-Rezeptorantagonisten (LU135252) die Entstehung von Hypertonie und Endorganschäden bei der salzsensitiven Sabra-Ratte (SBH) beeinflussen kann. Um funktionelle Veränderungen an Aorta und Niere bestimmen zu können, wurden Relaxations- und Kontraktionsexperimente mit isolierten Aortenringen in Organkammern, biochemische Urin- und Blutanalysen sowie Blutdruckmessungen durchgeführt. Unsere Untersuchungen konnten zeigen, dass eine ChD bei der SHR zu einer Albuminurie, einem Anstieg des CRP und einer abgeschwächten endothel- vermittelten Relaxation führt. Nach in vitro-Behandlung mit LU135252 zeigte sich eine deutliche Abschwächung der Kontraktionen auf Phenylephrin. Dies deutet auf eine endothelinvermittelte Modulation der alpha1-rezeptorvermittelten Kontraktionen bei diesen Tieren hin. Die deutlich ausgeprägte Albuminurie der MWF-Ratte wurde durch eine ChD trotz Nierenhypertrophie nicht weiter erhöht. Eine veränderte endothel-abhängige Relaxation konnte auch nach Behandlung mit einer ChD nicht festgestellt werden, ebenso zeigte sich nach in vitro-Behandlung mit L-NMMA oder LU135252 keine Abschwächung der Kontraktionen auf Phenylephrin. Bei der salzsensitiven Sabra-Ratte (SBH) verhinderte die orale Gabe von LU135252 eine linksventrikuläre Herzhypertrophie und bewirkte eine deutliche Abschwächung des systolischen Blutdruckanstiegs und der Albuminurie nach Salzbehandlung. Kontraktionen auf ET-1 waren bei normotensiven SBH im Vergleich zu salzresistenten SBN deutlich geringer ausgeprägt und nach Salzbehandlung oder gleichzeitiger Gabe von LU135252 noch weiter abgeschwächt. Diese Befunde deuten auf eine spezifische, stark gestörte funktionelle Einschränkung der ET(A)-vermittelten intrazellulären Signaltransduktion in der Aorta von SBH hin, die sich von den bekannten Hypertoniemodellen unterscheidet. Die vorliegenden Untersuchungen zeigen erstmals die Bedeutung von exogen zugeführtem Cholesterin bzw. DOCA-Salz auf funktionelle Parameter von Aorta und Niere bei verschiedenen experimentellen Hypertoniemodellen sowie die Rolle des Vasokonstriktors und Wachstumsfaktors Endothelin in diesem Zusammenhang.Arterial hypertension is a major risk factor for the development of atherosclerosis, which still accounts for the majority of cardiovascular morbidity and mortality in industrialized countries and its incidence is increasing in developing countries. Hypertension may cause impairment of vascular endothelial cell function as well as microalbuminuria which both are important determinants of disease progression in patients with increased cardiovascular risk. We therefore investigated whether a high-cholesterol diet (ChD) increases endorgan-damage of the kidney or the aorta in the spontaneously hypertensive rat (SHR) and the Munich Wistar Fromter rat (MWF). Moreover, we investigated whether treatment with an orally active endothelin ET(A) receptor-antagonist (LU135252) prevents hypertension or endorgan-damage in the Sabra model of salt-sensitive hypertension (SBH). To assess functional alterations of aorta and kidneys, contractions and relaxations of isolated aortic rings suspended in organ chambers, biochemical analysis of blood and urine, and blood pressure measurements were performed. In this study, we demonstrate that ChD increases albuminuria and C-reactive protein serum levels, and attenuates endothelium-dependent relaxations in SHR rats. After in vitro treatment with LU135252, contractions to phenylephrine were markedly decreased which indicates endothelin-1 mediated modulation of alpha1-receptor mediated contractions. Interestingly, ChD did not affect distinct albuminuria in MWF rats, although animals showed renal hypertrophy. Endothelium-dependent relaxations were neither attenuated in this model, nor affected by ChD. Furthermore, contractions to phenylephrine were not affected by in vitro treatment with L-NAME or LU135252. In contrast, oral treatment with LU135252 prevented leftventricular hypertrophy in the Sabra model of hypertension and ameliorated increased systolic blood pressure as well as albuminuria after salt-loading. Contractions to endothelin-1 were markedly decreased in normotensive SBH rats as compared with salt-resistent SBN, and further decreased after salt-loading with or without LU135252 treatment. These results indicate a pronounced functional impairment of ET(A) receptor mediated intracellular signalling in the aorta of SBH rats which is different from other experimental models of hypertension. In summary, this study demonstrates the effect of high-cholesterol diet and salt-loading on vascular and renal function in different animal models of hypertension, including the role of endothelin-1

Cause or effect of arteriogenesis: compositional alterations of microparticles from CAD patients undergoing external counterpulsation therapy

Recently, a clinical study on patients with stable coronary artery disease (CAD) showed that external counterpulsation therapy (ECP) at high (300 mmHg) but not at low inflation pressure (80 mmHg) promoted coronary collateral growth, most likely due to shear stress-induced arteriogenesis. The exact molecular mechanisms behind shear stress-induced arteriogenesis are still obscure. We therefore characterized plasma levels of circulating microparticles (MPs) from these CAD patients because of their ambivalent nature as a known cardiovascular risk factor and as a promoter of neovascularization in the case of platelet-derived MPs. MPs positive for Annexin V and CD31CD41 were increased, albeit statistically significant (P<0.05, vs. baseline) only in patients receiving high inflation pressure ECP as determined by flow cytometry. MPs positive for CD62E, CD146, and CD14 were unaffected. In high, but not in low, inflation pressure treatment, change of CD31CD41 was inversely correlated to the change in collateral flow index (CFI), a measure for collateral growth. MPs from the high inflation pressure group had a more sustained pro-angiogenic effect than the ones from the low inflation pressure group, with the exception of one patient showing also an increased CFI after treatment. A total of 1005 proteins were identified by a label-free proteomics approach from MPs of three patients of each group applying stringent acceptance criteria. Based on semi-quantitative protein abundance measurements, MPs after ECP therapy contained more cellular proteins and increased CD31, corroborating the increase in MPs. Furthermore, we show that MP-associated factors of the innate immune system were decreased, many membrane-associated signaling proteins, and the known arteriogenesis stimulating protein transforming growth factor beta-1 were increased after ECP therapy. In conclusion, our data show that ECP therapy increases platelet-derived MPs in patients with CAD and that the change in protein cargo of MPs is likely in favor of a pro angiogenic/arteriogenic property

Oral contraceptives and the risk of thrombosis and atherosclerosis.

Oral contraceptives containing synthetic oestrogens have been used successfully as birth control for > 40 years and are currently prescribed to > 100 million women worldwide. Several new progestins have been introduced and the third generation of progestins has now been available for two decades. Oral contraceptives are prescribed over a prolonged period of time and therefore substantially impact on hormonal, metabolic and plasmatic functions. Oral contraceptives increase the risk for venous thrombosis and pulmonary embolism, particularly if associated with confounding factors, such as genetic predisposition, smoking, hypertension or obesity. The risk of developing coronary artery disease is also increased in users with cardiovascular risk factors. This article discusses mechanistic and clinical issues and reviews the need for novel approaches targeting the considerable side effects in order to reduce cardiovascular morbidity in women using oral contraceptives

Physical coronary arteriogenesis: a human "model" of collateral growth promotion

In patients with coronary artery disease, the size of myocardial infarction mainly determines the subsequent clinical outcome. Accordingly, it is the primary strategy to decrease cardiovascular mortality by minimizing infarct size. Promotion of collateral artery growth (arteriogenesis) is an appealing option of reducing infarct size. It has been demonstrated in experimental models that tangential fluid shear stress is the major trigger of arterial remodeling and, thus, of collateral growth. Lower-leg, high-pressure external counterpulsation triggered to occur during diastole induces a flow velocity signal and thus tangential endothelial shear stress in addition to the flow signal caused by cardiac stroke volume. We here present two cases of cardiac transplant recipients as human "models" of physical coronary arteriogenesis, providing an example of progressing and regressing clinical arteriogenesis, and review available evidence from clinical studies on other feasible forms of physical arteriogenesis