Effect of ivabradine-induced heart rate reduction on flow-mediated dilation measured with high-sensitivity ultrasound in patients with stable coronary heart disease.

BACKGROUND: Experimental data suggests that exclusive heart rate reduction with ivabradine is associated with the amelioration of the endothelial function. Since it is presently unknown whether this also applies to humans, the aim of this pilot study was to investigate whether heart rate reduction with ivabradine modulates the endothelial function in humans with an established coronary heart disease. METHODS: Using high-sensitivity ultrasound, we analysed the flow-mediated (FMD) and nitro-mediated dilation (NMD) of the brachial artery in 25 patients (62.9 ± 8.4 years) with a stable coronary heart disease and a resting heart rate of ≥70 beats per minute (bpm). To assess acute effects, measurements were performed before and 4 hours after the first intake of ivabradine 7.5 mg. Sustained effects of an ivabradine therapy (5 mg to 7.5 mg twice daily) were investigated after 4 weeks. RESULTS: We found a significant decrease in heart rate, both 4 hours after the intake of 7.5 mg of ivabradine (median -8 [interquartile range (IQR) -14 to -4] bpm) and after 4 weeks of twice daily intake (median -10 [IQR-17 to -5] bpm) (p < 0.05). However, the FMD did not change significantly: neither after first dose of ivabradine nor after sustained therapy (baseline FMD: median 5.0 [IQR 2.4 to 7.9]%; FMD 4 hours after 7.5 mg of ivabradine: median 4.9 [IQR 2.7 to 9.8]%; FMD after 4 weeks of ivabradine therapy: median 6.1 [IQR 4.3 to 8.2]%). No significant changes of the NMD were observed. In regression analysis, the heart rate and FMD did not correlated, irrespective of the ivabradine intake (r2 = 0.086). CONCLUSION: In conclusion, in our study heart rate reduction through ivabradine does not improve the endothelial function in patients with a stable coronary heart disease. Moreover, we found no correlation between the heart rate and the endothelial function.

Lack of effects of tomato products on endothelial function in human subjects: results of a randomised, placebo-controlled cross-over study.

Epidemiological studies suggest that consumption of tomato products reduces the risk of CVD via antioxidant, hypocholesterolaemic and anti-inflammatory mechanisms. Although experimental data also describe beneficial effects on endothelial function, clinical data in human subjects are lacking. To test the hypothesis that tomato ingestion ameliorates endothelial function, we randomised healthy non-smoking postmenopausal women to consume a buttered roll with and without tomato purée (70 g) in a cross-over design. Endothelial-dependent flow-mediated dilation (FMD) and endothelial-independent nitro-mediated dilation of the brachial artery were assessed with high-resolution ultrasound (13 MHz linear array transducer). Acute (24 h) and long-term (7 d) effects were examined after daily consumption of the described meal. Nineteen volunteers completed the protocol and provided technically suitable ultrasound measurement data. Plasma lycopene levels increased from 0·30 (sem 0·04) (baseline) to 0·42 (sem 0·04) and to 0·74 (sem 0·06) µm after 24 h and 7 d, respectively, with tomato purée consumption. These data indicated an effective absorption of the tomato product. However, both acute and long-term tomato purée consumption had no effects on endothelium-dependent or -independent dilation of the brachial artery. In addition, we found no correlation between lycopene plasma levels and FMD. In conclusion, consumption of tomato products associated with a significant increase in plasma lycopene levels had no effects on endothelial function in healthy postmenopausal women.

Smoking decreases the level of circulating CD34+ progenitor cells in young healthy women--a pilot study.

BACKGROUND: Decreased levels of circulating bone marrow-derived progenitor cells have been associated with risk factors and cardiovascular diseases. Smoking is the most important modifiable risk factor for atherosclerosis in young women. The aim of this pilot study was to assess in healthy premenopausal women without other risk factors for cardiovascular disease the influence of nicotine abuse on the number of circulating progenitor cells in relation to endothelial function. METHODS: The number of endothelial progenitor cells, measured as colony-forming units in a cell-culture assay (EPC-CFU) and the number of circulating CD34 + and CD34 + /CD133 + cells, measured by flow cytometry, was estimated in 32 women at the menstrual phase of the menstrual cycle. In addition, flow-mediated dilation (FMD) was assessed as a marker for vascular function. In a subgroup of these women (n = 20), progenitor cells were also investigated at the mid-follicular and luteal phases of the menstrual cycle. RESULTS: Compared to non-smokers, the abundance of circulating CD34 + cells was significantly lower in smoking women in the menstrual, mid-luteal, and mid-follicular phases of the menstrual cycle. The number of CD34 + progenitor cells was revealed to have significant positive correlation with FMD in young healthy women, whereas CD34 + /CD133 + progenitor cells and EPC-CFU showed no significant correlation. CONCLUSION: The number of CD34 + progenitor cells positively correlates with FMD in young healthy women and is decreased by smoking.

Potential role of autoantibodies belonging to the immunoglobulin G-3 subclass in cardiac dysfunction among patients with dilated cardiomyopathy.

BACKGROUND: Immunoadsorption capable of removing circulating autoantibodies represents an additional therapeutic approach in dilated cardiomyopathy (DCM). The role played by autoantibodies belonging to the immunoglobulin (Ig) subclass G-3 in cardiac dysfunction remains to be elucidated. METHODS AND RESULTS: Patients with DCM (left ventricular ejection fraction <30%) participated in this case-control study. Nine patients underwent immunoadsorption with protein A (low affinity to IgG-3), and 9 patients were treated with anti-IgG, which removes all IgG subclasses. Immunoadsorption was performed in 4 courses at 1-month intervals until month 3. In the 2 groups, immunoadsorption induced comparable reduction of total IgG (>80%). IgG-3 was effectively eliminated only by anti-IgG adsorption (eg, during the first immunoadsorption course; protein A, -37+/-4%; anti-IgG, -89+/-3%; P<0.001 versus protein A). The beta1-receptor autoantibody was effectively reduced only by anti-IgG (P<0.01 versus protein A). Hemodynamics did not change in the protein A group. In the anti-IgG group during the first immunoadsorption course, cardiac index increased from 2.3+/-0.1 to 3.0+/-0.1 L x min(-1) x m(-2) (P<0.01 versus protein A). After 3 months, before the last immunoadsorption course, cardiac index was 2.2+/-0.1 L x min(-1) x m(-2) in the protein A group and 3.0+/-0.2 L x min(-1) x m(-2) in the anti-IgG group (P<0.01 versus protein A). Left ventricular ejection fraction increased only in the anti-IgG group (P<0.05 versus protein A). CONCLUSIONS: Autoantibodies belonging to IgG-3 may play an important role in cardiac dysfunction of DCM. The removal of antibodies of the IgG-3 subclass may represent an essential mechanism of immunoadsorption in DCM.

Long-term therapy of interferon-alpha induced pulmonary arterial hypertension with different PDE-5 inhibitors: a case report.

BACKGROUND: Interferon alpha2 is widely used in hepatitis and high-risk melanoma. Interferon-induced pulmonary arterial hypertension as a side effect is rare. CASE PRESENTATION: We describe a melanoma patient who developed severe pulmonary arterial hypertension 30 months after initiation of adjuvant interferon alpha2b therapy. Discontinuation of interferon did not improve pulmonary arterial hypertension. This patient could be treated successfully with phosphodiesterase-5 inhibitor therapy. CONCLUSION: This is only the 5th case of interferon-induced pulmonary arterial hypertension and the first documented case where pulmonary arterial hypertension was not reversible after termination of interferon alpha2 therapy. If interferon alpha2 treated patients develop respiratory symptoms, pulmonary arterial hypertension should be considered in the differential diagnosis. For these patients phosphodiesterase-5 inhibitors, e.g. sildenafil or vardenafil, could be an effective therapeutic approach.

Serum pattern of circulating free leptin, bound leptin, and soluble leptin receptor in the physiological menstrual cycle.

OBJECTIVE: To investigate the serum pattern of free leptin, bound leptin, and soluble leptin receptor throughout the physiological menstrual cycle. DESIGN: Prospective observational study. SETTING: Tertiary care center for gynecological endocrinology and reproductive medicine and a university research laboratory. PATIENT(S): Thirty regularly cycling volunteers (age, 29 +/- 4.2 years). INTERVENTION(S): Blood sampling was performed at different phases (early and mid follicular phase, preovulatory phase, and early and late luteal phase) of three consecutive menstrual cycles; each phase of the menstrual cycle was investigated twice. MAIN OUTCOME MEASURE(S): Free leptin, bound leptin, soluble leptin receptor, LH, E(2), P, vaginal ultrasound. RESULT(S): A peak of serum free leptin levels was found in the late luteal phase followed by a significant drop in the early follicular phase and again by a continuous increase up to the next luteal peak. There were no significant alterations in serum bound leptin and soluble leptin receptor levels. CONCLUSION(S): The present study shows that there are significant circacyclic fluctuations of free leptin levels with the highest concentrations in the late luteal phase and the lowest levels in the early follicular phase, which suggests that circulating free leptin is up-regulated by the C(21)-steroid (P). Circulating bound leptin and soluble leptin receptor are not altered by the cyclic hormone status. The significant rise of the leptin bioequivalent, free leptin, in the late luteal phase might be of importance for the luteal-follicular and the luteal-preimplantatory functional shift.

Reduction of morbidity by immunoadsorption therapy in patients with dilated cardiomyopathy.

BACKGROUND: In patients with dilated cardiomyopathy (DCM) and severe congestive heart failure, immunoadsorption (IA) and subsequent IgG substitution leads to an acute and prolonged hemodynamic improvement. Goal of this study was to investigate the long-term effect of immunoadsorption on morbidity. METHODS: In a retrospective analysis of 34 patients (17 patients who have received immunoadsorption therapy and 17 control patients) were included. Inclusion criteria were DCM, left ventricular ejection fraction less than 35%, NYHA classes II-III. The average time after immunoadsorption was 3.0 years (median 2.3 years). Both groups did not differ concerning sex, age, duration of disease, medication, baseline ejection fraction and NYHA class. RESULTS: In patients who have received immunoadsorption (IA) the days of hospitalisation for congestive heart failure per year could be significantly reduced in contrast to the control patients (17.2 days prior to IA, 4.3 days after IA). Even if the procedural days for immunoadsorption were included there was still a significant reduction of hospitalisation if IA therapy was longer than 2.5 years ago. The days of hospitalisation increased gradually with time during the follow up period. IA induced an acute increase in EF (19.8-25.7%, p<0.01 vs. baseline). CONCLUSION: IA not only leads to an acute hemodynamic improvement in patients with DCM but may also reduce morbidity in these patients during the next 3 years.

Chronic smoking prevents amelioration of endothelial function in the course of the menstrual cycle.

BACKGROUND: Smoking is the most important modifiable cardiovascular risk factor in young women. The aim of this study was to investigate whether tobacco use influences physiological changes in endothelial function during the menstrual cycle. METHODS AND RESULTS: Flow-mediated dilation (FMD) and nitro-mediated dilation (NMD) were assessed in healthy smoking and non-smoking women, by high-resolution ultrasound at 3 time points during the menstrual cycle: at menstruation, in the mid-follicular phase, and in the mid-luteal phase. A total of 25 women (12 non-smokers, 13 smokers) completed the study protocol. FMD did not show differences between smoking and non-smoking women at menstruation and the mid-follicular phase. At the mid-luteal phase, however, FMD was significantly reduced in smoking when compared with non-smoking women. NMD did not differ between smoking and non-smoking women, nor between the different cycle phases. CONCLUSIONS: In healthy women, smoking eliminates the physiological amelioration of endothelial function during the menstrual cycle. This study underlines the importance of an exact description of menstrual cycle phase and smoking status in studies investigating endothelial function in premenopausal women.

Green tea and cardiovascular disease: from molecular targets towards human health.

PURPOSE OF REVIEW: To summarize current knowledge of the protective effects of green tea and green tea constituents, particularly catechins, on the cardiovascular system. RECENT FINDINGS: Consumption of green tea has been inversely associated with the development and progression of cardiovascular diseases and cardiovascular risk factors. Mechanisms that have been suggested as being involved in the antiatherosclerotic effects of green tea consumption primarily entail antioxidative, antiinflammatory, antiproliferative, and antithrombotic properties, as well as beneficial effects on endothelial function. Moreover, evidence exists for myocardial effects of tea constituents, including positive inotropic and antihypertrophic effects, and beneficial impact in myocardial ischaemia-reperfusion injury. SUMMARY: Green tea represents a promising tool for the prevention of cardiovascular disorders.

The efficacy of black tea in ameliorating endothelial function is equivalent to that of green tea.

Consumption of tea has been shown to improve endothelial function. It is assumed that catechins are the tea components responsible for these beneficial effects. In black tea, catechin concentrations are significantly lower than in green tea. The present study was designed to compare green and black tea with regard to amelioration of endothelial function. Endothelial function in response to both teas was assessed in bovine aortic endothelial cells (BAEC) and rat aortic rings. To elucidate whether these findings are also applicable to humans, flow-mediated dilation (FMD) and nitro-mediated dilation (NMD) were assessed by ultrasound in twenty-one healthy women before and 2 h after consumption of green and black tea (2 h of FMD and NMD), in comparison with water (control). In BAEC, green and black tea significantly increased endothelial NO synthase activity to the same extent. Similarly, both teas induced comparable endothelial-dependent vasodilation in rat aortic rings. In human subjects, ingestion of green and black tea led to significant increases in FMD: from 5.4 (sd 2.3) to 10.2 (sd 3) % (baseline-adjusted difference (BAD) for 2 h of FMD, green tea v. water: 5.0 (95 % CI 3.0, 7.0) %; P < 0.001) and from 5 (sd 2.6) to 9.1 (sd 3.6) % (BAD for 2 h of FMD, black tea v. water: 4.4 (95 % CI 2.3, 6.5) %; P < 0.001), respectively. The increase in FMD was not significantly different between the two tea preparations (BAD for 2 h of FMD, green tea v. black tea: 0.66 (95 % CI - 0.76, 2.09) %; P = 0.36). NMD did not vary between any of the groups. In conclusion, green and black tea are equally effective in improving endothelial function.

Addition of milk prevents vascular protective effects of tea.

AIMS: Experimental and clinical studies indicate that tea exerts protection against cardiovascular diseases. However, a question of much debate is whether addition of milk modifies the biological activities of tea. We studied the vascular effects of tea, with or without milk, in humans and elucidated the impact of individual milk proteins in cell culture experiments, with isolated rat aortic rings and by HPLC analysis. METHODS AND RESULTS: A total of 16 healthy female volunteers consumed either 500 mL of freshly brewed black tea, black tea with 10% skimmed milk, or boiled water as control. Flow-mediated dilation (FMD) was measured by high-resolution vascular ultrasound before and 2 h after consumption. Black tea significantly improved FMD in humans compared with water, whereas addition of milk completely blunted the effects of tea. To support these findings, similar experiments were performed in isolated rat aortic rings and endothelial cells. Tea induced vasorelaxation in rat aortic rings and increased the activity of endothelial nitric oxide synthase by phosphorylation of the enzyme in endothelial cells. All effects were completely inhibited by the addition of milk to tea. Of the various kinds of milk proteins, the caseins accounted for these inhibiting effects of milk, probably by formation of complexes with tea catechins. CONCLUSION: Milk counteracts the favourable health effects of tea on vascular function. This finding indicates the need for particular awareness in the interpretation and design of studies comprising nutritional flavonoids.

Female-specific aspects in the pharmacotherapy of chronic cardiovascular diseases.

Differences in pharmacokinetics, pharmacodynamics, and physiology contribute to the phenomenon that women and men frequently respond differently to cardiovascular drugs. Hormonal influences, in addition, can play an important role: for example, the menstrual cycle, menopause, and pregnancy--as a result of fluctuations in concentrations of sexual steroids, and of changes in total body water--can be associated with gender-specific differences in the plasma levels of cardiovascular drugs. Clinical relevance accordingly results, especially for substances with a narrow therapeutic margin. This review treats the most important pharmacodynamic gender-relevant differences in this context, and surveys available evidence on the benefits of therapy of chronic cardiovascular diseases in women. On the whole, the study situation for women is appreciably less favourable than for men: owing to the fact that women are under-represented in most studies, and that few gender-specific analyses have been conducted.