Background— Elevated heart rate is associated with increased cardiovascular morbidity. We hypothesized that selective heart rate reduction may influence endothelial function and atherogenesis and tested the effects of the I (f) current inhibitor ivabradine in apolipoprotein E–deficient mice. Methods and Results— Male apolipoprotein E–deficient mice fed a high-cholesterol diet were treated with ivabradine (10 mg · kg −1 · d −1 ) or vehicle for 6 weeks (n=10 per group). Ivabradine reduced heart rate by 13.4% (472±9 versus 545±11 bpm; P <0.01) but did not alter blood pressure or lipid levels. Endothelium-dependent relaxation of aortic rings was significantly improved in ivabradine-fed animals ( P <0.01). Ivabradine decreased atherosclerotic plaque size in the aortic root by >40% and in the ascending aorta by >70% ( P <0.05). Heart rate reduction by ivabradine had no effect on the number of endothelial progenitor cells and did not alter aortic endothelial nitric oxide synthase, phosphorylated Akt, vascular cell adhesion molecule-1, or intercellular adhesion molecule-1 expression but decreased monocyte chemotactic protein-1 mRNA and exerted potent antioxidative effects. Ivabradine reduced vascular NADPH oxidase activity to 48±6% and decreased markers of superoxide production and lipid peroxidation in the aortic wall ( P <0.05). The in vivo effects of ivabradine were absent at a dose that did not lower heart rate, in aortic rings treated ex vivo, and in cultured vascular cells. In contrast to ivabradine, treatment with hydralazine (25 mg · kg −1 · d −1 for 6 weeks) reduced blood pressure (−15%) but increased heart rate (37%) and did not improve endothelial function, atherosclerosis, or oxidative stress. Conclusions— Selective heart rate reduction with ivabradine decreases markers of vascular oxidative stress, improves endothelial function, and reduces atherosclerotic plaque formation in apolipoprotein E–deficient mice.

This review summarizes the current literature and the open questions regarding the physiology and pathophysiology of the mechanical effects of heart rate on the vessel wall and the associated molecular signaling that may have implications for patient care. Epidemiological evidence shows that resting heart rate is associated with cardiovascular morbidity and mortality in the general population and in patients with cardiovascular disease. As a consequence, increased resting heart rate has emerged as an independent risk factor both in primary prevention and in patients with hypertension, coronary artery disease, and myocardial infarction. Experimental and clinical data suggest that sustained elevation of heart rate-independent of the underlying trigger-contributes to the pathogenesis of vascular disease. In animal studies, accelerated heart rate is associated with cellular signaling events leading to vascular oxidative stress, endothelial dysfunction, and acceleration of atherogenesis. The underlying mechanisms are only partially understood and appear to involve alterations of mechanic properties such as reduction of vascular compliance. Clinical studies reported a positive correlation between increased resting heart rate and circulating markers of inflammation. In patients with coronary heart disease, increased resting heart rate may influence the clinical course of atherosclerotic disease by facilitation of plaque disruption and progression of coronary atherosclerosis. While a benefit of pharmacological or interventional heart rate reduction on different vascular outcomes was observed in experimental studies, prospective clinical data are limited, and prospective evidence determining whether modulation of heart rate can reduce cardiovascular events in different patient populations is needed.

AimsClinical outcomes of patients with chronic heart failure (CHF) have improved, but evidence-based treatment appears to be imbalanced depending on patients' and physicians' gender. We aimed to determine the interactions of gender with medical treatment of CHF. Methods and resultsConsecutive patients with CHF (n ¼ 1857) were evaluated regarding co-morbidities, New York Heart Association classification, current medical treatment, and dosage of angiotensin-converting enzyme-inhibitors (ACE-Is) and betablockers. Gender of patients and treating physicians was recorded. Baseline characteristics of patients and physicians were comparable for males and females. Female patients were less frequently treated with ACE-Is, angiotensinreceptor blockers, or beta-blockers. Achieved doses were lower in female compared with male patients. Guideline-recommended drug use and achieved target doses tended to be higher in patients treated by female physicians. There was no different treatment for male or female patients by female physicians, whereas male physicians used significantly less medication and lower doses in female patients. In multivariable analysis, female gender of physicians was an independent predictor of use of beta-blockers. ConclusionTreatment of CHF is influenced by patients', but also physicians' gender with regard to evidenced-based drugs and their dosage. Physicians should be aware of this problem in order to avoid gender-related treatment imbalances.--

Summary Aims:  Erectile dysfunction is a major problem with an increasing prevalence in cardiovascular high‐risk patients due to its association with cardiovascular risk factors. Drugs used for evidence‐based treatment of cardiovascular diseases have been reported to decrease erectile function, but possible mechanisms are poorly characterised. Methods:  MEDLINE, EMBASE and Cochrane Registry search were performed including manuscripts until January 2010. Searching terms are: ‘erectile dysfunction or impotence’ in combination with ‘ACE‐inhibitors’, ‘angiotensin’, ‘beta‐blockers’, ‘calcium antagonist’ and ‘diuretics’. Animal studies, letters, reviews, case‐reports and manuscripts other than English language and trials dealing with combination treatment are excluded. Results:  Analysis of literature revealed five epidemiological trials evaluating the effect of different cardiovascular drugs on erectile function. There were eight trials evaluating the effect of beta‐blockers, five trials evaluating the effect of ace‐inhibitors or angiotensin‐receptor‐blockers and one trial evaluating the effect of diuretics on erectile function. Results of these trials demonstrate that only thiazide diuretics and beta‐blockers except nebivolol may adversely influence erectile function. ACE‐inhibitors, angiotensin‐receptor‐blockers and calcium‐channel‐blockers are reported to have no relevant or even a positive effect on erectile function. Conclusion:  Inappropriate patients’ concerns about adverse effects of cardiovascular drugs on erectile function might limit the use of important medications in cardiovascular high‐risk patients. Knowledge about the effects of drug‐treatments on erectile function and about the major role of the endothelium in penile function might improve patients’ adherence to evidence based treatment of cardiovascular diseases.

Cardiovascular disease represents a continuum that starts with risk factors such as hypertension and progresses to atherosclerosis, target organ damage, and ultimately to myocardial infarction, heart failure, stroke or death. Renin-angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT(1)-receptor blockers (ARBs) has turned out to be beneficial at all stages of this continuum. Both classes of agent can prevent or reverse endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardiovascular events. Such a reduction has been shown mainly for ACE inhibitors in patients with coronary artery disease, but recent studies revealed that ARBs are not inferior in this respect. However, no such data are currently available on the combination of these drugs. Both ACE inhibitors and ARBs have been shown to reduce target organ damage in organs such as the kidney, brain and heart, and to decrease cardiovascular mortality and morbidity in patients with congestive heart failure. Experimental data point to an influence of ACE inhibitors and ARBs on the number and function of endothelial progenitor cells revealing additional mechanisms of action of these drugs. The VALIANT trial has shown equivalent effects of ARB valsartan and the ACE-inhibitor captopril in patients post myocardial infarction, but the dual RAS-blockade, compared to monotherapy, did not further reduce events. In secondary prevention, the most-recently published ONTARGET study provides evidence that on top of a better tolerability AT(1)-receptors antagonists are equal to ACE inhibitors in the prevention of clinical endpoints like cardiovascular mortality and morbidity, myocardial infarction and stroke. The combined RAS blockade, however, achieved no further benefits in vascular high-risk patients and was associated with more adverse events. In chronic heart failure, ValHeFT and CHARM-ADDED have shown that combined RAS inhibition with ACE inhibitor and valsartan or candesartan reduced morbidity and mortality in certain patient subgroups. Accumulating evidence also points to benefits of the combination therapy in individuals with proteinuric nephropathies. In conclusion, while combined RAS-inhibition is not generally indicated in patients along the cardio-reno-vascular continuum, it has already proven to be effective in heart failure patients with incomplete neuroendocrine blockade. In secondary prevention, monotherapy with either RAS inhibitor is equally efficacious. Furthermore, novel pharmacologic agents such as renin inhibitors may prove useful in preventing common side effects of RAS blockade such as angiotensin escape and AT(1)-receptor upregulation, giving clinicians additional therapeutic tools to optimally treat the individual patient.