Comparison of trimetazidine plus sildenafil to chronic nitrates in the control of myocardial ischemia during sexual activity in patients with coronary artery disease

A large proportion of patients who have erectile dysfunction also have coronary artery disease (CAD). In these patients, nitrate therapy is a contraindication to the use of sildenafil. To assess whether the metabolic anti-ischemic agent, trimetazidine, is effective in controlling episodes of myocardial ischemia during sexual activity in patients who have CAD and use long-term nitrate therapy, we studied 38 men (57 +/- 6 years of age) who had proved CAD. Patients underwent 24-hour ambulatory electrocardiographic monitoring at baseline, after 1 week of oral nitrate therapy (20 mg 3 times a day), and after 1 week of trimetazidine (20 mg 3 times a day). Patients were asked to engage in >/=1 session of sexual intercourse during each session of ambulatory electrocardiographic monitoring. They were instructed to take sildenafil (100 mg) 1 hour before sexual intercourse performed at baseline and during therapy with trimetazidine and sildenafil or placebo (blinded) during therapy with nitrates. A decrease in total ischemic burden was observed with nitrates and trimetazidine compared with baseline (-3 +/- 1.2 episodes/patient/24 hours vs -5 +/- 1.3 episodes/patient/24 hours and -6 +/- 5 min/patient/24 hours vs -8 +/- 3 min/patient/24 hours, p <0.01 for nitrates and trimetazidine vs baseline). Trimetazidine plus sildenafil was more effective in controlling episodes of myocardial ischemia during sexual activity than nitrates alone (-45 +/- 11% vs -18 +/- 7%, p <0.04). In conclusion, in patients who have CAD, combination therapy with sildenafil and trimetazidine is more effective than nitrate therapy in the control of ischemic episodes during sexual activity, suggesting that long-term nitrate therapy may be safely switched to trimetazidine therapy when therapy for erectile dysfunction is required.     

Peripartum cardiomyopathy

Peripartum cardiomyopathy is a rare and life-threatening disease of unknown etiology. This diagnosis should be limited to previously healthy women who present with congestive heart failure (CHF) and decreased left ventricular systolic function in the last month of pregnancy or within 5 months after delivery. The diagnosis is not made in the presence of other causes of cardiac dysfunction. Patients who fail to demonstrate improvement within 2 weeks after the onset of symptoms should be evaluated for myocarditis. The type and duration of heart failure treatment is determined by the patient's heart performance at rest and with exertion. Those with normal left ventricular function at rest and with exercise or dobutamine have a good prognosis, and their medical therapy can be tapered off or discontinued over a period of 6-12 months. Patients with normal ventricular function at rest, but abnormal response to exercise should be treated for long periods of time with angiotensin converting enzyme (ACE) inhibitors or beta-blockers. Patients who continue to have depressed LV function have a poor prognosis and require treatment with appropriate medications for the rest of their lives. Pharmacological treatment includes ACE inhibitors, beta-blocking agents, diuretics, digoxin, and anticoagulation. Angiotensin converting enzyme inhibitors are used only after delivery because of their teratogenic effects. Patients who fail to recover may require inotropic therapy, intra-aortic balloon pump and left ventricular assist device as needed. Cardiac transplantation should be considered for patients who fail therapy.     

Coronary and systemic hemodynamic effects of sildenafil citrate: from basic science to clinical studies in patients with cardiovascular disease

Sildenafil citrate is the first oral phosphodiesterase type 5 inhibitor approved for the treatment of erectile dysfunction. The wide use of sildenafil by patients with erectile dysfunction and cardiovascular disease has resulted in a considerable number of independent studies investigating the cardiovascular safety and functional role of the phosphodiesterase type 5-cyclic guanosine monophosphate-nitric oxide pathway in the cardiovascular system. Endothelial dysfunction, defined as a reduction in the bioavailability of nitric oxide, is associated with many of the common risk factors for cardiovascular disease and erectile dysfunction. Sildenafil has been demonstrated to improve the vasomotor aspect of endothelial dysfunction in patients with heart failure and diabetes. Hemodynamic studies suggest that sildenafil is a modest vasodilator with the potential to increase coronary blood flow and coronary flow reserve. In patients with ischemic heart disease, sildenafil is associated with reductions in mean arterial and pulmonary pressure with little effect on heart rate, cardiac output, and systemic or pulmonary vascular resistance. The absence of an effect on cardiac output supports the lack of an inotropic effect of sildenafil. This is consistent with the finding that sildenafil has no effect on cyclic adenosine monophosphate levels in the vasculature. Finally, exciting reports have emerged from clinical experience with the use of phosphodiesterase type 5 inhibitors in patients with pulmonary hypertension.     

Should the patient with coronary artery disease use sildenafil?

Since the etiology of erectile dysfunction is frequently related to endothelial dysfunction, a problem in common with much vascular disease, erectile dysfunction disproportionately affects patients with cardiovascular disease. With the development of phosphodiesterase 5 inhibitors, the first of which was sildenafil (Viagra), an effective oral medication became available. The question of safety of these drugs, especially in patients with latent or overt coronary artery disease, is of concern. Sildenafil relaxes smooth muscle and therefore lowers systolic and diastolic blood pressure slightly. With organic nitrates, the drop in blood pressure is potentiated, at times dangerously, thereby making it contraindicated to take nitrates within 24 hours of using sildenafil. In double-blind, placebo-controlled trials, there was no difference between sildenafil subjects and control patients in the incidence of myocardial infarction, cardiovascular, and total deaths. Coronary disease patients with stable angina, controlled on medications, were included in the trials. Therefore, sildenafil, as a drug, is safe in such patients. With a patient with coronary artery disease suddenly engaging in the physical exercise associated with sexual intercourse, there is the danger of increased risk of precipitating myocardial infarction or death. The cardiovascular metabolic cost of sexual activity is reviewed and appears to be approximately at the level of 3-5 metabolic equivalents of exercise. Sexual activity occurs within 2 hours of the onset of an acute myocardial infarction in <1.0% of patients. Although sexual intercourse is estimated to increase the risk of myocardial infarction by a factor of 2x, there is still only a very small increase in risk, a risk acceptable to patients who feel their quality of life will be markedly improved by their ability to engage in sexual activity.     

New treatment options for erectile dysfunction. Pharmacologic and nonpharmacologic options

Erectile dysfunction is a medical condition that influences the sexual life of millions of men and women worldwide. Due to a large number of currently available drugs, the therapy of erectile dysfunction has changed profoundly during the last decades. The pharmacologic options are divided into initiators versus conditioners and central- or peripheral-acting drugs. Besides intraurethral and intracavernous application of prostaglandin E(1) (PGE(1), peripheral initiator)--a transdermal application is still in clinical testing--there are drugs for oral application. PGE(1), the vasoactive drug mainly used, was replaced by sildenafil in first-line-therapy. PGE(1), administered intracavernosally or intraurethrally, is highly effective with success rates up to 90%, but the attrition rate due to personal inconvenience remains significant. Yohimbine is known as a central amplifier of erection and is useful in psychogenic and mild organic erectile dysfunction. Apomorphine, a central initiator of erection, amplifies erectile response as a central dopamine agonist in mild and moderate erectile dysfunction and starts acting 15-20 min after sublingual application. The phosphodiesterase type 5 (PDE-5) inhibitors sildenafil, vardenafil, and taldalafil are peripheral conditioners. Sildenafil, the most distributed oral agent worldwide, should be taken orally 60 min before sexual intercourse in combination with sexual stimulation. Sildenafil shows a high efficacy-safety profile with success rates for all etiologies between 50-80%. Paralleling nitrate-containing medication is an absolute contraindication. Vardenafil, another selective PDE-5 inhibitor with potentially higher selectivity and efficacy compared to sildenafil was just approved. The data from the clinical trials show the same adverse events and success rates as sildenafil. Tadalafil, just launched as well, amplifies erectile function for up to 24 h, allowing the patient to engage in sexual activity for this period. Adverse events and success rates resemble those of the other two substances. If medical treatment fails, there are nonpharmacologic options such as the vacuum constriction device and penile implants. The vacuum device is a safe and effective option for well-selected patients. Penile implants, especially the inflatable ones, completely imitate the physiologic erection. Due to recent research, infection rates and mechanical failures were minimized. Therefore penile implant surgery is well accepted by the patients and their partners. Despite this wide variety of options, therapy of erectile dysfunction should be performed in an individually adapted way. The patient's exact history, physical examination, collaboration of medical disciplines and choice of therapy will offer all patients the possibility to achieve or regain a satisfying sexual life.     

Myocarditis

Opinion statement Myocarditis and its sequela, dilated cardiomyopathy (DCM), cause substantial morbidity and mortality, especially in children and young adults. Physicians should include myocarditis in the differential diagnosis of all patients who have new symptoms of heart failure, arrhythmia, or chest pain syndromes of unclear cause, and should strongly consider performing endomyocardial biopsy (EMB) to establish the diagnosis. It may be necessary to perform multiple or serial biopsies to increase sensitivity. Patients with myocarditis and symptomatic heart failure, chest pain, or arrhythmias need hospitalization for evaluation and treatment. Patients with symptomatic left ventricular dysfunction should be treated with conventional heart failure therapy, including angiotensin-converting enzyme (ACE) inhibitors, digitalis, diuretics, and β-blockers. Patients with arrhythmias or syncope may require electrophysiologic evaluation. In addition to conventional therapy, physicians should consider a course of immunosuppressive therapy in selected patients. The clinical course, response to therapy, and left ventricular function need close monitoring. Patients with myocarditis and rapidly progressive heart failure or cardiogenic shock should be referred early to an advanced heart failure center for implantation of a ventricular assist device and consideration for cardiac transplantation.     

Peripartum cardiomyopathy

Opinion statement It is critical that the diagnosis of peripartum cardiomyopathy is limited to women with congestive heart failure and decreased systolic function of the left ventricle in last month of pregnancy or within 5 months after delivery. Patients must have no pre-existing cardiac disease and no other cause for current cardiac dysfunction. The inclusion of patients before the last month of pregnancy or after 5 months postpartum introduces a large number of patients with cardiac disorders due to causes other than peripartum cardiomyopathy. Ventricular performance at rest and with exertion determines the type of management, its intensity, and duration. Patients whose ventricular function is normal at rest and with exercise or dobutamine can have their heart failure therapy tapered and ultimately discontinued after 6 to 12 months of standard treatment. Those with normal resting but abnormal stress cardiac function should continue some form of medical therapy (afterload reduction or beta-blocker) for longer periods of time, if not for life. Those with persistently abnormal ventricular function must receive optimal heart failure therapy forever and face the same relatively poor prognosis as patients with dilated cardiomyopathy from any cause. Options for management include standard heart failure therapy (digoxin, diuretics, afterload reduction, and anticoagulation), Swan-Ganz catheter monitoring and use of inotropic agents, intra-aortic balloon counterpulsation, and left ventricular assist device. Patients with peripartum cardiomyopathy are candidates for heart transplantation, assuming they meet all other criteria.     

Prevalence of erectile dysfunction in vascular surgery patients

Erectile dysfunction (ED) is frequently associated with cardiovascular disease. Epidemiological data on the frequency of ED in vascular surgery patients is rarely reported. We evaluated the prevalence of this comorbidity in patients consulting the vascular surgery outpatient clinic. Over a 6-month period, a short version of the International Index of Erectile Function (IIEF) questionnaire consisting of six ED-relevant questions was handed out to 440 vascular surgery outpatients. Clinical data were collected from patients' records. Linear regression models with forward selection were used to investigate associations between erectile function score and possible risk factors. The return rate was 31% (137 patients). Eight patients (6%) were taking phosphodiesterase inhibitors. ED, as defined by an erectile function score of 25 or less and/or use of phosphodiesterase inhibitors, was found in 90% (95% CI: 84% to 95%) of cases. Moderate or severe ED, as defined by an erectile function score of 16 or less and/or use of phosphodiesterase inhibitors, was found in 70% (95% CI: 62% to 78%) of cases. Increased age, abdominal aortic aneurysm, peripheral arterial disease, urologic disease, insulin-dependent diabetes mellitus, and use of beta-blockers were significantly associated with a lower erectile function score. In conclusion, erectile dysfunction is a frequent and often missed comorbidity in vascular surgery patients. While ED may have a profound impact on the patient's quality of life, attention should also be paid to the patient's preoperative sexual function, considering the availability of oral pharmacotherapies and possible consequences concerning liability in postoperative patients in whom pre-existing ED was not identified properly.     

The cardiovascular response to sexual activity: Do we know enough?

Interest in comprehensive cardiac rehabilitation over the past 25 years spawned a series of small investigations concerning the heart rate, blood pressure, and ischemic response to sexual intercourse. This information was adequate for advising patients about return to sexual activity after a myocardial infarction or cardiac surgery. However, the introduction of medications for erectile dysfunction enabled impotent cardiac patients to engage in sexual activity and has highlighted the need for more detailed information concerning cardiovascular physiology during coitus. Review of the medical literature indicates a remarkable paucity of such data despite dramatic advances in most other aspects of cardiovascular physiology and pathophysiology. This brief paper gives an overview of the current knowledge of the cardiovascular response to sexual activity and, within the framework of advances in cardiology, highlights areas where it appears important to fill in the knowledge gap.     

Might erectile dysfunction be due to the thermolabile variant of methylenetetrahydrofolate reductase?

Hyperhomocysteinemia is considered one of the most important cardiovascular risk factors increasing considerably the risk of stroke and myocardial infarction. With respect to endothelial function, direct effects of hyperhomocysteinemia on vascular endothelial cells have been demonstrated through the reduction of endothelial nitric oxide production. In this paper, we report the case of a young man with homozygote genotype mutated with 5-methylenetetrahydrofolate reductase (MTHFR) thermolabile variant who, in the absence of relational stress, developed an erectile dysfunction (ED) refractory to the vasoactive type-V phosphodiesterase (PDE5) inhibitor therapy. After one month of treatment with 5 mg/day folic acid and 1000 microg/day cyanocobalamin, the patient restarted the assumption of 50 mg sildenafil, obtaining satisfying erections during sexual intercourse. We suggest that hyperhomocysteinemia may interfere with penile blood supply and, thus, be responsible for ED. If this relationship is confirmed, plasma levels and urinary homocysteine (HCy) should be evaluated in selected young patients with vascular ED. Furthermore, careful attention should be given to the risk of ED when dealing with this metabolic disturbance.     

Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference)

Recent studies have highlighted the relation between erectile dysfunction (ED) and cardiovascular disease. In particular, the role of endothelial dysfunction and nitric oxide in ED and atherosclerotic disease has been elucidated. Given the large number of men receiving medical treatment for ED, concerns regarding the risk for sexual activity triggering acute cardiovascular events and potential risks of adverse or unanticipated drug interactions need to be addressed. A risk stratification algorithm was developed by the First Princeton Consensus Panel to evaluate the degree of cardiovascular risk associated with sexual activity for men with varying degrees of cardiovascular disease. Patients were assigned to 3 categories: low, intermediate (including those requiring further evaluation), and high risk. This consensus study from the Second Princeton Consensus Conference corroborates and clarifies the algorithm and emphasizes the importance of risk factor evaluation and management for all patients with ED. The panel reviewed recent safety and drug interaction data for 3 phosphodiesterase (PDE)-5 inhibitors (sildenafil, tadalafil, vardenafil), with emphasis on the safety of these agents in men with ED and concomitant cardiovascular disease. Increasing evidence supports the role of lifestyle intervention in ED, specifically weight loss and increased physical activity, particularly in patients with ED and concomitant cardiovascular disease. Special management recommendations for patients taking PDE-5 inhibitors who present at the emergency department and other emergency medical situations are described. Finally, further research on the role of PDE-5 inhibition in treating patients with other medical or cardiovascular disorders is recommended.     

Sexualstörungen bei Diabetes mellitus

In diabetology sexual dysfunction has been for years and still is a neglected area. Diabetologists may fail to recognize that sexual disorders, especially erectile dysfunction, are complications of diabetic metabolism. Thus sexual dysfunction in diabetic patients may be considered to represent only a slight change in lifestyle and not a disease that needs to be treated. A main objective in treating diabetic patients today is to keep their quality of life as high as possible. Sexual dysfunction means a reduction in quality of life. Therefore, if desired, it should be treated. In diabetic patients sexual dysfunction is found more often and at a younger age than in the non-diabetic population. Sexual dysfunction in diabetic women has not been well investigated and treated. Erectile dysfunction is the most important sexual disorder in diabetic men. There are many therapeutic opportunities that work very well in these men. At present many of these men prefer to take PDE-5 inhibitors which is the most comfortable treatment.     

Medical therapy options for aging men with benign prostatic hyperplasia: focus on alfuzosin 10 mg once daily

Lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) are common in aging men and can significantly affect quality of life. Men with bothersome LUTS/BPH often present with various other age-related conditions, including sexual dysfunction, heart disease, hypertension, diabetes, and the metabolic syndrome, which can complicate management decisions. Therefore, healthcare providers should be familiar with first-line treatment options for LUTS/BPH and their differing safety profiles, particularly with respect to cardiovascular and sexual function side effects. This article presents a review of first-line medical therapy options for managing aging men with LUTS/BPH and patient considerations when evaluating and selecting these therapies, with a focus on the clinical efficacy and cardiovascular and sexual function safety profiles of the uroselective α₁-adrenergic receptor antagonist alfuzosin 10 mg once daily. Alfuzosin improves LUTS, peak urinary flow rates, and disease-specific quality of life, reduces the long-term risk of overall BPH progression, and is well tolerated in aging men, with minimal vasodilatory and sexual function side effects, even in those with comorbidities. Alfuzosin is well tolerated when used in combination with antihypertensive medications and phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction. The long-term clinical efficacy and good cardiovascular and sexual function safety profile of alfuzosin can contribute to an improved quality of life for aging men with LUTS/BPH.     

Detection of erectile dysfunction and peculiarities of its treatment in men with high cardiovascular risk

It has been demonstrated in a series of studies that erectile dysfunction (ED) appears to be one of risk factors and predictors of ischemic heart disease (IHD). According to the SSRC PM data in a cohort of 300 men with high cardiovascular risk ED was diagnosed in 61% of cases, while among 300 men with verified diagnosis of IHD was detected in 92.7% of cases. According to recommendations of the European Society of Urology changes of life style and correction of risk factors should precede therapy of ED or be components of complex therapy. It is known that some antihypertensive drugs (nonselective beta-adrenoblockers, thiazide diuretics) can negatively affect erectile function. According to data of comparative randomized clinical study average therapeutic doses of thiazide-like and thiazide diuretics in combination with ACE inhibitors do not worsen erectile function. Data on effect of lipid lowering therapy on erectile function are equivocal. Type 5 phosphodiesterase inhibitors (PDI) are first line preparations for the treatment of patients with ED. Safety of combination of type 5 PDI with main groups of antihypertensive drugs has been demonstrated in persons with risk factors of CVD and ED. The use of type 5 PDI in men depends on degree of compensation of cardiovascular system. In unstable cardiovascular events preparations of this group can be also carefully used. Simultaneous administration of nitrates is a contraindication for type 5 PDI.     

Procedural Guidance Using Advance Imaging Techniques for Percutaneous Edge-to-Edge Mitral Valve Repair

Human sexuality is an important aspect of health and quality of life. Many patients with ischemic heart disease – and their partners – are concerned that sexual activity could exacerbate their cardiac condition, possibly causing myocardial infarction or cardiac death. Patients with ischemic heart disease who wish to initiate or resume sexual activity should be evaluated with a thorough medical history and physical examination. Sexual activity is reasonable for individuals with no or mild angina and those who can exercise ≥3-5 METS without angina, excessive dyspnea, or ischemic ST segment changes. For the patient who is considered not be at low cardiovascular (CV) risk or in whom the CV risk is unknown, an exercise stress test is reasonable in order to determine his or her exercise capacity and to ascertain if symptoms or ischemia may occur. Regular exercise and cardiac rehabilitation can be effective in reducing the risk of CV complications associated with sexual activity for the patient with ischemic heart disease.     

Sildenafil in the cardiologist's office: patients' attitudes and physicians' practices toward discussions about sexual functioning

Sildenafil is a medication increasingly prescribed to improve sexual function in patients who have erectile dysfunction. Because a major contraindication to the use of sildenafil is a history of coronary disease and the concomitant use of nitrates, it becomes increasingly important for cardiologists to prescribe this medication. We evaluated the nature of discussions in all 70 patients for whom sildenafil was prescribed in a cardiology practice between April and July 1998. We used a standardized questionnaire to determine the patients' perspective on the sexual history and the extent to which they wanted their physicians to take a detailed history about sexuality. A separate chart review evaluated the nature of physicians' discussions about sexual functioning before sildenafil was prescribed. Fifty-five of the 70 patients (79%) responded to the survey. The majority of patients (98%) felt that physicians should talk with patients about sexual functioning. However, only 73% of patients believed their doctor was comfortable talking with them about this subject. Sixty percent of patients reported that their doctor had ever talked with them about erectile function and only 15% had ever had a discussion with their doctors about specific difficulties during intercourse. Based on the results of the chart review, only 24% of the patients ever specifically discussed the used of sildenafil with their physician prior to the time that it was prescribed. The results of the study suggest that patients with coronary disease erectile dysfunction are comfortable talking with their physicians about sexual functioning, but these conversations occur infrequently.     

Myocarditis

Opinion statement  

Therapy of ED: PDE-5 Inhibitors

The development of phosphodiesterase inhibitors, which are selective for the type 5 isoenzyme, has revolutionized the initial evaluation and treatment of men with erectile dysfunction. These agents can be taken orally and are effective in 60-70% of patients with erectile dysfunction, and they have low incidences of side effects when taken as recommended. The major contraindications are concomitant use with nitrates or the alpha-blockers terazosin and doxazosin. The major difference in the three approved inhibitors is that tadalafil has a considerably longer serum half-life, which provides a longer window of opportunity and potentially side effects.     

Regular intercourse protects against erectile dysfunction: Tampere Aging Male Urologic Study

Background

Erectile dysfunction is common among men aged more than 60 years. Its cause involves both physiologic and psychosocial factors.

Methods

To evaluate the effects of coital frequency on subsequent risk of erectile dysfunction, data were analyzed from a population-based 5-year follow-up study that was conducted in Pirkanmaa, Finland, using postal questionnaires. Assessment was based on the 5-item version of the validated International Index of Erectile Function. Men with erectile dysfunction at entry were excluded from the analysis. The study sample consisted of 989 men aged 55 to 75 years (mean 59.2 years). The most common comorbidities were hypertension (32%), heart disease (12%), depression (7%), diabetes (4%,) and cerebrovascular disorder (4%).

Results

The overall incidence of moderate or complete erectile dysfunction was 32 cases per 1000 person-years (95% confidence interval [CI], 27-38). After adjustment for comorbidity and other major risk factors, men reporting intercourse less than once per week at baseline had twice the incidence of erectile dysfunction compared with those reporting intercourse once per week (79 vs 33/1000, incidence rate ratio 2.2, 95% CI, 1.3-3.8). The risk of erectile dysfunction was inversely related to the frequency of intercourse. No relationship between morning erections and incidence of moderate or severe erectile dysfunction was found.

Conclusion

Regular intercourse protects against the development of erectile dysfunction among men aged 55 to 75 years. This may have an impact on general health and quality of life; therefore, doctors should support patients' sexual activity.