Erectile Dysfunction And Coronary Artery Diseases

Management of Erectile- Dysfunction in CAD patients. Dr. Rashed J. Al-Hamdan, M.D., FRCP(C),

Al-Jahra Hospital.

Erectile Dysfunction Erectile dysfunction ( ED ) is defined as the impairment of the ability to achieve and maintain a penile erection adequate to sustain sexual intercourse. ED is a major health problem which presence affects not only the patients physical well being, but his psyche as well as his social interactions.

ED - How Big is the Problem? There are various degrees of ED: Mild, Moderate and Severe. The problem affects 52% Americans between the ages of 40 – 70 years. It affects 19-64% of men between the ages of 40-80 in both developing and developed countries. It affects 64% of men in Turkey, 54% in Egypt and 51% in Nigeria.

ED - How Big is the Problem? ED is a notoriously under reported, under recognized, and under treated chronic illness. Only 11.6% of patients in a recent US survey of 62 general medical practices received care for ED. The mean delay for physician consultation in a Dutch study was 13 months.

ED - How Big is the Problem?

ED – How and Why it Happens? The concept of andropause refers to a constellation of symptoms. They include depression, irritability, insomnia, mood swings, lack of energy, decreased libido and ED. The big underlying association/ cause is the decrease in the circulating testosterone levels.

ED – How and Why it Happens? Circulating testosterone levels drop due to variables like testicular arterial perfusion, genetic factors, body mass index, stress, smoking, reduced density of the Leydig cells in aging testicles, age related increase in the Sex Hormones Binding Globulin (SHBG), and arteriosclerosis.

ED – How and Why it Happens? The reduction in the circulating levels of testosterone is associated with unfavorable lipid profile and progression of atherosclerosis. Testosterone is a vasodilator that acts via multiple pathways, some are NO dependant to dilate blood vessels. These vasomotor effects are gender dependant and are NOT via the conversion to estrogen.

ED – How and Why it Happens? Risk factors for ED were found to be the same risk factors for CAD. The presence of diabetes, dyslipidemia, hypertension, and smoking predicted the presence of both CAD and ED. These risk factors act synergistically to adversely affect the endothelial function.

In the US, 64% of men over the age of 55 have hypertension. 27% of elderly men have sub-syndromal depression and, around 18% have type 2 diabetes.

ED – How and Why it Happens? The role of an intact endothelium has been studied in the field of ED. The cavernosal endothelial cells contribute to the process of erection by producing NO. NO is essential for it stimulates the production of c-GMP which causes smooth muscles relaxation and erection.

ED – How and Why it Happens? Billups et al suggested in a recent study that an abnormality in the systemic NO-cGMP vasodilator system may result in ED as the first clinical manifestation of cardiovascular disease. This may occur prior to the development of other demonstrable vascular disease.

ED – How and Why it Happens? Dyslipidemia is associated with ED. LDL ≥ 6.1 or HDL ≤ 0.77 was found to be associated with a significant decline in erectile function. Around 2% of patients on some medications, namely, β-blockers and thiazide diuretics develop ED.

ED – How and Why it Happens? When talking about ED, the psychological aspect of the problem, both as a cause and as an effect is of great importance. up to 90% of men with severe depression suffer moderate to complete erectile dysfunction

The issue of Anxiety Anxiety can play a role as an independent risk factor for CAD. It also is a comorbid complication of CAD. Anxiety disorders represent a very large fraction of the mental health problems far exceeding depression in prevalence. Subjects with panic disorders have twice the risk of developing stroke, and a higher likelihood of developing CAD than normal subjects.

The issue of Anxiety Similarly, patients with anxiety neurosis have a higher chance of developing hypertension compared with control ( 17% vs. 7% ). The more disabling the anxiety symptoms are, the more the likelihood is for developing or harboring CAD.

Depression and CAD Major depression is found in 16%-23% of patients with advanced CAD or those who have had MIs. Murphy et al showed that the relative risk of depression for cardiovascular related death is 2.5 in males and 1.5 in females. Aromaa et al reported the same risk to be 2.62 for males and 1.9 for females.

Depression and CAD A possible way that depression is linked to CAD is as follows: Mental stress leads to dysregulation of the hypothalamic–pituitary–adreno cortical axis and sympatho–adrenal system via changes in corticotropinreleasing factor, adrenocorticotropic hormone, endorphin, and catecholamines.

Depression and CAD This dysregulation results in ventricular instability, myocardial ischemia, decreased heart rate variability, and altered platelets’ receptors and reactivity. These actions precipitate atherosclerotic occlusive vascular disease and cardiac and cerebro-vascular disease.

Depression and CAD–New Model. Both ED and depressive symptoms exhibit multifactorial etiologies, including organic and non-organic components. CAD shares many of the risk factors with the 2 conditions and can be a manifestation for some of the same predisposing risk facgors. CAD can first present in the form of ED as well as ED being a manifestation or a cause of depression.

Depression and CAD–New Model.

Co-morbidities in aging males

ED and CAD The important message is that once one patient has one condition, it is wise to look for the other 2 either to prevent them from occurring, or to ameliorate their effects.

ED and CAD

ED and CAD

Now, we have a CAD patient with ED. Is it safe for him to be treated in order to have sex?!

Cardiovascular Response to Sexual Activity Each one MET ( metabolic equivalent of oxygen consumption) is equal to 3.5 mL O2/kg/min. 1 MET is equivalent to the resting state. Pre-orgasmic sexual activity requires 2-3 METs. Sexual activity during orgasm requires 3-4 METs.

Cardviovascular Response to Sexual Activity In the old days (60’s) there was a lack of real data. The data we had, were collected in a unreal situations. In one old study by Masters and Johnson, subjects ( Students and Faculty couples ) were placed in a lab, connected ECG monitors and asked them to signal each phase of the sexual act while the investigators were next door recording the data!.

Cardiovascular Response to Sexual Activity In these un-natural settings, the peak coital heart rate was 140-180 bpm, and the mean increase in BP was 80mmHg systolic and 50mmHg diastolic. The respiratory rate reached 60/min in a similar study were the subjects had mouth pieces placed to collect air in order to calculate the tidal volume and respiratory rate.

Cardiovascular Response to Sexual Activity More realistic studies followed by Hellerstein and Friedman in 1970. They proved that in a “natural” situation, the heart rate of subjects engaged in sexual interaction had a mean heart rate increase of 117.4 ranging between 90-144 bpm. The mean estimated BP at coital activity was only 162/89 mmHg. They found also that the peak coital heart rate was lower than the mean peak heart rate achieved with daily activities of 120.1 bpm.

Cardiovascular Response to Sexual Activity Stein et al studied the peak coital heart rate in a group of post MI pts before and after a 16 week training program. The peak coital heart rate before training was 127 (120-130), and after training was 120 (115-122). The peak coital VO2 max increased in the training group vs. the control group. They concluded that the response to the coital work load after training program was similar.

Cardiovascular Response to Sexual Activity Muller and his group on the other hand in 1996 had different conclusions in the Myocardial Infarction Onset Study. Out of 858 pts who were sexually active in the year prior to their MI, 27 pts (3%) were engaged in sexual activities within 2 hours prior to the MI. They found that the relative risk of triggering an MI in pts with angina was 2.1, and in pts with previous MI was 2.9. None was statistically higher than the relative risk of 2.5 in pts without prior cardiac disease.

Cardiovascular Response to Sexual Activity Another important finding of the Onset study was that frequent weekly exercise of ≥ 6 METs per episode lessens the relative risk of MI associated with sexual activity. The relative risk of men exercising ≤ 1 time per week was 3, twice weekly was 1.9 and ≥ 3 times weekly was 1.2. Regular exercise can eliminate the increased risk of MI triggered by sexual activity.

Cardiovascular Response to Sexual Activity

Cardiovascular Response to Sexual Activity Bohlen et al studied the coital activity in 4 different situations and in 4 different stages (baseline, foreplay, stimulation and orgasm) in healthy subjects. The peak response to sexual intercourse occurs in the orgasmic phase and it lasted only 10-16 sec. The rate pressure product was not significantly different for the 2 coital positions nor for any of the 4 activities.

Cardiovascular Response to Sexual Activity

Cardiovascular Response to Sexual Activity The study of Bohlen was limited by the fact that the subjects were healthy individual, and hence their maximal achieved heart rate was lower than those reported by Stein et al.

However, it showed that training was effective in lowering the mean peak coital heart rate, which was not much different between the two studies.

Cardiovascular Response to Sexual Activity Another interesting study came from Japan in 1963. 5,559 cases of sudden death were recorded to have happened during coitus. 18 of the 34 have been determined to have been cardiac in origin. Of note was that 27 of the 34 cases occurred during extramarital coitus. This study suggested an event rate of 0.06% for sudden death during coitus. Also, it suggests that marital coitus is less dangerous than extramarital coitus.

Cardiovascular Response to Sexual Activity What is also important is the functional reserve which is the difference between the peak exercise heart rate and the peak coital heart rate. It drops with age.

Cardiovascular Response to Sexual Activity Among patients with CAD who underwent ergometric exercise and ambulatory ECG, Drory et al found that the coital HR exceeded that during treadmill exercise.

Cardiovascular Response to Sexual Activity Drory and his group also found that 31% of their study group developed ST depression during coitus consistent with myocardial ischemia, most without angina. They also found that all those with coitus induced ischemia had ischemia during their stress tests. Patients with negative stress tests had no coital induced myocardial ischemia.

Cardiovascular Response to Sexual Activity Drory and his group concluded that a negative stress test was good to exclude patients who will develop coital induced myocardial ischemia. Jackson et al reached the same conclusion in an earlier study.

Cardiovascular Response to Sexual Activity Treadmill test is not required to assess patients who have no symptoms during vigorous activities. A patient who can climb 2 flights of stairs without limitations can generally but not necessarily get engaged in sexual activities without cardiac symptoms. Patients who have extramarital sexual activities substantially increase the degree of sexual arousal and exertion.

Cardiovascular Response to Sexual Activity In general, EST is useful in stratifying the prognosis of pts with angina. The same poor prognostic signs in the usual EST for post MI prognosis apply in here e.g. lower angina threshold, lower work load before ST depression and longer duration of the ischemic ECG changes.

Cardiovascular Response to Sexual Activity However, and to complicate things, we know that it is NOT the critically stenosed vessel that is going usually to cause UA or NSTEMI, rather it is the one with a smaller unstable plaque. The plaque rupture because of many factors and coitus might be one of them. But EST is not the best test to identify these smaller lesions unless they are multiple (3 vessels) or they involve the left main coronary artery !!!.

OK, Now we have patients who has CAD and ED. The question is Whom Shall We Treat???.

Whom Shall We Treat It is essential that the cardiologist opens a dialog with his or her patient and their spouses. The psycho-social factors are very important. Even in the western societies, the majority of patients will NOT bring out the subject of ED until it is brought out by the treating doctor.

Whom Shall We Treat? We shall not dismiss a patient because of his age as not requiring help for his ED. In fact, 30-70% of patients in their 6th decade are involved in regular sexual activities. An estimated 40% septuagenarians have sexual relations on weekly basis.

Whom Shall We Treat? Among a surveyed group of 50-80 years olds, 13% said sex was very important. 29% said that sex was important. 41% reported that sex was occasionally enjoyable. Another 17% said they could live without it. In another study, 94% of respondents stated that they believe sexual satisfaction adds to the quality of life at any age.

Whom Shall We Treat? High risk patients should have the treatment of their ED delayed and their conditions monitored. They include: 1-Refractory angina patients. 2-Patients with class III/IV HF. 3-Pts with moderate to severe vavular diseases. 4-Pts with uncontrolled hypertension. 5-Patients post MI or stroke of ≤ 2 weeks. 6-High risk arrhythmias. 7-HOCM patients.

Whom Shall We Treat? In short, we have to bring the topic of sexuality with our patients, for the chances are if did not bring it out, they will shy away from doing so themselves. Also, we have to ask them for what they want and expect. We have to keep in mind that many will not have sexual activities either being afraid of triggering an event in themselves or in their partners, so, spouse involvement , if possible, is important.

Whom Shall We Treat? The patient should be interviewed in a comfortable environment, with no interruptions. Do not add to the patients’ discomfort by frequently asking them to repeat what they have already said. Although not widely available here, it is better to use a structured questionnaire in order to standardize the approach to the problem, and its management.

Benefits of treatment of ED Improvement of the patients’ social interactions. Improvement of the patients’ psychological status and avoidance of depression. A time to review and treat the underlying causes of ED. A chance to encourage a healthier life style change like abstinence and quitting recreational drugs. A time to review the medications a patient is prescribed and to attempt to changing them to abolish ED due to side effects of some of the cardiovascular medications.

Now that we are going to treat, What agents are available? and What shall we use?

What agents are available? There is a variety of agents available for the treating doctor, some oral, others are transurethral or intracavernosal. The oral agents include: Sildenafil (Viagra), Tadalafil (Cialis and ‫) سنافي‬, Vardenafil (Levitra), Yohimbin, Apomorphine SL, L-Argenine and Phentolamine. The intracavernosal/transurethral include: Alprostadil, Moxisylyte, Papaverine/Phntolamine and VIP/Phentolamine.

The Physiology of Erection For the non-urologist, we shall try to simplify the process of erection. Erection is the net result of a complex process involving the secretion of nitric oxide (NO) by the nerve terminals on the cavernous smooth muscle cell or at parasympathetic cholinergic nerve terminals on the endothelial cell lining of the sinusoids. NO activates guanylate cyclase, which induces cleavage of guanosine triphosphate to 3',5'-cyclic guanosine monophosphate (3',5'-cGMP).

The Physiology of Erection The smooth muscle-relaxing effects of NO are mediated by this second messenger (cGMP). Cyclic GMP activates protein kinase G (PKG), which phosphorylates proteins at the so-called maxi-potassium channels. This results in an outflow of potassium (K+) ions into the extracellular space with subsequent hyperpolarization, with inhibition or blockade of voltage-dependent calcium (Ca++) channels. This will cause a decrease in intracellular Ca++ ion concentrations.

The Physiology of Erection The intracellular decline in Ca++ ions suppresses the activity of myosin light chain (MLC) kinase and thus increases the intracellular content of dephosphorylated MLC, which enables the smooth muscle cell to relax. NO and cGMP are the most important transmitters for onset and maintenance of erection. 3',5'-cGMP is permanently broken down to the biologically inactive 5'-GMP by the enzyme PDE5.

The Physiology of Erection

The Physiology of Erection The 3',5'-cyclic nucleotide PDEs are key regulators of intracellular cGMP and cAMP activity and, hence, relaxation of corporal smooth muscle. There are at least 11 isoforms and isoenzymes of these enzymes distributed in nearly all body tissues. The PDEs are responsible for enzymatic degradation of the biologically active cGMP and cAMP to the biological inactive molecules GMP and AMP.

The Physiology of Erection

The Physiology of Erection By inhibiting the degradation of cGMP, PDE5 inhibitors prolong the activity of this cyclic nucleotide second messenger within the cavernous vasculature and smooth musculature. This will potentiate the erectile response. Selective inhibitors of PDE5 are our cornerstone treatment for ED.

P D E – 5 Inhibitors

P D E – 5 Inhibitors

P D E – 5 Inhibitors

P D E – 5 Inhibitors There are no head to head data available to compare the efficacy of the 3 different available medications. In general, it seams that all 3 different drugs are as efficacious in achieving the goal. It also seams that all 3 drugs work as well in the same subgroup of patients like diabetics and patients with prostatectomy.

P D E – 5 Inhibitors The side effects are mild to moderate in general, and are transient. 2nd generation PDE5 inhibitors offer more dosing flexibility. With sildenafil, the systolic BP drops by about 8mmHg and the diastolic by 56mmHg. With tadalafil, the same drops were 7mmHg with systolic BP and 4mmHg with the diastolic BP. The effects with vardenafil were minimal as well, with more pronounced compensatory tachycardia which was not significant.

P D E – 5 Inhibitors Sildenafil was associated with a greater hypotensive response in a subset of patients after nitrate administration. Almost twice as many patients had a standing systolic blood pressure of less than 85 mm Hg (outliers) compared with placebo Compared with placebo, tadalafil 5 mg or 10 mg potentiated the hypotensive effects of sublingual nitroglycerin or long-acting nitrates in patients with stable angina.

P D E – 5 Inhibitors Vardenafil in one study on healthy individuals did not show a worsening of the hypotensive effect of nitrate, but it is still prudent to assume that it exists. All 3 agents did not alter significantly the response to exercise nor the time for ischemia on either EST or Stress Echo. There is no evidence of an increase in rate of myocardial infarction with any of theses agents from the data we do have. It should be noted to exercise caution when prescribing PDE5-I to a patient on an α blocker like doxazosin.

Sildenafil

Tadalafil

Vardenafil

Sildenafil It is a first generation PDE5 inhibitor, and the first known in its class. Sildenafil has shown in studies since 1998, that it improves ED in men regardless of disease etiology, severity of disease, or even age. Response rates for men with organic ED and combined psychogenic and organic disease are reported to be 69% and 80% respectively.

Sildenafil For men with severe disease vs mild-tomoderate disease, the response rates are 65% to 87%. Although the response rates start to drop as a man gets older, response rates in men ≥ 65 show a 69% improvement. Studies show that sildenafil also improves sexual functioning in men with chronic health conditions who are at increased risk of developing ED and having ED.

Sildenafil

Sildenafil

Sildenafil

Sildenafil In terms of safety, data indicate that sildenafil is well tolerated.  The most common side effects include facial flushing, headache, nasal congestion, dyspepsia, and dizziness. Of most concern are the potential cardiac side effects, including sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, myocardial infarction, and hypertension. In men taking organic nitrates, sildenafil is absolutely contraindicated.

Tadalafil Tadalafil achieves maximum plasma concentrations within 2 hours and has a mean terminal half-life of 17.5 hours. With adequate sexual stimulation, significant erectile responses have been observed as early as 16 minutes and as long as 36 hours after dosing. Tadalafil is taken without restrictions on food or alcohol intake.

Tadalafil A number of studies show that tadalafil improves ED in men with mild-tosevere ED. Analysis of 5 trials in which patients were randomized to receive placebo, tadalafil 10 mg, or tadalafil 20 mg found that men treated with tadalafil reported increased satisfaction with sexual functioning as measured objectively.

Tadalafil Of the men who received the 20-mg dose, 75% and 81% reported a positive objective and subjective response, respectively, vs 61% and 67% in the 10-mg group and 32% and 35% in the placebo group.

Tadalafil

Tadalafil

Tadalafil Works up to 36 hours.

Take Home Messages ED shares the same risk factors as CAD, so when seeing a patient with one, look for the other. Do not refrain from asking your patient about ED just because he is old, sexual interactions are important to all age groups in our CAD population.

If you do not bring out the issue of ED with your patient, chances are no one will. Talking to the spouse might be important, after all, the patient and his spouse are in this together. Work up the patient with the intention of finding who is at a high risk and should have his treatment delayed.

Take Home Messages Look for controllable factors like medications especially β-blockers and thiazides. Not all the patients require EST to evaluate them. Those who can climb 2 flights of stairs with no symptoms, should be able to engaged in coitus with no problems.

Take Home Messages The first line of treatment is PDE5-I. Caution should be exercised when prescribing them to patients on αblockers. Patients should not be on nitrates when they use any of the PDE5-I agents, if most be, allow 24 between one another when prescribing sildenafil or vardenafil, and more than 48 hours when prescribing tadalafil.

Take Home Messages Know Thy Limits. If your patient is not showing up improvement with the PDE5-I, maybe it is time to refer him to a urologist for further management. But, First, “DO NO HARM”.

Take Home Messages

Take Home Messages