	As our population ages, congestive heart failure (CHF) will pose serious problems to health care. Current therapy is not effective in reducing mortality in patients with New York Heart Association functional class IV heart failure. The left ventricular assist devices used today are cumbersome, are associated with significant morbidity, and require a high level of clinical care as well as engineering care. Future therapy will involve mechanical heart assist devices.

	The largest study of left ventricular assist devices to date, the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH),1 disclosed that mortality was lower in the device group, with improvements in the quality of life, compared with the group receiving medical management. Unfortunately, few patients survived for longer than 2 years. The device group was plagued by an increased incidence of infection, bleeding, and cerebrovascular accidents.

	Some of the devices used today, such as the Heartmate and Novacor assist systems, are totally implanted, whereas the Thoratec VAD resides upon the abdomen. The Jarvik 2000 FlowMaker is a new, small assist device the size of a thumb. This device is an axial flow pump and is used in association with a contracting left ventricle. It allows a natural pulsatile flow with aortic valve opening. In the future, newer pumps will require less sophisticated support.

	A totally implantable unit, the AbioCor implantable replacement heart,2 provides both right and left ventricular support. The unit weighs 2 pounds and energy is developed from both internal and external lithium batteries. This is accomplished via transcutaneous energy transmission. The unit is made of a titanium and polyether-based polyurethane plastic. The system is a hydraulic chamber that creates left and right ventricular pumping. This replacement heart and others to follow hold promise for the future.

	Patients with poor ejection fractions and left ventricular conduction delays have shown improvements with biventricular pacing. The asynchronous contraction produced by the conduction delay is corrected by placing an atrial lead, a right ventricular lead, and a left vetricular lead via the coronary sinus. This creates synchronous contraction. Thus far, studies have had mixed results. However, the recent Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial3 disclosed a 19% reduction in all-cause mortality and hospitalizations in the biventricular pacing group. In the pacer-defibrillation arm, there was a 19% reduction in all-cause mortality and hospitalizations.

	The neurohormonal system has been the cornerstone of therapy in CHF. Human B-type natriuretic peptide was recently introduced into the treatment of CHF with nesiritide (Natrecor). In its natural form in the body, B-type natriuretic peptide is released in response to stress and increased volumes in the ventricles. Nesiritide dilates veins, improves sodium excretion, reduces aldosterone levels, and inhibits the renin-angiotensin system as well as the sympathetic nervous system. Data have shown that the drug is safe and effective in the early treatment of CHF when compared with intravenous nitroglycerin and intravenous dobutamine. It is not arrhythmogenic.4 Intermittent outpatient therapy with nesiritide has been studied recently with favorable results, and it is hoped it will keep patients out of the hospital.

	Arginine vasopressin,5 vasopeptidase inhibitors,6 and eplerenone (Inspra)7 are newer neurohormonal agents. Arginine vasopressin is elevated in CHF patients, and it causes vasoconstriction and retention of fluid via the V1A receptor. There have been early studies in animals as well as humans with V1A antagonists blocking this response. Vasopeptidase inhibitors, such as omapatrilat (Vanlev), inhibit renin-angiotensin I as well as neuroendo-peptidase, an enzyme that metabolizes endogenous vasodilator peptides, such as atrial natriuretic factor and bradykinin. These inhibitors increase the activity of endogenous vasodilators. They decrease the production

	of an-giotensin II via the angiotensin-converting enzyme inhibitor. Eplerenone is a new aldosterone inhibitor that has been effective in reducing mortality in patients with myocardial infarction (MI) and left ventricular dysfunction. As opposed to spironolactone (Spironol, Aldactone), eplerenone causes less gynecomastia.

	Future science will make it possible to regenerate the human cardiomyocyte. We are not certain if the hu-

	Proliferating myocardial cells in the myocardium could result from stimulation of cardiac resident cardiomyocytes or from circulating stem cells. Bone marrow cells have been injected into the circulation of athymic rats

	to the areas of MI with proliferation. These cells have differentiated into blood cells, decreased apoptosis and scar formation, and restored left ventricular function.8

	Skeletal myoblasts taken from biopsies of human muscle have been grown in culture mediums and then transplanted with catheters or surgically implanted into the area of the scar, and there have been improvements in segmental wall motion abnormalities and ejection fractions. The transplantation of skeletal myoblasts from the same donor does not require immunosuppression. Embryonic cells derived from mylocyst-stage embryos, however, create significant moral and ethical problems, as well as the need for immunosuppression. Embryonic stem cells generate into normal myocardial cells, and these may be the only cells that create a natural communication both muscularly and electrically with normal heart cells. Skeletal myoblasts turn into skeletal myocytes. The myoblasts do not form normal neuron connections with myocytes and may permit re-entrant arrhythmias. We are in the infancy of understanding transplantation and regeneration of cells and will have to develop quicker cell growth and be able to stop cell growth to prevent cardiac tumors.

	In the future, we will be using all these modalities in specialized units. The heart failure specialist will be able to define which patient will benefit from pacing, neurohormonal drugs, intermittent neurohormonal therapy, or myocardial regeneration therapy. The most critical patients will have the option of artificial hearts or assist devices.

Articles

Cardiology Review Online

Future treatment of congestive  heart failure

	In 1998, sildenafil (Viagra) was introduced as the first effective oral drug for the treatment of erectile dysfunction (ED). At that time, there was concern that these drugs might place patients with coronary artery and other cardiovascular diseases at risk because the drugs act as mild vasodilators. There was also fear that an excessive drop in blood pressure might precipitate myocardial ischemia, myocardial infarction (MI), fatal arrhythmia, or stroke. This would be of special concern with elderly patients. Organic nitrates increase the production of cyclic guanosine monophosphate (GMP), the second messenger of nitric oxide (NO), resulting in smooth muscle relaxation and vasodilatation. Phosphodiesterase-5 (PDE5) inhibitors can magnify the degree of vasodilatation and cause a marked decrease in blood pressure. For this reason, the concomitant use of nitrates and PDE5 inhibitors is prohibited.1

	Since 1998, two new PDE5 inhibitors have been released, vardenafil (Levitra) and tadalafil (Cialis). There is ample evidence from double-blind, placebo-controlled trials and open-label studies that the drugs themselves do not increase the incidence of MI or total death.2-4 More information is available for sildenafil than for the other drugs because it was the first PDE5 inhibitor released. From a pooled study of more than 120 trials between 1993 and 2002, the incidence of acute MI in patients in the placebo-controlled studies was 0.81 per 100 person-years for patients taking sildenafil (n = 7,462 patients) compared with 0.84 per 100 person-years for patients taking placebo (n = 5,753 patients).4 In open-label studies with 11,540 person-years of sildenafil exposure, the incidence of MI was 0.53 per 100 person-years. In an analysis of 29 clinical studies among patients taking tadalafil, the incidence of MI in the double-blind studies was 0.25 per 100 person-years (n = 3,666 patients) for the tadalafil patients and 0.60 per 100 person-years for the placebo patients (n = 1,437).5

	Other possible problems noted in the American College of Cardiology/

	American Heart Association Consensus document have also been extensively investigated. There is no evidence that a PDE5 inhibitor causes a marked drop in blood pressure in hypertensive patients taking multiple antihypertensive drugs. In large retrospective studies of hypertensive patients taking all classes of antihypertensive drugs, small decreases in systolic pressure occurred when sildenafil was added, with no difference in adverse effects (headache, dizziness, flushing, and esophageal reflux) compared with placebo.6

	There was also no difference in adverse effects in those taking one, two, three, or more antihypertensive agents compared with those taking no antihypertensive drugs.6 An analysis of 35 sildenafil double-blind trials (4,819 sildenafil patients and 3,296 placebo patients) showed similar results.7 A study with a sample of hypertensive patients taking multiple antihypertensive drugs who were also taking tadalafil showed a similar lack of increase in side effects compared with placebo.8 These findings might have been anticipated because the PDE5 inhibitors are only weak vasodilators.

	There was also a question of whether patients with congestive heart failure might have excessive decreases in blood pressure while taking PDE5 inhibitors. Bocchi and colleagues showed that patients with heart failure who were taking sildenafil had an increase in exercise duration and no change or a beneficial change in central hemodynamics.9 The one question still unanswered is whether patients who have undergone excessive diuresis and who are hypovolemic might have a marked drop in blood pressure if given a PDE5 inhibitor.

	The most important problem is treating ED and enabling sexual intercourse in patients with known or latent coronary artery disease (CAD). As already stated, there is no evidence that the PDE5 inhibitor drugs themselves increase the risk in such patients. However, the sudden increase in the physical activity required by sexual intercourse increases oxygen consumption (VO2) and myocardial VO2. There are precious few studies on the increased VO2 that occurs with sexual activity. The best of these studies is one conducted by Bohlen and colleagues, who found that sexual activity involves a modest increase in VO2 of approximately 3 to 5 metabolic equivalents (METs) for just a few minutes, peaking at the time of orgasm.10 In the face of critical obstructive CAD, it is possible that sudden myocardial ischemia and its complications could occur.

	The evidence that sexual activity increases the risk of MI was reported by Muller and colleagues, who showed that within 2 hours of sexual activity, there is a slight increase in the risk of acute MI, with the risk being 2.5 times that not related to sex.11 Because the risk of acute MI occurring within a short period of time is very low, even in patients with known CAD, 2.5 times that risk is still very low. Furthermore, if the individual engages in activities equal to or greater than 6 METs three times a week or more, the increased risk associated with sexual activity is eliminated.11

	There is an important relationship between ED and CAD. Most ED is caused by endothelial dysfunction. Normal endothelial function depends on the neural stimulation and release of NO by the vascular endothelium and smooth muscle of the lacunae of the corpus cavernosum. This stimulates the formation of cyclic GMP, which ultimately results in smooth muscle relaxation and vascular dilatation. The enzyme PDE5 catalyzes the breakdown of cyclic GMP, thereby allowing vasoconstriction and detumescence. PDE5 inhibitors competitively block the breakdown of cyclic GMP, allowing a given amount of NO to have a greater effect on vasodilatation. The endothelial dysfunction that results in ED limits the release of NO, which has multiple consequences aside from its effect on smooth muscle relaxation and vasodilatation. Endothelial dysfunction is also involved in the initiation of atherosclerosis; therefore, ED and atherosclerosis have a common precursor, and it is not surprising that both have risk factors (hypertension, smoking, dyslipidemia, etc) in common.12 Kaiser and colleagues have shown that ED can be the earliest manifestation of vascular disease, prior to any evidence of CAD or carotid artery disease.13 The message is that the presence of ED should lead the physician to search for evidence of latent coronary or cerebrovascular disease. Further, because ED can be an important factor in the quality of life for some individuals, pa- tients with coronary or other arterial disease who might be reluctant to discuss the subject with their doctors should be questioned about the adequacy of their sexual function.

	There have been several studies performed on patients with stable angina who were taking sildenafil, which showed that there was no increase in myocardial ischemia on exercise testing; in fact, there was a slight delay in the onset of ischemia compared with placebo.14,15 Arruda-Olson and coleagues found no increase in ischemia on exercise echocardiography,16 and invasive studies have shown either no change or a slight vasodilatation of atherosclerotic-obstructed coronary arteries when sildenafil was given.17,18

	In a prospective, double-blind, placebo-controlled 12-week trial including 151 men with ED and stable CAD, DeBusk and colleagues showed that there was no increase in angina, MI,

	The approach to the patient with known or suspected cardiovascular disease is addressed in a report from the Princeton Conference by DeBusk and colleagues.20 They presented an algorithm for the classification of pa- tients into low, intermediate, and high risk and recommended a plan to evaluate such patients before treating ED. A report developed at a second Princeton Conference in June 2004 is scheduled for publication in November 2005, in which their recommendations are updated. The suggested approach will be similar, with more emphasis on the history of the patient’s degree of physical activity. Because the danger of sexual activity is a sudden, unaccustomed increase in physical activity, if the patient is performing physical activity without difficulty at the level required for sexual activity, further workup before treating the ED is unnecessary.

	Since the approval of sildenafil, vardenafil and tadalafil have been approved by the Food and Drug Administration. The effectiveness of these PDE5 inhibitors appears to be equivalent. Vardenafil and sildenafil have similar molecular structures, which mimic the structure of cyclic GMP. Tadalafil has a markedly different structure, but a portion of the molecule is configured so that it competes for the cyclic GMP receptor. Clinically important differences among the three PDE5 inhibitors exist, probably based on their molecular differences (Table). Vardenafil is the most potent inhibitor, followed by sildenafil and tadalafil. Inhibition of PDE5 reaches a plateau within the therapeutic dose of all three drugs, however, and a further increase in dose does not cause greater PDE5 inhibition. The major difference among the three drugs is the duration of action. The effective half-life of sildenafil and vardenafil is similar, about 4 hours. The effective half-life of tadalafil is 17.5 hours. Tadalafil is therefore effective after a single dose for at least 36 hours, much longer than either of the other two drugs. How important this is clinically depends on how long after a single dose the individual wishes to have effective erectile function. There are also differences in the rate of absorption after a fatty meal, with sildenafil and vardenafil having delayed absorption and therefore delayed onset of activity. Tadalafil is not affected by eating, but because absorption occurs in the small intestine, it has a longer delay in onset of activity compared with the other two drugs, which are taken while fasting.

	Recently, there have been reports of nonarteritic ischemic optic neuropathy (NAION) in patients who have taken PDE5 inhibitors,21 both sildenafil and tadalafil. NAION is not an uncommon problem, especially in patients with diabetes and in the elderly. Although there is no evidence that there is a causal relationship, the possibility is taken seriously. NAION, as the name implies, is an ischemic neuropathy, probably caused by hypotension in the ophthalmic artery, resulting in marked visual impairment. Since PDE5 inhibitors are mild vasodilators and cause a minimal drop in systemic pressure, the possibility exists that such a drop in blood pressure in patients at risk might be responsible for the few cases of NAION occurring after PDE5 inhibitors.

	Evidence against PDE5 inhibitors as a cause of NAION is the fact that there was not a single report of NAION in all the placebo-controlled trials or open-label follow-up experience. Boshier and colleagues22 reported one patient with NAION identified from a cohort of 8,893 patients from a prescription event-monitoring study prescribed sildenafil in England between April and June 1999; epidemiologic data suggested that was the expected incidence of NAION in that number of patients. Hattenhauer and colleagues23 reported the incidence of NAION in Olmsted County between 1981 and 1990, adjusted to the age and sex distribution of the white US population of 1990 to be 10.2 per 100,000. Extrapolated to the US population, this means that each year there would be 5,700 new cases of NAION. Furthermore, the risk factors for NAION are diabetes, hypertension, advanced age, a small optic-cup-to-disc ratio, and nocturnal hypotension,24 and many of the patients reported with NAION after PDE5 inhibitors had one of these risk factors. Patients with ED have as risk factors diabetes and hy-pertension, so patients taking PDE5 inhibitors are at risk from NAION without there being a causal relationship. Finally, in a small, double-blind, randomized, placebo-controlled crossover trial reported by Grunwald and colleagues,25 100 mg of sildenafil caused no significant change in intraocular choroidal or optic nerve circulatory parameters. However, the possibility of this serious adverse effect is such that caution is advised in using PDE5 inhibitors in patients who have had one eye affected by NAION.

	Finally, there are new possible uses for PDE5 inhibitors beyond that of ED. Most important is the use of PDE5 inhibitors for patients with pulmonary hypertension.26,27 For patients with normal pulmonary artery pressure and vascular resistance, there is little change when they are given PDE5 inhibitors. With pulmonary hypertension, there is an upregulation of PDE5 receptors in the pulmonary vascular bed. Sildenafil has been shown to decrease pulmonary arterial pressure and pulmonary vascular resistance, similar to that obtained by inhalation of NO. Unlike NO, sildenafil increases cardiac output and decreases pulmonary capillary pressure.27 Ghofrani and colleagues28 showed that, for patients who have had inadequate response to prostacyclin therapy, adding sildenafil can further decrease pulmonary artery pressure and pulmonary vascular resistance without significantly affecting systemic vascular resistance. Most of the studies have been done in patients with primary pulmonary hypertension, but there are suggestions that PDE5 inhibitors could be effective in treating patients with pulmonary hypertension secondary to congenital heart disease, connective tissue diseases, and even left ventricular failure.29 With its longer duration of activity, tadalafil might be the best agent for long-term use.

	The benefits of PDE5 inhibitors are being investigated for the treatment of other vasospastic diseases, such as Raynaud’s phenomenon. Be- cause endothelial dysfunction is such a basic pathophysiologic mechanism leading to a variety of clinical diseases, the indications for the use of PDE5 inhibitors are likely to increase in the future, for both the elderly and younger age groups. Stay tuned.

PDE5 inhibitors: Two new drugs  and cardiovascular uses beyond  erectile dysfunction

	Obesity is considered by the World Health Organization to be a chronic disease and a massive public health problem. Abdominal obesity is particularly problematic as it relates to cardiovascular disease (CVD) risk. Although most of the relationship between abdominal obesity and CVD risk is mediated through the standard CVD risk factors, there does seem to be some additional risk imparted by abdominal obesity. These observations have led to the identification of the insulin resistance syndrome (or metabolic syndrome) characterized by abdominal obesity.

	As a result of the obesity “epidemic,” a number of new therapeutic approaches are being investigated. Clearly, these new approaches have to be built upon a foundation of dietary restriction and lifestyle modification, but it is just as clear that these approaches alone are not satisfactory. One example of a new therapeutic intervention is orlistat (Xenical), an inhibitor of gastrointestinal lipase that reduces absorption of dietary fat by about 30%. Studies have confirmed the success of orlistat for weight reduction, and short-term studies have shown improved insulin sensitivity and cardiovascular risk profiles in Caucasian and Asian populations.

	Interest in obesity interventions has also led to the discovery and exploration of the endocannabinoid system.1 One such cannabinoid receptor blocker under study is rimonabant (Acomplia), a CB1 receptor antagonist. To date, two cannabinoid receptors have been identified (CB1 and CB2). The endocannabinoids are produced on demand from the cell membrane; they act locally and are immediately metabolized. Overactivity of this system stimulates the hypothalamus with a resultant increase in appetite, and it stimulates the nucleus accumbens, which increases one’s motivation to eat and smoke, and peripherally affects adipocytes to increase fat accumulation.2 The relationship between this system and nicotine dependence is exemplified by observations that endocannabinoids are released by chronic nicotine use and that rimonabant decreases nicotine self-administration. In obese rodents, the endocannabinoid system becomes permanently activated in the hypothalamus, peripheral adipocytes, and the nucleus accumbens.

	Rimonabant is one of the first selective antagonists of the CB1 cannabinoid receptors under intense study. Three multicenter, double-blind, placebo-controlled studies in obese patients have consistently reported weight loss, as well as improvements in CVD risk factors. The Rimonabant in Obesity (RIO)-Europe study was the largest of the three and presented 1-year follow-up.2 For this trial, 3,040 patients were randomly assigned to either placebo, or 5 mg or 20 mg of rimonabant. Participants receiving the 20-mg dose lost more than 19 lb (vs 5.1 lb in the control group). This was associated with a 24.5% increase in high-density lipoprotein (HDL) cholesterol (compared with 13.8% on placebo) and a greater than 7% benefit in triglycerides compared with placebo. In addition, there was an improvement in insulin sensitivity. These improvements were greater than what was predicted by the degree of weight loss, raising the hypothesis that there is an independent effect of CB1 blockade on CVD risk factors. In fact, the authors suggested that about half of the effect of rimonabant on HDL and triglycerides was independent of weight loss. In addition, the weight loss observed in 39% of the patients treated with the 20-mg dose was associated with a concomitant reduction in waist circumference of about 9 cm, a value that could be associated with a 30% decrease in intra-abdominal adiposity.

	To date, the reported incidence of adverse effects is low. In the RIO-North America Study, for the 20-mg group, a slightly higher incidence of depression, anxiety, and irritability was reported. There was also more nausea reported in the 20-mg group.

	Obesity is a manifestation of multifactorial origins, and future approaches to its management will undoubtedly surface. The endocannabinoid system is an important addition to our understanding of obesity and will likely lead to other avenues of exploration.

The obesity epidemic:  New therapeutic approaches

	The Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial was an industry-sponsored, randomized study designed to address the question of equivalence between carotid artery stenting (CAS) and carotid endarterectomy (CEA) in a group of patients designated as being at high risk for complications during CEA. Although the results of this trial have been widely publicized, a number of serious concerns have been raised about the study regarding early termination because of recruitment problems, the large number of recurrent stenoses (20%), which is uncharacteristic of any surgical series of endarterectomies, and the definitions of high-risk patients.

	The medical definitions of high-risk patients are based on exclusion criteria for the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the Asymptomatic Carotid Atherosclerosis Study (ACAS). The exclusion criteria for these studies were based on concerns over long-term follow-up, not on any evidence that the criteria implied increased perioperative risk. In fact, several studies have demonstrated that excellent surgical results can be obtained in the high-risk medical group.1-3 Therefore, one may then question whether the actual selection criteria used for the SAPPHIRE trial reflect the realities of a clinical practice.

	When the trial results were finally published, a number of additional questions were raised, including:

	(1) Why were more than 50% of the patients (70% of whom were asymptomatic) unsuitable for endarterectomy, whereas less than 2% were unsuitable for stenting? What does this say about the perspective of the investigative centers?

	(2) Why did 5% of CEA patients fail to achieve “target artery revascularization”? This is highly unusual for any surgical series and raises questions about either patient selection or operative results.

	(3) The stenting group had a higher incidence of preprocedural coronary revascularization, and all of these patients received periprocedural clopidogrel (Plavix). How did these factors affect the 30-day myocardial infarction rate, which was the major difference in study outcome between the two groups?

	(4) Finally, given the results of both stenting and endarterectomy in this series, how can the authors recommend either approach from their experience for patients with asymptomatic carotid stenosis?

	Since SAPPHIRE’s publication, additional data have come out, raising concerns about the widespread application of carotid stenting. These include the Imaging in Carotid Angioplasty and Risk of Stroke (ICAROS) study in which 7.1% of patients with echo-lucent plaque had a stroke, a rate that was not influenced by use of embolic protection devices,4 as well as the lead in results of the Carotid Revasculari-

	zation Endarterectomy versus Stenting Trial (CREST) in which the stroke rate after stent-ing was higher than 5% in patients older than age 70 and higher than 12% in patients older than age 80.5 The increased risk of stroke after CAS that is associated with advanced age, which was one of the risk factors in the SAPPHIRE study, may shed some light on the high complication rates seen in the SAPPHIRE investigation. Taken together, these recent publications on carotid stenting cause one to continue to regard the procedure with a healthy concern.

	Advocates of stenting have used the SAPPHIRE trial results to justify a broader application of carotid stenting to clinical situations that have not been properly investigated. The fallacy of this approach is highlighted by the case report by Gurm and Yadav (page 32) in which an asymptomatic, high-grade carotid stenosis was stented prior to coronary artery bypass graft (CABG) surgery. Although this may ultimately prove to be appropriate therapy, there are no data to justify this approach at present. The appropriate treatment of combined coronary artery disease itself is unsettled. After over a decade of studying this problem, my colleagues and I have concluded that the increased complication rates associated with combined CEA and CABG surgery are primarily a reflection of the comorbidities of the patients with combined disease, not the addition of the CEA.6-8 Put another way, in a patient having CABG surgery, adding CEA, particularly for an asymptomatic stenosis, does not seem to increase morbidity or mortality. No data on CAS in this patient group are available (pre-CABG surgery). Stenting may be associated with increased risk in these patients, given their 5% to 8% incidence of aortic arch, and it does

	not avoid an open operation (CABG surgery). Unless carotid stenting can reduce stroke risk in these patients, its only effect would seem to be to delay the coronary bypass by 6 to 8 weeks, as in the case reported by Gurm and Yadav. Clearly, further studies are needed.

	There is no doubt that carotid stenting has a role in the overall treatment of carotid bifurcation stenosis. At present, its clearest role is in “anatomic high-risk” patients. These patients constitute approximately 5% of the overall endarterectomy population.1 Data suggest that stenting may be inferior

	to endarterectomy in patients with echo-lucent plaque or advanced age.4,5 SAPPHIRE notwithstanding, CAS has not been shown to be superior to well-performed endarterectomy in properly selected patients. The clearest lesson from SAPPHIRE is that asymptomatic patients should not have interventions of any sort if the anticipated stroke and death rate exceeds 5%, which was the case in the SAPPHIRE trial.

	The reason the morbidity and mortality rates reported with CEA in the SAPPHIRE trial are so much higher than those reported from single centers cannot be determined. Perhaps it has to do with patient selection and surgeons deferring any interventions in asymptomatic patients who are truly thought to be at high risk. Clearly a trial comparing stenting, endarterectomy, and medical therapy in asymptomatic patients, as well as a trial comparing stenting plus coronary bypass with concurrent endarterectomy and bypass is the logical next step.

Questions from the SAPPHIRE trial

	A 58-year-old man presented with a 6-week history of worsening of his chronic stable angina pectoris. He had known coronary artery disease (CAD), having had a myocardial infarction 8 years before presentation and, until recently, he had been successfully treated medically. He also had a history of deep vein thrombosis, hypertriglyceridemia, and pancreatitis. He had undergone percutaneous intervention to his left anterior tibial artery for lifestyle-limiting claudication 4 years before presentation and to his right anterior tibial artery 3 years prior to presentation. His other medical problems included hypertension and painful neuropathy. His medications included an analgesic, a beta blocking agent, an HMG-CoA reductase inhibitor (statin), an aspirin, and a fibrate with good control of his lipids, hypertension, and heart rate.

	Because of the change in his symptoms he underwent cardiac catheterization. His ejection fraction was 55% and his coronary tree was heavily calcified. He had a complex bifurcation lesion involving his proximal left anterior descending (LAD) artery and a large diagonal with 70% narrowing of the diagonal and 90% narrowing of the LAD artery. His right coronary artery was totally occluded in the mid-segment with filling of a large posterior descending artery via collaterals from the left coronary artery. His circumflex artery had moderate diffuse disease. Given the angiographic nature of his lesions he was referred for coronary artery bypass grafting (CABG). He underwent routine carotid duplex ultrasound as part of his preoperative evaluation and was found to have a severe left internal carotid artery stenosis. Specifically, the ultrasound noted heterogeneous plaque from the origin to the proximal vessel with an 80% to 99% stenosis. The peak systolic velocity was 315 cm/sec with the end-diastolic velocity being 148 cm/sec and an internal carotid artery/common carotid artery velocity ratio of 5.62. Given the severity of both his carotid and coronary artery disease, it was decided to electively perform carotid artery stenting (CAS) to reduce his risk of stroke during CABG surgery. Accordingly, he underwent successful balloon an-gioplasty and stenting to the left internal carotid artery using emboli protection with an AngioGuard filter (Cordis, Figure). He had no procedural complications and was discharged from the hospital the day following the procedure. He was treated with aspirin and clopidogrel (Plavix) for 4 weeks. He subsequently was taken off clopidogrel and 2 months after undergoing his CAS underwent CABG with left internal thoracic artery graft to the LAD, saphenous vein graft to the diagonal, and saphenous vein graft to the posterior descending artery. He had no peri- or postoperative complications and went back to work 6 weeks after his surgery.

Treating severe carotid artery stenosis in a patient with severe CAD: Insights from the SAPPHIRE trial

	Stroke is one of the major causes of morbidity and mortality in the United States. While myriad processes can cause strokes, carotid artery disease is responsible for approximately one third of strokes. Given a clear relation between the degree of carotid stenosis and the risk of ipsilateral stroke,1,2 carotid revascularization in the form of carotid endarterectomy (CEA) has been highly successful in reducing the incidence of stroke in patients with moderate-to-severe symptomatic carotid stenosis,1 as well as in those with severe asymptomatic stenosis.3 While CEA has been highly effective in the setting of clinical trials at reducing the long-term risk of stroke, it carries with it the early hazard of perioperative stroke and death, along with other complications such as periprocedural myocardial infarctions, cranial nerve palsies, and wound infections.

	It was realized that the hazard of death and stroke associated with CEA was much higher in the community than had been recognized in clinical trials.4,5 Furthermore, the procedure was increasingly being performed in patients who were deemed to be at greater surgical risk owing to anatomical reasons or secondary to medical comorbidities, a cohort that had been excluded from the clinical trials.   

	In parallel with the development of percutaneous coronary interventions, there was a concerted effort to develop a percutaneous technique to treat carotid stenosis. The recognition of embolism as an obligate hazard at every step of the procedure prompted the development of emboli-protection devices (EPDs) that have subsequently made the procedure safer and more appealing.6 The improved safety of carotid stenting with the availability of EPDs and self-expanding stents has made endovascular treatment of carotid stenosis a viable alternative to CEA. The recently published Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial directly compared carotid artery stenting (CAS) with CEA in patients deemed to be at high risk secondary to difficult anatomy or medical comorbidities.7  

	The trial enrolled patients across 29 centers. Each patient had to be evaluated by a team comprised of a neurologist, an interventionalist, and a vascular surgeon or a neurosurgeon. All members had to agree on the need for revascularization before a patient could be enrolled into the trial. Following this, the patient was randomly assigned to CAS or CEA if the surgeon and the interventionalist concurred that revascularization could be successfully carried out with either technique. Patients deemed to be at high risk for CEA by the local surgeon but in whom CAS was judged feasible by the interventionalist were enrolled in a stent registry. Conversely, patients deemed suitable for only surgery were enrolled in a CEA registry.

	Inclusion criteria mandated the presence of one or more high-risk criteria and either a symptomatic stenosis that was greater than 50% or a greater than 80% asymptomatic stenosis. The high-risk criteria included the presence of at least one of the following: significant cardiac disease (congestive heart failure, abnormal stress test, or the need for open heart surgery), severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal nerve palsy, recurrent stenosis after CEA, previous radical neck surgery or radiation therapy to the neck, or age older than 80 years.

	Patients with any of the following were excluded: stroke within the previous 48 hours, presence of intraluminal thrombus, total occlusion, arterial disease precluding the use of catheter-based techniques, large intracranial aneurysm, need for three or more stents, a bleeding diathesis, planned percutaneous or surgical intervention within 30 days, life expectancy of under 1 year, and ostial lesion of the common carotid artery or brachiocephalic artery.

	All patients received aspirin and were given therapeutic doses of heparin during the procedure. CEA was performed as per the surgeon’s favored technique. Patients in the CAS arm were pretreated with clopidogrel (Plavix) and continued this agent for 2 to 4 weeks after the procedure. All patients received a self-expanding nitinol stent (Smart or Precise, Cordis) with an EPD (AngioGuard, Cordis). The AngioGuard is a 0.014 guidewire with an expandable filter basket with a pore size of 100 µm.

	The trial had a noninferiority design with the primary end point of the trial being the cumulative incidence of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and 1 year. The secondary end points included target-vessel revascularization (TVR) at 1 year, cranial nerve palsy, and complications at the surgical site or vascular access site.

	The trial enrolled 747 patients, of whom 334 patients were randomly assigned to CEA or CAS. Of the 413 patients not randomized, the overwhelming majority (406) underwent stenting, while seven were followed in the CEA registry. The baseline characteristics of the patients were similar in both arms, except for a higher prevalence of coronary artery disease in patients in the CAS arm. An intention-to-treat analysis demonstrated non-inferiority of CAS versus CEA with no statistically significant difference in the incidence of major adverse events between the two groups (Figure 1). When the patients actually treated were compared, the CAS arm had a significantly lower incidence of the composite end point (12% versus 20.1%, P = .048). The incidence of cranial nerve palsy and TVR was significantly lower in the CAS arm (Figure 2). The average length of hospitalization was significantly shorter in patients receiving CAS (1.84 days versus 2.85 days, P = .002). The benefits of CAS over CEA were seen in both symptomatic and asymptomatic patients. The incidence of bleeding in the two arms was similar.

	The SAPPHIRE study demonstrated the noninferiority of the less invasive strategy of CAS with EPD compared with CEA in patients deemed to be at high risk for complications. The benefits of CAS were evident in both symptomatic and asymptomatic patients and were achieved without any increase in major periprocedural complications in either group. Further, the incidence of cranial nerve palsies and restenosis was significantly lower in the CAS arm. This study thus validates the approach of using CAS with EPD in patients at high risk for complications with CEA. Compared with CEA, this strategy achieves the goal of carotid revascularization with a similar (or lesser) hazard of major complications and a marked reduction in minor complications. This low risk of periprocedural complications and a similar long-term outcome establishes CAS with EPD as a viable strategy in this challenging population. Further studies are warranted to assess this exciting approach in low-risk patients.

A new look at treatment of carotid artery disease in high-risk patients 

	Erectile dysfunction (ED) is a problem that affects over 50% of men at some point during their lifetime and becomes increasingly problematic with age. For decades, the only oral treatments physicians could prescribe for ED were complementary medications; however, there was scant scientific evidence to support the effectiveness of these medications. In addition to these treatments, urologists offered treatment with penile vacuum pumps, penile injections, or surgery with the implantation of a rigid or flexible penile prosthesis or inflatable penile prosthesis. With the advent of phosphodiesterase-5 (PDE5) inhibitors, which were first introduced in 1978 with sildenafil (Viagra) followed by vardenafil (Levitra) and tadalafil (Cialis), the diagnosis and treatment of ED changed dramatically.

	PDE5 inhibitors have shown efficacy in approximately 70% of the patients to whom they are prescribed. Over 80 million prescriptions for these drugs have been written since 2000. Prior to the introduction of PDE5 inhibitors, many men were reluctant to discuss the treatment of ED with their family, their friends, and even their physicians. As a result of the extensive press coverage and marketing blitz that accompanied the introduction and widespread use of PDE5 inhibitors, more men now come to physicians’ offices seeking treatment for ED. Others, however, remain hesitant to try this new class of drugs. Both patients and their spouses are concerned that PDE5 inhibitors will cause serious cardiovascular adverse effects, such as angina, myocardial infarction (MI), and death. In addition, many primary care physicians and cardiologists have concerns about the safety of PDE5 inhibitors.

	In his article, Cheitlin (page 18) has put to rest many of the cardiovascular concerns shared by patients, their families, and physicians. Cheitlin states that the incidence of acute MI in patients taking PDE5 inhibitors is no different than that in placebo controls. He explains further that patients with coronary artery disease and other cardiovascular problems who take PDE5 inhibitors experience, at the most, a very minor decrease in their blood pressure. This minor blood pressure reduction has not been shown to precipitate any significant myocardial ischemia, infarctions, or arrhythmias. Cheitlin also found no evidence that men who took PDE5 inhibitors in combination with multiple antihypertensive medications experienced a significant decrease in blood pressure.

	Recently, the Food and Drug Administration (FDA) has removed the cautions it had placed on the combination of PDE5 inhibitors with certain alpha-blocking medications. Therefore, there are only two remaining groups for which the use of PDE5 inhibitors is contraindicated—patients taking nitroglycerin and those who are too ill to engage in sexual intercourse.

	Now that the relative safety of PDE5 inhibitors is being recognized, these drugs have become an excellent addition to the armamentarium of

	primary care physicians and urologists. Another benefit of the increase in patients seeking treatment for ED that has accompanied the introduction of PDE5 inhibitors is that certain un-

	derlying causes of ED, such as arteriosclerosis and diabetes, are being

	recognized and treated before they become serious.

	To add a cautionary note, during the past few months there have been reports that the FDA is investigating 42 incidents of sudden partial or total blindness in men taking PDE5 inhibitors. These incidents have been attributed to nonarteritic ischemic op- tic neuropathy (NAION), a rare condition that can cause partial loss

	of vision and even total blindness. Although some PDE5 inhibitors have been associated to some degree with minor visual disturbances since their initial studies, the reports of these 42 cases of NAION are new. Furthermore, the relatively small number of men who have experienced these serious symptoms need to be viewed in

	who have used or are currently using PDE5 inhibitors. In addition, men who have experienced this sudden partial or total blindness appear to have significant comorbidities, such as diabetes, high blood pressure, and high cholesterol. The comorbidities may have been responsible for the onset of NAION, rather than the use of PDE5 inhibitors. This obviously is an issue that bears watching. But in light of the general safety of these medications as reported by Cheitlin, it is unlikely to significantly affect the ability of physicians to prescribe PDE5 inhibitors to successfully treat a large percentage of men with ED.

The safety of PDE5 inhibitors in  ED treatment: Putting cardiovascular concerns to rest 

	The incidence of diabetes in the elderly is increasing rapidly, and as Pasmantier points out in her review (page 12), the number of patients requiring treatment increases if seniors are challenged by oral glucose tolerance testing. Because type 2 diabetes is a syndrome that includes elevated blood glucose, dyslipidemia, and hypertension, the patients identified to be at risk would benefit from aggressive treatment of all the components of the diabetic syndrome.

	Is it worth the effort of glucose tolerance testing to identify unrecognized patients with diabetes? The data from several clinical trials reviewed by Pasmantier are convincing. In the Rancho Bernardo study, subjects underwent 75-g oral glucose tolerance testing and blood glucose was measured after 2 hours. Results showed at least 50% of the subjects were diabetic patients who would not have been diagnosed if fasting plasma glucose alone was measured.1

	How can we identify patients at risk for diabetes who would benefit from glucose tolerance testing? Patients with fasting blood glucose of 100 to 125 mg/dL, dyslipidemia, especially high triglycerides, low high-density lipoprotein cholesterol, central obesity, body mass indexes greater than 30 kg/m2, hypertension, and a family history of diabetes would be candidates for the glucose challenge.

	Because there are special issues regarding management in the elderly diabetic patient, a referral to a certified diabetes educator can alleviate many potential risks. Detailed education regarding foot care, insulin delivery skills, glucose monitoring, individualized meal planning, and timing of medication with food are all areas that need close scrutiny.

	Weight management, which is essential in all patients with diabetes, is especially important in the elderly. The Diabetes Prevention Program provides important information for our elderly prediabetic and diabetic patients.2 No medication can achieve better blood glucose lowering and cardiovascular disease prevention than diet and exercise. Exercising five times a week for 30 minutes and losing 7% of body weight by careful dietary management achieves a 58% reduction in the incidence of diabetes in patients with impaired glucose tolerance.

	Attention should also be focused on the increased risk of hypoglycemia in elderly diabetic patients. An emphasis on tight blood glucose control can leave elderly patients particularly vulnerable to hypoglycemia because of several factors, such as decreases in counterregulatory hormones at night, decreases in appetite resulting in intake of fewer calories, and changes in activity level.

	It will take a concerted effort by insurance companies, the American Diabetes Association, and the American Heart Association to encourage physicians to identify patients with diabetes as early as possible. It will take a team effort between primary care physicians, cardiologists, endocrinologists, and diabetes educators to manage the complex strategies and multiple medications needed for controlling blood glucose, blood pressure, lipid levels, smoking, and weight in elderly patients who are at risk for or diagnosed with diabetes.

Identifying unrecognized diabetes  in the elderly

	Diabetes mellitus affects 18.2 million people in the United States1; 13 million were known to have diabetes and 5.2 million went undiagnosed in 2002. The majority of elderly patients with diabetes have type 2, which is associated with increasing age, obesity, family history, impaired glucose metabolism, a history of gestational diabetes, race, ethnicity, and a sedentary lifestyle. When analyzed by age it is clear that diabetes affects a higher percentage of older Americans (Figure).

	With life expectancy continuing to increase, we can also expect an increase in the prevalence of diabetes. How one defines diabetes—by fasting plasma glucose (FPG) alone or 2-hour postchallenge plasma glucose (2-hr PG) during a 75-g oral glucose tolerance test&mdash;will affect the number of cases diagnosed. This is a very important point, because treatment of patients with diabetes includes management of not only hyperglycemia, but also more aggressive treatment of other commonly associated conditions such as hypertension and dyslipidemia.

	The diagnosis of diabetes itself is considered a coronary heart disease risk equivalent that requires intensified cardiovascular risk factor modification. American Diabetes Association (ADA) Standards of Medical Care for individuals older than age 40 with diabetes and total cholesterol of 135 mg/dL or above but no overt cardiovascular disease include HMG-CoA reductase inhibitor (statin) therapy to achieve a low-density lipoprotein (LDL) cholesterol reduction of 30% to 40% regardless of baseline LDL cholesterol levels. The primary goal is an LDL cholesterol less than 100 mg/dL.2 For patients with diabetes and overt cardiovascular disease who are at very high risk for further events, treatment should include a high-dose statin with an LDL cholesterol goal of less than 70 mg/dL. The diagnosis of diabetes in the elderly also makes aspirin therapy for primary and secondary prevention of coronary heart disease an imperative, along with smoking cessation. Also recommended in diabetic patients older than 55 years with or without hypertension, but with another cardiovascular risk factor (history of cardiovascular

	disease, dyslipidemia, microalbuminuria, or smoking), is treatment with an angiotensin-converting enzyme inhibitor to reduce the risk of cardiovascular events.3

	The recently revised ADA diagnostic criteria for diabetes and impaired glucose regulation are listed in the Table. The fasting glucose cutpoint used to define normal glucose tolerance was lowered to less than 100 mg/dL, with impaired fasting glucose (IFG) now defined as 100 to 125 mg/dL. The 2-hr PG cutpoint used to define normal glucose tolerance remains at less than 140 mg/dL with impaired glucose tolerance (IGT) defined as 140 to 199 mg/dL. Both IFG and IGT are considered prediabetes. They have a similar risk of progression to diabetes, but they may have different risks of cardiovascular disease. The Expert Committee on the Diagnosis and Classification of Diabetes concluded that the FPG and the 2-hr PG (but not the glycosylated hemoglobin [A1C] test) remain the tests of choice for the diagnosis of diabetes.4 Using the 2-hr PG for the diagnosis of diabetes is more sensitive in most populations, particularly the elderly, while the FPG is more reproducible, less costly, and more convenient.

	Data from oral glucose tolerance testing carried out in 2,844 subjects aged 40 to 74 years without known diabetes identified more people with diabetes based on elevated 2-hr PG levels than using the FPG alone.5 A 2-hr PG of 200 mg/dL or greater in the setting of an FPG less than 126 mg/dL defines isolated postchallenge hyperglycemia (IPH). In subjects aged 60 to 64 years, the weighted age-specific prevalence of diabetes diagnosed by the FPG was 8%, which was almost identical to the prevalence of diabetes diagnosed by IPH. In subjects aged 70 to 74 years, the values were 7% prevalence of diabetes based on FPG and 9.1% based on IPH. This confirmed that with advancing age, IPH was more common and reaffirmed the use of the oral glucose tolerance test to diagnose diabetes in elderly subjects.

	IPH has been associated with increased cardiovascular disease mortality in a variety of studies. The Rancho Bernardo study, which performed 2-hour 75-g oral glucose tolerance tests in older subjects aged 50 to 89 years without known diabetes or myocardial infarction, found that a diagnosis of diabetes would have been missed in 88 of 125 women with diabetes (70%) and 60 of 133 men with diabetes (45%) using FPG alone.6 Seven-year age-adjusted cardiovascular mortality rates in women were doubled when isolated 2-hr PG levels of 200 mg/dL or above were used.

	There are also important data from the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe study group, a collaborative study of 22 cohorts in Europe with baseline measurements of 29,714 subjects aged 30 to 89 years with 11-year follow-up.7 They found that high FPGs, as well as very low FPGs below 80 mg/dL, were associated with an increased risk of death, resulting in a J-shaped curve. Individuals with IFG of 110 to 125 mg/dL showed hazard ratios for all-cause mortality, cardiovascular mortality, and noncardiovascular mortality of 1.1, while patients with previously undiagnosed diabetes and an FPG of 126 mg/dL or greater had hazard ratios of 1.6 for these pa-rameters. The relationship between cardiovascular mortality and 2-hr PG was linear, with IGT showing hazard ratios of 1.5 for all-cause mortality, 1.4 for cardiovascular mortality, and 1.6 for noncardiovascular mortality, while patients with previously undiagnosed diabetes based on a 2-hr PG value greater than or equal to 200 mg/dL (IPH) showed hazard ratios of 2.0 for all-cause mortality, 1.9 for cardiovascular disease mortality, and 2.1 for noncardiovascular disease mortality. They concluded that all-cause, cardiovascular, and noncardiovascular disease mortality hazard ratios for subjects with 2-hr PG greater than 180 mg/dL were not significantly different from subjects with known diabetes. This was significantly higher than that for undetected diabetes based on FPG. They also concluded that all-cause and cardiovascular disease mortality was significantly higher for subjects with IGT than for IFG.

	Further evidence to support the association of IGT with cardiovascular risk factors was obtained from the Baltimore Longitudinal Study on Aging.8 This was a prospective study of community-dwelling volunteers aged 21 to 96 years. They determined cardiovascular risk factors in 937 subjects without diabetes or cardiovascular disease at baseline and follow-up over 9.5 years. They excluded from analysis the 152 subjects who developed diabetes. When IFG was classified using the new criteria of 100 to 125 mg/dL, creating a similar baseline prevalence of IFG

	and IGT, they found that 24.8% of the subjects remained with normal glucose tolerance throughout, while isolated IFG was seen in 21.2%, isolated IGT was seen in 16.3%, and both IFG and IGT were seen in 37.7%. The subjects with normal glucose tolerance or IFG were younger and had lower triglycerides and higher high-density lipoprotein (HDL) cholesterol levels than those with IGT and both IFG and IGT. There were 28% of subjects with IGT and 47% with both IFG and IGT meeting the criteria for metabolic syndrome, which was much greater than in subjects with normal glucose tolerance (4%) or IFG (6%).

	The International Diabetes Federation IGT/IFG Consensus Statement workshop reported that the determinants of FPG and 2-hr PG differ.9 Elevated hepatic glucose production and a defect in early insulin secretion are characteristic of an elevated FPG. Peripheral insulin resistance, particularly at the skeletal muscle, is most characteristic of an elevated 2-hr PG. They found the prevalence of IFG tended to plateau in middle age, whereas the prevalence of IGT continued to rise in the elderly coincident with declining muscle mass (sarcopenia). While both IFG and IGT are similarly associated with a greater risk of developing diabetes (1%—10% per year), IGT is more strongly associated with cardiovascular disease. These reports have placed specific emphasis on the control of postprandial plasma glucose to prevent cardiovascular disease. Postprandial hyperglycemia may have a direct toxic effect on the vascular endothelium, mediated by oxidative stress that is independent of other classic cardiovascular risk factors.10

	A retrospective claims-based Medicare dataset found the mortality rate was 100.2/1,000 person-years among seniors with diabetes compared with 60.6/1,000 person-years without diabetes, resulting in an age-adjusted relative risk of 1.83.11 The mortality risk associated with diabetes decreased with increasing age, but remained significantly elevated even among those 85 years and older. In contrast, the absolute excess mortality (defined as the difference in mortality rates) increased with increasing age. The excess mortality was 28.7/1,000 for the 65- to 69-year age group and 66.3/1,000 among those 85 years or older. These data support the goal of diabetes prevention to decrease mortality.

	Lifestyle interventions are highly effective in delaying or preventing the onset of diabetes in people with IGT. The Diabetes Prevention Program found a 58% decrease in the onset of type 2 diabetes with a lifestyle modification program and a 31% decrease with metformin therapy in subjects with IGT who were followed up over 2.8 years.12 When subjects 60 years or older were analyzed, there was a 71% reduction in diabetes incidence with lifestyle intervention, while metformin was ineffective. The patients in the lifestyle modification group lost an average of 7% body weight and performed 150 minutes per week of moderate exercise. A low-fat (< 25%) diet was recommended, with caloric restriction added if needed. These are reasonable interventions for the prevention of diabetes in the elderly.  

	In conclusion, diabetes in the elderly is more than just hyperglycemia; it means a much greater burden for cardiovascular disease and therefore prevention of diabetes should be a priority. Good glycemic control is important

	in elderly patients already diagnosed with diabetes, though larger reductions in morbidity and mortality may re-

	sult from control of cardiovascular disease risk factors. Treatment of glucose, blood pressure, lipids, obesity, and platelet hyperactivity is needed. Treatment targets include an A1C less than 7%, blood pressure less than 130/80 mm Hg, LDL cholesterol less than 100 mg/dL, triglycerides less than 150 mg/dL, HDL cholesterol greater than 40 mg/dL in men and greater than 50 mg/dL in women, a body mass index less than 25 kg/m2 with aspirin therapy, and smoking cessation.13  

	Further research is needed to ascertain whether or not prevention of diabetes in the elderly will result in a decrease in cardiovascular events and mortality. Clinical trials are needed to see if there is a difference in cardiovascular morbidity and mortality in patients with normal glucose tolerance compared with IFG versus those with IGT and diabetes. Pharmacologic interventions are needed that will prevent the onset of diabetes in high-risk elderly patients with reversion to normal glucose tolerance a goal. The priority should be to improve cardiovascular outcomes and quality of life for the elderly.

Diabetes in the elderly 

	Prehypertension—a blood pressure category coined by the seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)&mdash;is associated with an increased risk of myocardial infarction (MI) and coronary artery disease (CAD) but not stroke, according to a recent analysis of data from the Framingham study. The study findings were published in Stroke (2005;36[9]:1859-1863).

	JNC 7 defined prehypertension as a systolic blood pressure (SBP) of 120 to 139 mm Hg and/or a diastolic blood pressure (DBP) of 80 to 89 mm Hg. About 59 million people in the United States fit the definition of prehypertension. Normal blood pressure was defined by JNC 7 as a blood pressure less than 120/80 mm Hg, and hypertension was defined as a blood pressure of 140/90 mm Hg or greater.

	To study the effect of prehypertension on the long-term risk of cardiovascular diseases, researchers led by Adnan I. Qureshi, MD, followed 5,181 participants from the Framingham study for a mean of 31 years, tallying the incidence of atherothrombotic brain infarction (ABI), all strokes, MI, and CAD.

	They found that the risk of developing hypertension over the follow-up period was twice as high in those participants with prehypertension compared with normal blood pressure. To account for this variation in blood pressure status, the authors converted the data into person observations.

	After adjusting for potential confounders, there was no increased risk of ABI or all strokes in prehypertensive patients compared with normotensive individuals. “This is somewhat surprising, but it may be related to the small number of stroke events in the study,” according to Dr. Qureshi, professor and director of the Cerebrovascular Program in the Zeenat Qureshi Stroke Research Center at the University of Medicine and Dentistry of New Jersey in Newark. As expected, hypertension increased the risk of ABI by 9-fold and the risk of all strokes by 7.1-fold.

	The adjusted risk of MI was 3.5 times higher and the adjusted risk of CAD was 70% higher among the prehypertensive individuals compared with the normotensive ones. When stratified by gender, prehypertension was associated with significantly increased risks of MI and CAD in men but not women. Hypertension increased the risk of MI by more than seven times and the risk of CAD by more than three times.

	Higher SBP was associated with an increasing risk of MI and ABI, whereas there was no relationship observed between higher DBP and the risk of MI or ABI.

	The authors also examined the population-attributable risk of prehypertension, which determines the impact of eliminating this risk factor on the disease. The population-attributable risk associated with prehypertension was 47% for MI and 20% for CAD, which means that “47% of the MI in the population could be reduced by treatment of prehypertension,” write the authors. They add that this effect of prehypertension may be somewhat overestimated because cardiovascular risk factors cluster within individuals.

	A previously published meta-analysis determined that vascular and overall mortality start to increase with blood pressures that exceed 115/75 mm Hg, note the authors.

	The present study raises questions about the appropriate treatment of prehypertension, said Dr. Qureshi. “While we classically recommend lifestyle modifications such as weight control, regular physical activity, and changes in diet for people with prehypertension, these findings raise the question of whether we should treat prehypertensive patients more aggressively,” he said.

Prehypertension triples MI risk

	C-reactive protein (CRP) levels differ by race and gender, which calls into question the use of uniform CRP thresholds for assessing cardiovascular risk. The finding comes from the Dallas Heart Study, a large, multiethnic, population-based sample, and was published in the Journal of the American College of Cardiology (2005;46[3]:464-469).

	CRP values higher than 3 mg/L are considered an indicator of increased cardiovascular risk, whereas those less than 1 mg/L are considered to be low risk. These thresholds have been proposed regardless of the patient’s race or gender. The new findings show that blacks have significantly higher CRP levels than whites, and that women have significantly higher levels than men.

	“Given the increasing use of CRP as a component of cardiovascular risk in clinical decision-making, our findings have important public health implications,” write the study’s authors.

	Amit Khera, MD, MSc, assistant pro-fessor at the University of Texas Southwestern Medical Center in Dallas, and colleagues measured CRP in 2,749 white and black adults aged 18 to 65 years who took part in the Dallas Heart Study, which was designed to study cardiovascular disease. The median CRP level in blacks was 3.0 mg/L compared with a median of 2.3 mg/L in whites (P < .001). The median CRP levels were 3.3 mg/L in women and 1.8 mg/L in men (P < .001).

	Black men, black women, and white women all had higher CRP levels compared with white men, with the highest levels observed among black women.

	The difference in CRP levels between blacks and whites held even after excluding those subjects who used HMG-CoA reductase inhibitors (statins) or oral estrogen (median levels, 2.6 versus 2.1 mg/L, respectively; P < .001).

	Black men, white women, and black women were significantly more likely to have CRP levels higher than 3 mg/L (high risk) than white men. Almost two thirds of the black women in the study had a CRP level greater than 3 mg/L, the authors noted. The differences persisted after excluding statin or oral estrogen users.

	“Adjustment for traditional cardiovascular risk factors, body mass index [BMI], statin and estrogen use, and sampling weights attenuated the differences between race and gender groups, yet an elevated CRP level remained more common in white women and black women than in white men (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1 to 2.5, P < .05; and OR 1.7, 95% CI 1.2 to 2.6, P < .05, respectively),” according to the authors. “In contrast, the differences between black men and white men were no longer statistically significant after multivariate adjustment (OR 1.3, 95% CI 0.8 to 1.9).”

	Increasing BMI was associated with higher CRP levels in each race and gender group, but the increase in CRP levels with obesity was greater for women than for men. The greater increase in CRP with increasing BMI in women than in men may explain part of the gender-based differences in CRP levels, they speculate.

	Furthermore, “black subjects have a greater prevalence of cardiovascular risk factors than white subjects, and higher CRP levels may reflect this risk factor

	burden.” Although racial differences in inflammation may directly contribute

	mortality rates in blacks, they add, the possibility also exists that relying on

	overestimate cardiovascular event risk in this population, leading to overuse of resources.

	“Studies with long-term follow-up will be needed to determine whether these differences in CRP distribution contribute to differences in clinical outcomes and whether CRP risk thresholds should be adjusted for different race and gender groups,” the authors conclude.

 CRP levels differ by race and gender

	New York City—Flushing episodes with niacin can be managed with a few simple precautions, said Allen J. Taylor, MD, at the 2nd International Symposium on Triglycerides and HDL: Role in Cardiovascular Disease and the Metabolic Syndrome.

	Niacin is currently the most potent therapy available to raise high-density lipoprotein (HDL) cholesterol, resulting in increases as high as 35%; when used in combination with an HMG-CoA reductase inhibitor (statin), it has the potential to reduce cardiovascular risk more so than statin monotherapy, said presenters at the meeting.

	Flushing has traditionally limited compliance with niacin. In a study known as Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER-2), flushing occurred in 69% of niacin-treated patients compared with 13% of those assigned to placebo.

	“Although most patients flush with niacin, most do so infrequently and the incidence is much less with extended-release niacin than with the sustained-release form,” said Dr. Taylor, associate professor and director of cardiovascular disease research at Walter Reed Army Medical Center, Washington, DC. “Describe the flushing as a prickly heat. Tell patients that it’s normal, harmless, and short-lived.”

	Taking niacin at bedtime and with aspirin can limit the frequency and intensity of flushing. A bedtime snack may also help. Patients should also be cautioned against high-fat meals and alcohol use, which can exacerbate flushing.

	If flushing does occur, “you can rapidly abort it with judicious use of nonsteroidal anti-inflammatory drugs,” he continued. “Ibuprofen, 200 mg, will knock out a flush in 10 minutes. It’s remarkably effective in patients with occasional flush.”

	With the use of these simple steps, adherence to niacin exceeded 90% in ARBITER-2, he said. No elevations of liver enzymes or cases of rhabdomyolysis were observed with the use of niacin together with a statin in this study, he added.

	Because vitamin E and vitamin C may blunt the effects of niacin, these vitamins should be avoided, advised Dr. Taylor.

	As monotherapy, statins reduce the risk of major cardiovascular events by 30% to 35% in high-risk patients, which means that about two thirds of statin-treated patients still have a substantial risk of an event, said Ernst J. Schaefer, MD.

	HDL cholesterol has been identified as an independent predictor of cardiovascular risk, raising the possibility that simultaneous treatment of HDL and low-density lipoprotein cholesterol may extend the beneficial clinical results obtained with statin monotherapy.

	“We should try to target HDL cholesterol, especially if patients have established heart disease,” said Dr. Schaefer, director, Lipid and Heart Disease Prevention Program, Tufts University, Boston.

	ARBITER-2 was conducted in 167 patients with known coronary heart disease (CHD) who had baseline HDL cholesterol < 45 mg/dL. The patients were randomized to once-daily extended-release niacin, initiated at 500 mg for 1 month followed by 1,000 mg, or placebo added to background statin therapy. In the placebo group, common carotid intima-media thickness (CIMT) increased from baseline to 1 year by a mean 0.044 mm (P < .001), whereas it was virtually unchanged (0.014 mm; P = .23) in the niacin group. The rate of common CIMT progression is directly associated with the risk for future myocardial infarction and CHD death, noted Dr. Taylor, who was lead investigator of the study.

	Although the results of ARBITER-2 require confirmation in clinical events trials, it is the first study to show the incremental benefit of a treatment strategy that combines a statin with niacin, he said.

September 2005

Future treatment of congestive heart failure

PDE5 inhibitors: Two new drugs and cardiovascular uses beyond erectile dysfunction

The obesity epidemic: New therapeutic approaches

Questions from the SAPPHIRE trial

Treating severe carotid artery stenosis in a patient with severe CAD: Insights from the SAPPHIRE trial

A new look at treatment of carotid artery disease in high-risk patients

The safety of PDE5 inhibitors in ED treatment: Putting cardiovascular concerns to rest

Identifying unrecognized diabetes in the elderly

Diabetes in the elderly

Prehypertension triples MI risk

CRP levels differ by race and gender

A few simple precautions can avoid flushing with niacin

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