Regression of left ventricular hypertrophy: Are there preferred drugs?

The presence of left ventricular hypertrophy (LVH) confers markedly increased risk of cardiovascular morbidity and mortality in patients with hypertension. Regression of left ventricular (LV) mass with antihypertensive therapy is associated with reduction in cardiovascular events. In studies based on monotherapy, among the classes of antihypertensive drugs that have been adequately tested, diuretics and angiotensin-converting enzyme inhibitors appear to be the most effective agents for reducing LV mass. New avenues of research, based on combination antihypertensive therapy and on a more sophisticated understanding of the molecular mechanisms of LVH, may yield new pharmacologic approaches to regressing LV mass.     

PDE5 inhibitors: are there differences?

The introduction of oral agents for the treatment of erectile dysfunction (ED) has revolutionized the treatment of men with erection problems of all severities and etiologies. Sildenafil, available on the world market since 1998 was joined in 2003 by tadalafil and vardenafil as effective save and reliable oral agents. While these agents share the method of action in common and are all contraindicated with nitrate medications, these are differences among the three agents. Sildenafil has the longest patient experience and the most robust data confirming its activity, safety and tolerability. It has recently been released for use in pulmonary hypertension as well as ED. Vardenafil, the most biochemically potent of the molecules has also been demonstrated to be effective in men with severe ED and in some patients failing sildenafil. Tadalafil is unique in its longer half life and is also tolerable, safe and effective in all severities and etiologies of ED. Tadalafil is also unique in its inhibition of PDE 11, a characteristic of unknown but probably negligible importance. Newer data have also suggested that these agents may be helpful in the treatment of lower urinary tract symptoms. Since the introduction of sildenafil in 1998, erectile dysfunction has been effectively treated with oral medications. The recent addition of vardenafil and tadalafil to the market has increased the number of phosphodiesterase type 5 inhibitors (PDE5) to three agents used throughout the world. Each of these agents has similar mechanism of action, but has distinct differences. All three drugs in this class have similar pharmacokinetic and pharmacodynamic profiles and each is effective for patients with ED of all ages, severities and etiologies. While there are clear pharmacokinetic and pharmacodynamic differences amongst these agents, clinical differences are somewhat more difficult to identify. Indeed the data of preference trials, head to head clinical trials, and selection trials are few. The differences in pharmacokinetics while having distinct advantages in marketing each drug may be difficult for clinicians and patients to identify. With the lack of data and well done clinical trials, it is difficult for the clinician to differentiate amongst the three agents and to select a PDE5 inhibitor for a specific ED patient or a specific agent to switch to if an initial PDE5 agent is unsuccessful or poorly tolerated. This discussion summarizes some of the current data on PDE5 inhibitors and their efficacy, safety, and use in other conditions.     

Dementia and race: are there differences between African Americans and Caucasians?

This study provides an overview of racial differences in etiology and prevalence of dementia. Preliminary findings indicate that the clinical and molecular etiologies of dementia differ between races. African Americans have a higher prevalence of vascular dementia and a lower prevalence of Parkinsonian dementia than do Caucasians. The genetic etiologies of Alzheimer's-type dementia appear to differ between African Americans and Caucasians. The variations in dementia etiologies and in cognitive testing accuracy between races suggests the urgent need to develop racially appropriate cognitive assessment methods and to develop preventive and treatment etiologies differently according to racial background of individual patients.     

Is there an association between angiotensin-converting enzyme gene variants and chronic nonproductive cough?

BACKGROUND: It is unclear why some patients develop a chronic nonproductive cough. Angiotensin-converting enzyme (ACE) inactivates tussive peptides in the airways such as bradykinin and tachykinins. An insertion/deletion polymorphism in the ACE gene accounts for variation in ACE levels, and patients with the II genotype have lowest serum ACE levels compared with ID and DD genotypes. We hypothesized that the II genotype would be associated with increased risk of developing a chronic cough. MATERIALS AND METHODS: We recruited 47 patients (33 women), referred for evaluation of cough (median cough duration, 24 months; range, 2 to 240 months). Cough patients were evaluated using a comprehensive diagnostic protocol, and cough reflex sensitivity was measured using a capsaicin inhalation challenge. ACE genotyping was performed on DNA samples from patients using the polymerase chain reaction followed by agarose gel electrophoresis. ACE genotypes in patients with chronic cough were compared with those in 199 healthy control subjects. Serum ACE levels were determined using a colorimetric assay. RESULTS: Genotype frequencies for the ACE gene were similar between patients and control subjects. There was no correlation between capsaicin sensitivity and ACE genotypes or serum ACE levels. CONCLUSION: Susceptibility to develop chronic cough is not associated with ACE genotype.     

Does Chinese ethnicity affect the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors?

Information from clinical and pharmacokinetic studies of angiotensin-converting enzyme inhibitors (ACEIs) has come from subjects who are mostly male and Caucasian, but the use of ACEIs extends to populations worldwide. Significant differences between Chinese in general and male Caucasians have been demonstrated in the pharmacokinetics/dynamics of other drug classes that could have implications for the use of ACEIs in the Chinese population. These include: significant Chinese/Caucasian genetic variation in the renin-angiotensin system based on an insertion/deletion (O/D) polymorphism of the ACE gene; the genetic determination of plasma ACE activity in the Chinese population; and genetic factors involving the disease substrate which may also influence the response to treatment. Oral and IV pharmacokinetic data from various studies of Chinese and Caucasian subjects are available for cilazapril, fosinopril, and perindopril, and pharmacodynamic data are available for eight different ACEIs. Based on these data, there are few differences among the pharmacokinetics of ACEIs between Chinese and Caucasians. Most ACEIs showed good blood pressure lowering efficacy in Chinese (benazepril, enalapril, fosinopril and spirapril), with perhaps less blood pressure lowering with cilazapril or a relatively shorter-term effect with cilazapril or perindopril compared to Caucasions. Chinese experience more cough from ACEIs (captopril and enalapril) than Caucasians. Data suggest that fosinopril may not induce cough in as many subjects as other ACEIs, and this seems to be true of Chinese as well. The mechanism, currently unknown, could involve fosinopril's dual elimination pathway (hepatic and renal). Pharmacokinetic data also support the use of fosinopril in congestive heart failure where elimination pathways may be impaired. In conclusion, ethnic differences between Chinese and Caucasians with respect to ACE and AGT gene polymorphism, which might be expected to differentially affect the action of ACEIs in these two ethnic groups, do not, in fact, have such an effect. Rather, differences among the ACEIs appear to be more important. Journal of Human Hypertension (2000) 14, 163-170.     

Are physicians aware of the side effects of angiotensin-converting enzyme inhibitors?: a questionnaire survey in different medical categories

STUDY OBJECTIVE: Angiotensin-converting enzyme inhibitors (ACE-I) are considered safe, but they are associated with characteristic side effects, namely cough and angioedema, usually requiring discontinuation. We perceived that referrals for these side effects have become more and more frequent; therefore, we evaluated the degree of knowledge on the safety of ACE-I in different medical categories. DESIGN: A questionnaire (13 questions) on side effects of ACE-I was posted to physicians. SETTING: Everyday clinical practice. PARTICIPANTS: Cardiologists, allergists, and general practitioners (GPs) from the National Healthcare System. MEASUREMENT AND RESULTS: Three hundred twelve physicians were contacted, and 154 returned questionnaires that could be analyzed. Of the 154 physicians (mean age, 45 years) 48 were cardiologists, 52 were GPs, and 54 were allergists. The percentage of correct answers was low: 31.9% for cardiologists, 40% for GPs, and 33% for allergists. Thus, GPs provided a significantly higher percentage of correct answers with respect to the remaining categories (p = 0.05). The lower rate of correct answers (0 to 15.9%) concerned the time of onset of cough and the action to take. Cardiologists seemed to be less aware of the fact that angiotensin receptor blockers (sartans) can cross-react with ACE-I. CONCLUSION: Overall, there was a poor knowledge of the side effects of ACE-I. This may account for the increased referrals for chronic cough and angioedema.     

Aging widows and widowers: are there mental health differences?

Israeli Prime Minister Menachem Begin resigned shortly after the death of his wife. A classic portrait of the grieving widower, his despondency did not surprise mental health professionals. One psychiatrist explained that "Women take bereavement better than men because the widow keeps her domain" while the widower tends to become disoriented. This article examines the perception that men, specifically aging men, are more emotionally distressed than aging women by their spouse's death. A literature review reveals little evidence from behavioral or psychological studies to support the perception, along with mixed evidence of higher male mortality rates in some age groups. Data from a random probability community mental health survey are presented. Prevalence rates for the bereaved are significantly greater than are married rates for only one of the five measures of mental disorders. Widows report significantly more overall distress and depression, but these differences disappear when gender is examined, along with other sociodemographic variables in regression analyses. Clearly, these findings and those from studies of elders, do not support the perception that aging widowers experience more emotional problems during bereavement than do aging widows. Perceptions and mental health policies should be revised to reflect the reality of more similarities than differences among aging widows and widowers.     

Interaction between aspirin and angiotensin-converting enzyme inhibitors: should they be used together in older adults with heart failure?

PURPOSE: To determine whether the prostacyclin-inhibiting properties of aspirin counteracts the bradykinin-induced prostacyclin-stimulating effects of angiotensin-converting enzyme (ACE) inhibitors, thereby attenuating the beneficial effects of ACE inhibitors in heart failure patients. BACKGROUND: Most heart failure patients are older adults. Heart failure is the number one hospital discharge diagnosis of older Americans. The renin-angiotensin system plays a major role in the pathophysiology of heart failure, and ACE inhibitors play a pivotal role in the management of heart failure. Large-scale double-blind randomized trials have demonstrated the survival benefits of using ACE inhibitors in patients with heart failure associated with left ventricular systolic dysfunction. In addition to inhibiting the conversion of angiotensin I to angiotensin II, ACE inhibitors also decrease the breakdown of bradykinin. Bradykinin, a potent vasodilator, acts by stimulating formation of vasodilatory prostaglandins such as prostacyclin, whereas aspirin or acetyl salicylic acid inhibits the enzyme cyclooxygenase, which in turn decreases the production of the prostaglandins. Coronary artery disease and hypertension are the two major underlying causes of heart failure. Most heart failure patients are also on aspirin. There is evidence that aspirin at a daily dose of 80 to 100 mg prevents the synthesis of thromboxane A2 by platelets while relatively sparing the synthesis of prostacyclin in the vascular endothelium. Aspirin at a daily dose of 325 mg has significant inhibitory effects on the vasodilatory prostacyclin synthesis. Studies have demonstrated that, in heart failure patients, low-dose aspirin has no adverse effect on hemodynamic, neurohumoral, or renal functions. Whether the prostacyclin-inhibiting effects of aspirin attenuate some of the beneficial effects of ACE inhibitors mediated by prostacyclin stimulation in heart failure patients is currently unknown. METHODS: Data from large clinical trials investigating the interaction between aspirin and ACE inhibitors were analyzed to determine the effect of aspirin on the vasodilatory actions of ACE inhibitors in heart failure patients, and the results were analyzed on the basis of theoretical and laboratory findings. The studies included are the Studies of Left Ventricular Dysfunction (SOLVD) (N=6,797), the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) (N=6,090), the Captopril and Thrombolysis Study (CATS) (N=296), and another study involving 317 subjects. The data from these clinical trials investigating the interaction between aspirin and ACE inhibitors included 13,470 subjects. Most of the subjects received aspirin. In the SOLVD study, subjects received aspirin or dipyridamole. Subjects were followed up for an average of about 6 years. RESULTS: In the SOLVD study, subjects were followed up for 41.1 months in the treatment trial and 37.4 months in the prevention trial. Patients who received aspirin or dipyridamole at baseline did not receive the survival benefits of enalapril, whereas patients who received enalapril did not receive the survival benefits of aspirin. In a rather small study of 317 subjects with left ventricular systolic dysfunction (ejection fraction <35%) who were followed up for a relatively longer period of time (5.7 years), the favorable long-term prognosis of patients receiving aspirin was independent of receipt of an ACE inhibitor. A retrospective subgroup analysis of data from the CONSENSUS II study demonstrated that the 6-month mortality rate of patients with acute myocardial infarction (MI) who received enalapril and aspirin was higher than the combined mortality rates of patients receiving enalapril or aspirin alone. This strong interaction between aspirin and the ACE inhibitor enalapril suggests that the survival benefit of enalapril was significantly lower in patients also taking aspirin than in those taking enalapril alone. This interaction was not associated with other nonfatal major events. In the CATS study, use of low-dose aspirin (80 or 100 mg) did not attenuate beneficial effects of captopril (immediate and 1-year follow up) after acute MI. CONCLUSION: There is a theoretical possibility that the negative interaction between ACE inhibitors and aspirin may reduce the beneficial effects of ACE inhibitors in patients with heart failure, but the information obtained from the existing databases is limited by the retrospective nature of the analyses and does not establish the association definitively. Double-blind randomized controlled trials should be conducted to determine whether such a negative interaction indeed exists.     

Renin-angiotensin-aldosterone system blockade and renal protection: angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers?

Renal function is closely associated with cardiovascular risk, to the extent that even minor renal abnormalities, which are present in 10% of the general population, carry a greatly elevated risk of cardiovascular disease, target-organ damage and death. Reducing blood pressure by 20 mmHg or more in patients with severe hypertension (>160/100 mmHg) and advanced renal disease is sufficient to ensure a considerable reduction in proteinuria. In patients with less severe disease, however, blockade of the renin-angiotensin-aldosterone system (RAAS) is necessary to restore normal renal function. Clinical studies have shown that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), which both overcome the activity of angiotensin II, provide renoprotection in diabetics and non-diabetic populations. Which class of drugs is more effective remains a subject of debate, but the evidence favours ARBs for providing more effective renoprotection in patients at risk of diabetic nephropathy. The ARBs preserve renal haemodynamics and reduce progression to end-stage renal disease by around 25% in patients with overt nephropathy and prevent progression to overt disease by up to 70% in patients with mild renal impairment. The combination of ARBs and ACE inhibitors is even more protective, halving the number of patients with progression of renal impairment compared with either monotherapy. Long-term clinical studies now under way will help to establish the relative efficacies of the ARBs and ACE inhibitors and provide greater insight into the benefits of combination therapy.     

Combination pharmacologic therapies for heart failure: What next after angiotensin-converting enzyme inhibitors and beta-blockers?

Although the introduction of angiotensin-converting enzyme (ACE) inhibitors and β-adrenergic blockers has resulted in significant improvements in the management of heart failure (HF), morbidity and mortality remain high. Therefore, additional approaches have been sought to discover newer agents that might add incremental benefit. Although not all of these approaches have been successful, there have been some notable new approaches to therapy that have shown benefit or may be promising in terms of additional benefit. Most of these agents are targeted to achieve a more global neurohormonal blockade aiming to reduce or potentially reverse the ventricular remodeling process that occurs in HF. Some of the newer approaches aim for targets other than neurohormonal systems, eg, effects on myocardial metabolism or the vasculature. This article reviews the latest advances in pharmacologic therapy in HF, looking at several trials that may have a significant impact on the treatment of HF. We also discuss several newer agents with promising potential in HF management.     

Angiotensin II-receptor blockers: will they replace angiotensin-converting enzyme inhibitors in the treatment of hypertension?

In the past few years, angiotensin II-receptor blockers have become available and are being heavily marketed and increasingly used. In various ways they differ from angiotensin-converting enzyme inhibitors (ACEIs). Until outcome data are available, they should continue to be used primarily in patients who should receive an ACEI but cannot tolerate the drug because of cough.     

Ghrelin and peptide YY in youth: are there race-related differences?

OBJECTIVE: Obesity prevalence is higher in African-American (AA) vs. American white (AW) youth. Ghrelin is a "hunger" peptide that is high preprandially and decreases postprandially, and peptide YY (PYY) is a "satiety" hormone increasing after meals. Impaired regulation of ghrelin/PYY may be conducive to obesity. We hypothesized that racial differences in childhood obesity could partly be explained by differences in ghrelin/PYY dynamics. RESEARCH DESIGN AND METHODS: We investigated: 1) ghrelin suppression/PYY elevation in response to an oral glucose tolerance test (OGTT) in AA vs. AW, and 2) the relationship of ghrelin and PYY dynamics to insulin sensitivity. Thirty-three AA and 54 AW prepubertal children underwent an OGTT measuring ghrelin, PYY, glucose, and insulin. Fasting glucose to insulin ratio (G(F)/I(F)) was used to assess the relationship of insulin sensitivity to fasting and post-OGTT ghrelin and PYY levels. RESULTS: OGTT-induced suppression in ghrelin (Delta ghrelin) was lower in AA youth. Delta ghrelin correlated with G(F)/I(F) (r = 0.47, P < 0.001) and Delta insulin at 30 min (r = -0.47, P < 0.001). In multiple regression analysis, race (P = 0.013) and G(F)/I(F) (P = 0.004) contributed independently to the variance in Delta ghrelin (R(2) = 0.28, P < 0.001). Fasting and post-OGTT PYY levels were lower in AAs and were not related to insulin sensitivity. CONCLUSION: The lower suppression of ghrelin in AA, but not the lower PYY levels, correlates with insulinemia and insulin resistance. Less ghrelin suppression and PYY elevation after a meal in black youth could be a potential mechanism of race-related differences in hunger/satiety predisposing to risk of obesity.