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Recent international guidelines on the detection, clinical assessment and management of patients with hypertension have highlighted a number of themes that should be incorporated into routine clinical practice. First, although antihypertensive therapy is having a major impact on reducing the incidence of coronary heart disease, cerebrovascular disease and heart failure, community surveys show that most hypertensive patients remain untreated or have suboptimal blood pressure control. Second, the guidelines have emphasised the importance of making an overall assessment of individual patients to gauge their absolute risk of a cardiovascular event; risk factors include not only blood pressure but also target organ damage, the presence of coexisting symptomatic vascular disease and the number of associated cardiovascular risk factors. Patients at the highest risk, especially those with diabetes, the elderly and patients with target organ damage, merit vigorous antihypertensive therapy, and such patients often require treatment with more than one drug to achieve target levels of blood pressure (< 135/80 mm Hg). An additional important theme in recent guidelines has been a move towards using lower dosages and therapies that provide 24-hour blood pressure control with once-daily administration. Since diuretics have been reaffirmed as evidence-based first-line therapy in a broad spectrum of patients with hypertension, especially the elderly, a new lower dosage sustained release formulation of indapamide has been developed (indapamide SR 1.5 mg). Recent multicentre European clinical trials have defined the efficacy and tolerability of indapamide SR 1.5 mg, both relative to other antihypertensive drugs and in key subgroups of patients. Indapamide SR 1.5 mg has an antihypertensive effect, maintained throughout the 24-hour administration interval, equivalent to that of immediate release indapamide 2.5 mg, but the new formulation has even less effect on circulating K+ levels. Indapamide SR 1.5 mg is at least as effective as amlodipine or hydrochlorothiazide. In patients with left ventricular hypertrophy (LVH), a comparative study of indapamide SR 1.5 mg and enalapril (the LIVE study) used a rigorous unique study design with blinded reading of echocardiograms to show that after 1 year the ACE inhibitor had no significant effect on LVH regression, whereas indapamide SR 1.5 mg produced significant reductions in left ventricular mass index. Diuretic-based therapy for hypertension has been reaffirmed in international guidelines as effective first-line therapy, especially in the elderly and patients with LVH. Indapamide SR 1.5 mg shows an improved efficacy-tolerability profile, with impressive 24-hour effects on blood pressure, important ancillary properties with regard to LVH and cardiovascular protection.
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PMID:Clinical implications of indapamide sustained release 1.5 mg in hypertension. 1049 30

Primary pulmonary hypertension (PPH) is a pulmonary vascular disease characterized by an elevation in mean pulmonary artery pressure and pulmonary vascular resistance. Recently, PPH gained national attention because of its association with appetite suppressants. PPH may also be associated with pregnancy, hypothyroidism, autoimmune disorders, human immunodeficiency virus infection, and the use of drugs such as oral contraceptives and cocaine. Patients with PPH may report dyspnea on exertion and fatigue. Early diagnosis is crucial. New therapeutic regimens have dramatically reduced mortality rates and improved quality of life by halting the progression of pulmonary vascular remodeling and averting right-sided heart failure. These therapies include high-dose calcium channel antagonists, anticoagulants, and continuous intravenous prostacyclin. Lung or heart-lung transplantation remains a viable therapeutic option for patients who are treated late in the disease process, who are not responsive to medical management, or who remain symptomatic and continue to deteriorate.
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PMID:Diagnosing and treating primary pulmonary hypertension. 1050 69

The renin-angiotensin system (RAS) is a widely studied hormonal system that comprises substrate-enzyme interactions, the end result of which is production of the active peptide angiotensin II (Ang II). Because Ang II affects blood pressure control, sodium and water homeostasis, and cardiovascular function and structure, a great deal of research effort has been directed toward blocking the RAS. Angiotensin II may also be involved in end-organ damage in hypertension, heart failure, and vascular disease. At least two subtypes of angiotensin II receptors have been identified: AT1 and AT2. The AT1 mediates all of the known actions of Ang II on blood pressure control. Additionally, research has indicated that the AT1 receptor modulates cardiac contractility and glomerular filtration, and increases renal tubular sodium reabsorption, and cardiac and vascular hypertrophy. Less is known regarding the function of the AT2 receptor. Evidence suggests that the AT2 receptor inhibits cell proliferation and reverses AT1-induced hypertrophy. Indeed, these receptors are thought to exert opposing effects. Angiotensin II AT1 receptor antagonists (AT1RA) inhibit the RAS at the receptor level by specifically blocking the AT1 receptor subtype. These drugs induce a dose-dependent blockade of Ang II effects, resulting in reduced blood pressure, urinary protein, and glomerular sclerosis. It is postulated that AT1RA may provide end-organ protection by blocking Ang II effects via the AT1 receptor, yet leaving the AT2 receptor unopposed. Consequently, these agents may reduce the morbidity and mortality that result from myocardial infarction (MI) and other conditions resulting from structural alterations in the heart, kidney, and vasculature.
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PMID:Angiotensin II receptor blockade and end-organ protection. 1061 95

After a slow start, beta-blockers have become widely used as first-line agents in the treatment of hypertension, and recommended as such in recently published guidelines. There is evidence that the beta1-selective agents are more efficacious than non-selective blockers that inhibit both beta1 and beta2 receptors. Notwithstanding some earlier evidence to the contrary, it appears that beta1-selective drugs are equi-effective in young and elderly whites, younger, ie, under mid 60s, blacks. It is with the combination of age and being black that beta-blockers are usually less useful than some other groups of antihypertensive drugs, most notably calcium antagonists and diuretics. Primary prevention studies indicate beta-blockers reduce the incidence of cerebro-vascular disease and coronary heart disease in younger patients but they appear less effective than diuretics in the elderly. Beta-blockers are particularly indicated in patients who have experienced a myocardial infarction where they are often under used. There is some evidence that even in post-infarction patients with co-existent chronic obstructive airways disease, usually regarded as a contra-indication, experience an improved 2-year survival with the use of beta-blockers. Recently they have also been demonstrated to improve prognosis in heart failure patients, previously regarded as a contra-indication. Likewise, recent studies have shown that atenolol was at least as effective as captopril in improving the outlook in hypertensive patients with non-insulin dependent diabetes. While earlier comparisons with the non-selective lipid soluble propranolol indicated otherwise, comparisons with beta1-selective agents have indicated a similar effect on quality of life assessments with angiotensin-converting enzyme inhibitors.
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PMID:New approaches to the uses of beta blocking drugs in hypertension. 1085 83

It has been reported that some natural catastrophes increase morbidity rates for illness. In this study, we investigated the impact of the 1995 Hanshin-Awaji earthquake on morbidity rates for various illnesses by analysis for correlations between the extent of damage due to the earthquake and occurrences of various illnesses. We searched the medical records of 1948 patients hospitalized due to illness in 48 hospitals during the first 15 days after the earthquake. In each of 14 affected areas, the hospital admission rate and estimated morbidity ratio for each illness were calculated. Destruction ratios were determined based upon the number of dwellings completely destroyed in each area. For total illnesses and each major illness, linear regression analyses were performed comparing hospital admission rates, estimated morbidity ratios, and destruction ratios. Hospital admission rates and estimated morbidity ratios among the 1948 patients were significantly correlated to destruction ratios. With pneumonia, dehydration, acute heart failure, asthmatic attack, and peptic ulcer, hospital admission rates and estimated morbidity ratios were significantly related to destruction ratios, while no significant correlations between estimated morbidity ratios and destruction ratios existed for cerebral vascular disease or ischemic heart disease. Peptic ulcer and pneumonia showed especially high correlation values (age- and sex-adjusted R2>0.7). The present study revealed a strong link between the extent of damage due to the catastrophic earthquake and an increase in morbidity rates for acute illnesses, especially peptic ulcer and pneumonia.
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PMID:The impact of a catastrophic earthquake on morbidity rates for various illnesses. 1096 85

Atherosclerotic renal artery stenosis typically occurs in high-risk patients with coexistent vascular disease elsewhere. Patients with atherosclerotic renal artery stenosis may develop progressive renal failure but have a much higher risk of dying of stroke or myocardial infarction than of progressing to endstage renal disease. Recent controlled trials comparing medication to revascularization have shown that only a minority of such patients can expect hypertension cure, whereas trials designed to document the ability of revascularization to prevent progressive renal failure are not yet available. Revascularization should be undertaken in patients with atherosclerotic renal artery stenosis and resistant hypertension or heart failure, and probably in those with rapidly deteriorating renal function or an increase in plasma creatinine levels during angiotensin converting enzyme inhibition. With or without revascularization, medical therapy using antihypertensive agents, statins, and aspirin is necessary in almost all cases.
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PMID:Atherosclerotic renal artery stenosis: surgery, percutaneous transluminal angioplasty, or medical therapy? 1099 25

Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor beta (TGF-beta) cell-signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.
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PMID:BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. 1111 78

There are no clear data regarding whether to use warfarin, aspirin, or no therapy in patients with left ventricular systolic dysfunction. Aspirin use is widespread in patients with vascular disease but it can decrease renal blood flow in low output states. Warfarin may be used in patients with advancing heart failure due to the perceived risk of in situ thromboembolism. However, we know that ejection fraction and symptom class do not always match and that the regulation of warfarin dosing is more difficult in worsening heart failure. Drug use must be individualized, based on knowledge of underlying heart failure etiology, functional class, drug side effects, and renal function. We await ongoing studies to elucidate the differential effects of these drugs on global outcome as well as on the mechanisms by which they achieve their results.
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PMID:Anticoagulation and heart failure. 1113 2

National and international societies have issued guidelines on the management of heart failure: The European Society of Cardiology, WHO, ACC/AHA Task Force Report, US Department of Health and Human Services, German Society of Cardiology. The therapeutic approaches to heart failure have undergone considerable changes during the last few years. The guidelines have to be updated almost yearly due to new results from prospective randomized studies. Although an agreement could be reached with respect to general measures and drug treatment, no agreement on mechanical devices, pacemakers and surgical interventions has been reached. The basis for medical treatment of chronic heart failure depends on diuretics, digitalis, ACE inhibitors, and beta-blockers. Calcium antagonists and other positive inotropic drugs, other than digitalis, should be avoided as far as possible. Thiazides, loop diuretics and aldosterone antagonists are needed for acute and chronic treatment of heart failure, alone or in combination (diuretic resistant heart failure!). Digitalis glycosides are needed in patients with atrial fibrillation with a fast ventricular rate or atrial flutter and in patients with systolic dysfunction, large hearts and symptomatic failure class NYHA III and IV. However, digitalis does not convert atrial fibrillation to sinus rhythm. Today there is no question that ACE inhibitors improve the prognosis of all patients with heart failure in all stages, if ejection fraction is reduced. Therefore, most patients after myocardial infarction or after having experienced pump failure due to myocarditis or cardiomyopathy are treated with ACE inhibitors and diuretics. The beneficial effects of ACE inhibitors seem to be most pronounced the worse the situation is. Relative risk reductions (mortality!) between 10% and 40% have been published depending on the severity of symptomatic left ventricular dysfunction. Those patients with high absolute risk have more to gain than those with low risk for any given "risk reduction", of course. Recent studies also indicate that most high risk cardiac patients profit from ACE inhibitors even if pump function is normal (i.e., patients with coronary heart disease, diabetes mellitus, cerebral vascular disease, hypertension) (15). AT1 antagonists can substitute for ACE inhibitors, if the latter are not tolerated due to cough. Up to now, beta-blocking agents apart from diuretics seem to be the best investigated drugs in heart failure. Large controlled studies with bisoprolol, carvedilol and metoprolol in addition to diuretics, digitalis and ACE inhibitors convincingly yielded positive results in chronic left ventricular failure patients. Reduction of mortality by 35% and even of sudden cardiac deaths by 40% have been proven beyond doubt. Thus, heart failure patients today should also receive beta-blocking agents in all stages of the disease. In the era of controlled prospective studies (evidence-based medicine), physicians are well advised to use only drugs that have been proven beneficial in large controlled studies.
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PMID:The management of heart failure--an overview. 1119 49

The increased cardiovascular morbidity and mortality in hypertension are related to the target organs (ie, heart, brain, kidneys) involvement from vascular disease. Left ventricular hypertrophy (LVH), the major expression of cardiac involvement, is both a structural and functional adaptation to the afterload imposed by the vascular disease. Without this adaptation, cardiac failure would result much earlier in the natural history of hypertensive heart disease (HHD). However, LVH imposes an independent risk that is even greater than the risk associated with the height of systolic or diastolic pressure. The mechanisms that explain this risk have not been defined precisely; several have been postulated. Among these are the following: 1) coronary hemodynamic alterations associated with HHD (ie, increased coronary vascular and minimal vascular resistance, reduced coronary blood flow and flow reserve, and increased blood viscosity); 2) enhanced predisposition for lethal cardiac arrhythmias, cardiac failure, and accelerated atherosclerosis of the coronary arteries (with exacerbation of the ischemia); and 3) collagen deposition and ventricular fibrosis. From the earliest controlled therapeutic trials, deaths from stroke and coronary heart disease were significantly reduced. However, more recent data have indicated that the prevalence of cardiac failure (CHF) continues to rise progressively. The nature of the CHF is no longer primarily from systolic dysfunction, but is now chiefly from diastolic dysfunction. Diastolic dysfunction occurs primarily in the elderly hypertensive patient or in the patient with ischemic heart disease, both of which are associated with increased collagen deposition. Indeed, these effects continue to be suggested by the data from the Framingham Heart Study as well as NHANES-III that indicate CHF is the most common diagnosis occurring in hospitalized patients over 65 years of age. In this report, both experimental and clinical evidence demonstrating that increased ventricular fibrosis occurs in the spontaneously hypertensive rats and in hypertensive patients are provided, and that treatment with the newer antihypertensive agents reduce ventricular hydroxyproline (ie, collagen) content while, at the same time, improve coronary hemodynamics.
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PMID:Fibrosis and ischemia: the real risks in hypertensive heart disease. 1141 56


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