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Angiotensin II exerts its action via at least two distinct receptor subtypes designated AT1 and AT2. AT1 receptors seem to be responsible for most of the known angiotensin II effects while the role of AT2 receptors is not yet clear. Adipocytes of adult rats express exclusively the AT1 subtype. Angiotensin II stimulates prostacyclin release in adult rat adipocytes and in mouse preadipocytes. In the latter prostacyclin release is completely blocked by an AT2 receptor antagonist. Adipocyte angiotensin II receptors seem to be regulated by age and fat mass. Blockade of these receptors by an AT1 antagonist seems to prevent adipose tissue hypertrophy. Moreover, adipose tissue contains all the main components of the renin-angiotensin system such as angiotensinogen, angiotensin converting enzyme, angiotensin II and angiotensin II receptors. Angiotensinogen expression in adipocytes is stimulated by a high fat diet concurrent with enlargement of fat mass, associated with insulin resistance. Angiotensin converting enzyme inhibitors improve insulin sensitivity. Taken together, there is evidence of interaction between insulin and angiotensin II in regulation of adipose tissue metabolism and cellularity. Clarification of these interactions could lead to significant progress in pharmacological treatment of obesity and its comorbidity.
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PMID:The role of angiotensin II and its receptors in regulation of adipose tissue metabolism and cellularity. 878 38

The diaphragm is the primary muscle of inspiration, and as such uncompromised function is essential to support the ventilatory and gas exchange demands associated with physical activity. The normal healthy diaphragm may fatigue during intense exercise, and diaphragm function is compromised with aging and obesity. However, more insidiously, respiratory diseases such as emphysema mechanically disadvantage the diaphragm, sometimes leading to muscle failure and death. Based on metabolic considerations, recent evidence suggests that specific regions of the diaphragm may be or may become more susceptible to failure than others. This paper reviews the regional differences in mechanical and metabolic activity within the diaphragm and how such heterogeneities might influence diaphragm function in health and disease. Our objective is to address five principal areas: 1) Regional diaphragm structure and mechanics (GAF). 2) Regional differences in blood flow within the diaphragm (WLS). 3) Structural and functional interrelationships within the diaphragm microcirculation (DCP). 4) Nitric oxide and its vasoactive and contractile influences within the diaphragm (MBR). 5) Metabolic and contractile protein plasticity in the diaphragm (SKP). These topics have been incorporated into three discrete sections: Functional Anatomy and Morphology, Physiology, and Plasticity in Health and Disease. Where pertinent, limitations in our understanding of diaphragm function are addressed along with potential avenues for future research.
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PMID:Diaphragm structure and function in health and disease. 921 1

Hypertensive patients have an excess of other cardiovascular risk factors. Moreover, traditional therapy based on diuretics and beta-blockers may aggravate these risk factors. Therefore, attention must be given to the identification of all pertinent risk factors and their amelioration by appropriate therapy. Such therapy must include lifestyle changes including cessation of smoking, reduction of obesity, moderation of sodium intake and alcohol consumption, and increased physical activity. When antihypertensive drugs are chosen, consideration should be given to their potential influences, either negative or positive, on other cardiovascular risk factors. In particular, the adverse effects of diuretics and beta-blockers on lipids and insulin sensitivity may preclude their use. alpha-Blockers and ACE inhibitors may have beneficial effects on these metabolic indices. Calcium antagonists are neutral in most regards. Whatever agents are chosen, the use of low doses in combination is being increasingly recognized as a better way to achieve the desired antihypertensive efficacy while minimizing adverse effects. As has been noted in the other papers in this supplement, the combination of an ACE inhibitor and a calcium antagonist is particularly attractive, not only to treat hypertension, but also to ameliorate other cardiovascular risk factors.
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PMID:The challenge of managing multiple cardiovascular risk factors. 923 94

In subjects with coronary artery diseases (obstructive and vasospastic angina pectoris (AP)) who have no diabetes, hypertension, obesity and physical inactivity, insulin sensitivity was significantly reduced with compensated hyperinsulinemia on OGTT. Insulin resistance significantly correlated with coronary atherosclerosis score. In vasospastic AP (VAP), those who fulfilled more than 3 risk factors out of 5 (hyperinsulinemia, obesity, glucose intolerance, hypertension, dyslipidemia) consist of 70 and 40% for smokers and nonsmokers respectively. Insulin resistance syndrome who fulfilled all the criteria was 9-10% for VAP. In atherothrombotic brain infarction (ATTI) with the same exclusion criteria, the similar insulin resistance and hyperinsulinemia have been observed, but not in embolic (cardiac origin) or lacunar infarction. In ATTI, high TG and apo B with low HDL-chol were noted in blood. In essential hypertension without diabetes and obesity, hyperinsulinemia was noted in 25-35% and insulin resistance in 56-88%. Reduction of blood pressure with alpha blocker (bunazosin), ACE inhibitor (cilazapril), long-acting Ca++ blocker (amlodipine) significantly improved lowered insulin sensitivity. Insulin resistance rather than hyperinsulinemia is more closely associated with blood pressure. Cardiovascular diseases (vasospastic and obstructive AP, brain cortical artery diseases) are prone to develop diabetes because of insulin resistance and also promote the generation of cumulative risk factors resulting in a vicious cycle. Efforts to alleviate insulin resistance is crucial for the primary and secondary prevention of cardiovascular diseases.
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PMID:Clinical impact of insulin resistance syndrome in cardiovascular diseases and its therapeutic approach. 924 Jul 71

Between January 1990 and May 1995, 117 patients were admitted to the Intensive Care Unit at Holberton Hospital, Antigua, for chest pain due to suspected acute myocardial infarction. 39 (45%) of 86 patients whose records were available for retrospective review had confirmed (27 patients) or probable (12 patients) acute myocardial infarction. Risk factors identified among the patients included hypertension, diabetes, tobacco smoking, hypercholesterolaemia and obesity. On admission, 82% were Killip class I and 18% were Killip class II. Medications in the Intensive Care Unit included nitrates, aspirin, calcium channel blockers, beta-adrenergic blockers, heparin and angiotensin converting enzyme inhibitors (21%). No thrombolytic agents were available. The average hospital stay was 10 days and the in-hospital mortality rate was 13%. These data indicate that early mortality from acute myocardial infarction can be reduced in developing countries by early admission to an Intensive Care Unit and use of drugs known to be effective in its treatment.
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PMID:Myocardial infarction in Antigua. 1990 to 1995. 936 95

There has been increasing interest in the question of whether microalbuminuria can be used in the risk stratification of patients with essential hypertension. A cluster of cardiovascular and/or renal risk factors may be associated with microalbuminuria in hypertension. Despite this, prospective data about the potential role of microalbuminuria as a prognostic marker of cardiovascular and/or renal risk have been sparse and inconclusive until now. Blood pressure values have been considered the most important determinant of microalbuminuria in essential hypertension; however, hyperinsulinaemia--a metabolic component-was noted to be present in conjunction with high blood pressure. Furthermore, 2 other factors may be also related to microalbuminuria: salt sensitivity and renal structural changes (nephrosclerosis). We are now aware that the clinical and physiological implications of abnormal urinary albumin excretion (UAE) are much broader than anticipated, possibly involving haemodynamic, metabolic and vascular components overlapping several clinical syndromes. Achievement of short term UAE reduction with antihypertensive treatment depends on structural abnormalities established in the glomerulus, the extent of blood pressure reduction and the antihypertensive drug class used. In terms of UAE reduction, better results are obtained with ACE inhibitors or angiotensin II antagonists such as losartan and valsartan, than with other antihypertensive classes, although their true impact in preserving renal function needs to be assessed. The capacity of new calcium antagonists, such as amlodipine, lacidipine or mibefradil, to reduce UAE also needs to be assessed further. Thus, microalbuminuria may be seen as an integrated marker of risk and should be assessed in recently diagnosed patients with essential hypertension. In microalbuminuric patients, the target should be to decrease blood pressure < 135/85 mm Hg, reduce salt intake to around 100 mmol/day and prescribe a low-calorie diet if obesity is present. ACE inhibitors or angiotensin II antagonists have more potential benefits than the other classes of antihypertensive drugs in reducing UAE. Finally, a yearly assessment of microalbuminuria is recommended during treatment, to monitor the impact of therapy.
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PMID:Treatment of patients with essential hypertension and microalbuminuria. 942 93

The prevention of coronary artery disease is based on the control of several factors associated with a disease or clinical condition and suspected to play a pathogenetic role, defined as 'risk factors'. Smoking is a powerful risk factor for coronary artery disease, with risk of events increasing in relation to the number of cigarettes smoked daily. Smoking cessation is associated within 3-4 years, with a significant reduction in cardiovascular risk. Hyperlipidaemia is a powerful predictor of coronary disease with a strong, independent, continuous and graded positive association between cholesterol levels and risk of coronary events. Several large studies have shown the benefit of cholesterol reduction, and there is clear evidence of the efficacy of statins in the reduction of events in primary and secondary prevention. Hypertension is a significant, strong and independent risk factor for coronary artery disease morbidity and mortality and the reduction of events and mortality by antihypertensive treatment is well documented. Obesity is associated with an increase in all-cause mortality and cardiovascular mortality, with a particularly high risk for subjects with central obesity. Central obesity is also part of the so-called 'metabolic X syndrome' including insulin resistance, which appears to be associated with a particularly high risk of coronary artery disease. Type 1 and type 2 diabetes mellitus are associated with an increased risk of cardiovascular disease, especially in women. Several studies have shown that good metabolic control and multifactorial risk factor reduction significantly lower the coronary risk in these patients. Recent evidence is accumulating that some clotting factors (fibrinogen, factor VII, von Willebrand factor) and fibrinolytic factors (t-PA and PAI-1) are associated with an increased risk of coronary artery disease. The European Concerted Action on Thrombosis (ECAT) showed that the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent coronary syndromes in patients with angina pectoris, and that low fibrinogen is associated with a low risk of events despite high cholesterol levels. Post-menopausal status is associated with increased risk of coronary artery disease, particularly when menopause is premature (before the age of 45) or abrupt (surgical). There is strong, thought not yet completely definite evidence that post-menopausal hormone replacement therapy may significantly reduce the risk of events and improve survival. Hyperhomocysteinaemia is an emerging risk factor independently associated with an increased risk of coronary artery disease, cerebral vascular disease, and peripheral vascular disease. The administration of vitamin B6, B12 or folate seems to be useful and is currently under further evaluation. Recently, attention has been focused on the correlation between coronary artery disease and genetic factors, such as ACE gene polymorphism or the gene polymorphism for the IIIa-moiety of the platelet fibrinogen receptor IIb-IIIa. In primary prevention, control of the major risk factors mainly in patients with clustered factors will substantially reduce the risk of ischaemic events. Secondary prevention of CHD is based on: aggressive behavioural advice, blood pressure reduction in hypertensives, good metabolic control of diabetes, and cholesterol reduction. Aspirin, beta-blockers, ACE inhibitors, and oral anticoagulants, may be useful in selected patients.
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PMID:Classical risk factors and emerging elements in the risk profile for coronary artery disease. 951 44

OBESITY AND RISK OF MORBIDITY: Obesity is becoming an increasingly important factor in the pathogenesis of hypertension, dyslipidemia and diabetes, which together with hyperinsulinemia comprise the deadly quartet of the insulin resistance syndrome. Obesity in the absence of these other factors is only a minor risk factor, but most obesity is accompanied by one or more of these, worsening the prognosis. The presence of obesity complicates the management of hypertension, probably in large part because of the concomitant insulin resistance which adds to the pathogenetic mechanisms and subtracts from the therapeutic efficacy of many antihypertensive regimens. Unfortunately, some of the agents used to reduce obesity may further aggravate the problem through their stimulation of sympathetic nervous activity. Nonetheless, in the treatment of hypertension in most obese patients who have relatively little excess risk, attempts to reduce body weight should be attempted first, through sensible dietary restrictions, increased aerobic exercise and judicious use of non-hypertensinogenic appetite suppressants. Thereby, additional motivation to lose weight may be provided by the potential of escaping or at least delaying antihypertensive drug therapy. TREATMENT OF HIGHER-RISK OBESE INDIVIDUALS: Those obese hypertensive individuals at greater risk should be immediately started on antihypertensive drug therapy along with attempts to reduce the obesity. The choice of initial and subsequent therapy should take the patient's individual needs into account. For those with dyslipidemia or diabetes, diuretics and beta-blockers should be avoided unless there are specific indications for their use (e.g. reactive sodium retention or postmyocardial infarction). In such patients, an alpha-blocker, an angiotensin converting enzyme inhibitor or a calcium antagonist may be more appropriate. If the first drug is not sufficient, combination therapy should be considered. A diuretic may be needed to overcome reactive sodium retention. Because most obese hypertensive individuals will not be able to lose much weight, effective antihypertensive drug therapy will usually be indicated.
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PMID:Obesity in hypertension: effects on prognosis and treatment. 953 95

LVH AND RISK: Left ventricular hypertrophy (LVH) is a powerful predictor of cardiovascular morbidity and mortality, independent from blood pressure and other cardiovascular risk factors. Available data indicate that patients who fail to achieve a reduction in LVH are much more likely to suffer cardiovascular events than those in whom LVH is reduced or even normalized using antihypertensive treatment. Reversal of LVH, therefore, represents a major goal in the treatment of hypertensive patients. REGRESSION OF LVH: Since obesity and dietary sodium intake may modulate the degree of LVH, non-pharmacological intervention has achieved a successful reduction in left ventricular mass (LVM). LVM is more closely related to 24-h blood pressure values than to clinical blood pressure values. Recent evidence from the Study on Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation has shown that the regression of cardiac hypertrophy is predicted to a greater degree by the effect of antihypertensive treatment on 24-h average blood pressure than by that on clinic or home blood pressure. The increase in blood pressure variability may also be an independent determinant of cardiovascular target-organ damage, particularly of cardiac hypertrophy. However, the effects of antihypertensive drugs on blood pressure variability can be difficult to determine, mainly because a correct measurement of variability requires a beat-to-beat measurement of ambulatory blood pressure; several measures have been proposed to evaluate the smoothness of blood pressure control during antihypertensive treatment. Other important determinants of LVH reduction are represented by baseline values of LVM, extent of blood pressure reduction and duration of treatment. Furthermore, the degree of cardiac hypertrophy reduction is not the same for the different classes of antihypertensive drugs because, beyond the control of blood pressure, they may interfere differently with several non-haemodynamic stimuli, including the renin-angiotensin-aldosterone and the adrenergic systems or other growth factors. A more pronounced reduction in LVM with angiotensin converting enzyme inhibitors and calcium antagonists has been demonstrated in several recent meta-analyses. The results of further multicenter on-going trials are awaited to evaluate definitely whether various antihypertensive strategies differ in their ability to reverse LVH and to adequately assess the relationship between changes in LVM and subsequent prognosis, with serial control of blood pressure values measured in the clinic and by ambulatory monitoring.
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PMID:Left ventricular hypertrophy: how to influence an important risk factor in hypertension. 953 98

Two developments in molecular genetics will profoundly influence our understanding and the diagnosis of cardiovascular disorders. First, the identification of genes responsible for monogenic and polygenic traits by analysis of e.g. large pedigrees and affected sib pairs provides invaluable data regarding the role of specific genes in common diseases like arteriosclerosis, hypertension, diabetes, thrombosis/hemostasis and obesity. Besides the insights into the underlying pathophysiology, this knowledge will permit to identify persons at high risk for disease development. These patients can then obtain a targeted intervention. The second development is related to the availability of new analytical tools for molecular biology. New methods such as sequencing by hybridisation (SBH), DNA-array technology or matrix assisted laser desorption/ionisation-time of flight mass spectroscopy (MALDI-TOF) permit sequence analysis of complete genes within hours. Automated PCR-technologies with homogenous amplicon detection formats simplify PCR and permit its use in the routine laboratory setting. Considering cardiovascular diseases there is a number of genes involved in lipid metabolism (apolipoproteins, lipoprotein receptors, lipolytic enzymes), thrombosis/hemostasis (platelet receptors, pro- and anticoagulant proteins, fibrinogen, PAI's), hypertension (angiotensin converting enzyme, angiotensinogen) glucose metabolism (glucose transporters, enzymes) and obesity (hormones, receptors), that are interesting candidates for sophisticated genetic risk assessment. Furthermore, there are also gene candidates involved in processes of early atherogenesis and chronic inflammation such as complement proteins, cell adhesion molecules, and cellular receptors and enzymes. Most of these gene candidates were derived from pathophysiologic knowledge and subsequent epidemiological studies. However, it is foreseeable that in the coming years genes will be identified which were not known so far to be involved in cardiovascular diseases. Genetic studies will be of prime importance in this area, as is exemplified by animal models. In the long term, analysis of these candidate genes before the implementation of therapy will permit a targeted intervention approach towards high risk patients. This will reduce the overall costs of health care without reducing the quality.
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PMID:Recent advances in molecular genetics of cardiovascular disorders. Implications for atherosclerosis and diseases of cellular lipid metabolism. 965 2


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