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NONPHARMACOLOGIC APPROACHES TO HYPERTENSION
ESSENTIAL HYPERTENSION, PART I1
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NONPHARMACOLOGIC APPROACHES TO HYPERTENSION Weight, Sodium, Alcohol, Exercise, and Tobacco Considerations Efrain Reisin, MD
Several lifestyle modifications have been proposed as effective treatments for hypertension, and to date, one international and five national committees have issued recommendations on such treatment measures. These include weight reduction, salt and alcohol restriction, increased physical activity, and smoking cessation (Table 1).66Some of these nonpharmacologic approaches may control blood pressure without the concomitant use of antihypertensive^^^; they may reduce the frequency or or they may improve dosage levels of antihypertensive medicati~nsl~; cardiovascular morbidity and mortality. This article reviews the mechanisms that link obesity, increased salt or alcohol consumption, and smoking with hypertension. Also described are the changes that may occur in these mechanisms and in blood pressure levels when nonpharmacologic approaches, including exercise, are employed to treat hypertension.
From the Section of Nephrology, Department of Medicine, Louisiana State University School of Medicine, New Orleans, Louisiana
MEDICAL CLINICS OF NORTH AMERICA VOLUME 81 * NUMBER 6 * NOVEMBER 1997
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Table 1. NONPHARMACEUTICAL APPROACHES TO ANTIHYPERTENSIVE THERAPY Modalities Weight reduction
Salt restriction Decreased alcohol intake Endurance exercise
Smoking cessation
Mechanism of Action on Blood Pressure Improved insulin sensitivity; diminished sympathetic activity, plasma renin activity, and aldosterone; reverse hemodynamic alterations and left ventricular hypertrophy In salt-sensitive individuals, decreased reactivity of the reninangiotensin-aldosterone system Remains unclear but appears to be independent of changes in weight or salt intake Decreases cardiac output and vascular responsiveness to a-adrenergic receptors; may also reduce plasma renin activity and catecholamine levels Long-term cessation has no longterm favorable effects on blood pressure
Recommendation Weight loss of at least 10 kg
Salt intake of no more than 6 g daily, only in salt-sensitive patients Decrease alcohol intake to no more than 3 drinks (30 mL) daily Exercise 3-5 times weekly, for 30-45 minutes each session, at a level of perceived exertion with no distress May be indicated only to decrease premature cardiovascular morbidity and mortality
OBESITY AND HYPERTENSION
Several epidemiologic studies have linked obesity and hypertension, regardless of race or 86 and longitudinal studiesz9, 47 have described an increased prevalence of hypertension as weight and age increase. Various mechanisms have been suggested as explanations for the association between obesity and hypertension, among them dysregulation of the endocrine-metabolic systems and alterations in the fluid volume distribution with hemodynamic changes and cardiac morphologic alteration^.^^, 72 Some researchers consider insulin resistance and the consequent hyperinsulinemia to be the initial trigger in obesity-hyperten~ion.~~, 31, 44 however, cast some doubts about the long-term effect of hyperinsulinemia on hypertension because hypertension did not develop in obese dogs with chronic hyperins~linemia.~~ If insulin resistance is not an initial trigger of hypertension, it may nonetheless be related to other metabolic-endocrine associations with obesity-hyperten~ion.~~ For example, overfeeding may cause increased sympathetic activity and may enhance the aldosterone-to-plasma renin activity ratio-changes that may induce sodium and water retention.28Additionally the decreased
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Na +,K+-ATPase activity described in obese hypertensive patients may increase intracellular sodium content and decrease calcium efflux. These changes increase intracellular calcium concentration, smooth muscle tone, and vascular resistance.z,16,40 The author and other investigators', 3, 53, 69 have studied the hemodynamic characteristics and the cardiovascular adaptations that followed weight gain. The plasma and total blood volumes in obese hypertensive patients, compared with those in normotensive subjects, have been reported to increase when absolute values were ~ o n s i d e r e dFrohlich .~~ and colleaguesz2believe that this absolute increase in intravascular volume in obese hypertensives is the actual volume pumped by the heart; when redistributed centrally to the cardiopulmonary area, that volume increases venous return and cardiac output. Hypertension develops if systemic vascular resistance fails to decrease as cardiac output inand have shown that total peripheral c r e a s e ~ Messerli .~~ resistance was inappropriately normal in obese hypertensives compared with lean hypertensives. Using echocardiographic techniques in obese hypertensives, they also found an increase in left atrial, left ventricular, and aortic root diameters as well as in posterior wall and septa1 wall thickness and left ventricular mass.54These changes cause cardiac enlargement and impairment of left ventricular filling.55The myocardium adapts to chamber dilation by adding contractile elements in series'O and thickens as a result of the increased afterload by adding contractile elements in paralleLZ1This process results in the eccentric-concentric left ventricular hypertrophy that characterizes obesity-hyperten~ion.~~ The combined hemodynamic alterations of obesity and hypertension increase the risk of congestive heart failure.22 Effects of Weight Reduction
Numerous studies have demonstrated the positive effects of weight 69, 87 In the first study reduction on the management of hypertensi~n.~~, in which salt intake was not the author and colleagues reduced blood pressure to normal levels in 75% of the obese hypertensive patients treated with only a hypocaloric diet; their average weight loss was 10 kg. In a long-term follow-up (12 months) of the same 52% of those who had maintained their weight reduction also had systolic and diastolic blood pressure measurements under or equal to 140 mm Hg and 90 mm Hg. Investigators in the Dietary Intervention Study in Hypertension (DISH)&summarized their experience with obese hypertensives who were taken off their antihypertensive medications but encouraged to reduce their weight or to follow a sodium-restricted obese hypertensives remained normotendiet; in that study, 60% of
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sive without antihypertensive medications when they lost an average of 4.5 kg. In the same study, 46% of the patients remained normotensive when daily sodium intake was reduced to 40 mEq/day. The changes in blood pressure apparently followed a floor effect, or a degree of weight loss beyond which further reduction in blood pressure did not occur." The Trial of Antihypertensive Interventions and Management (TAIM) research a large cooperative intervention, compared the effect of weight loss to the effect of placebo, chlorthalidone (25 mg/ day), or propranolol (50 mg/day) treatments; by the end of the followup period, the investigators found that compared with the effects of placebo and the two antihypertensives, weight loss enhanced blood pressure control by 23%. Other investigators have shown that weight loss successfully reduced blood pressure and that when weight loss was added to the antihypertensive regimen blood pressure was better controlled in those patients who met the body mass index goal than it was in those who did not (95% versus 20%).15 Weight loss has reversed some of the previously discussed metabolic-endocrine-hemodynamicmechanisms that induce obesity-hypertension (Fig. l).67 For example, weight loss returned insulin levels to normal fasting levels and improved insulin sensitivity as a result of an apparent increase in the number of insulin-binding receptors in the
Weight Reduction Decreased lntravascular and Cardiopulmonary Blood Volume
Decreased Hyperinsulinemia
Decreased Cadiac Output
Decreased Adrenergic Activity
Alteration in Na+-K+and Ca++ lntracellular Distribution
/
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Muscle lone and Vascular Resistance
Figure 1. Physiologic changes induced by weight reductions. (Adapted from Reisin E: Obesity hypertension: non-pharmacologic and pharmacologic therapeutic modalities. In Laragh JH, Brenner BM (eds): Hypertension: Pathophysiology, Diagnosis, and Management, ed 2. New York, Raven Press, 1995, p 2688; with permission.)
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target cells.67Levels of plasma norepinephrine also have been shown to drop after weight reduction, a change explained as one based on diminished sympathetic nervous system 85 Weight loss also may decrease plasma renin activity and aldosterone, changes that may be mediated by decreased sympathetic activity or by changes in the plasma renin Previous studies have reported the effects of a lowcalorie diet on Na+,K+-ATPaseactivity, with different res~lts,8~ but a more recent study showed a decrease in free cytolytic platelet calcium levels associated with reduction in forearm resistance and a consequent increase in blood The author and colleagues have shown that following a weight reduction of 10 kg, obese hypertensives experienced a statistically significant reduction in intravascular and cardiopulmonary volume when absolute values were ~onsidered.~", 71 Hemodynamic studies performed after weight loss of 10 kg have shown a reduction in oxygen consumption, cardiac output, and left ventricular stroke work without changes in peripheral resistance-changes that suggest improved cardiac function.67 Echocardiographic studies after weight loss have demonstrated a decrease in intraventricular, septal, posterior wall thickness, and left ventricular mass, but only the decrease in left ventricular hypertrophy was correlated with the decrease in systolic blood pressure.52 Appetite Suppressants and Hypertension
A major problem for obese hypertensives is dietary noncomplian~e,6~, 72 and because a large number of prescribed or over-the-counter appetite suppressants are used as adjunct treatment in obese subjects, the mechanisms of action and the effect on blood pressure of some of these medications are discussed briefly. Pharmacologic agents may affect the process of satiation (control of meal size) and satiety (control of postmeal interval^).^ Certain serotonergic agents may function as important satiety agents by antagonizing the consumption of fat, thereby causing selective avoidance of fat and reducing daily lipid b1take.4~ 93 seem to act in this way; both Fenfluramine and dexfenfl~ramine~~, drugs reduce food intake and increase satiety. Phente~mine~~ appears to suppress appetite through noradrenergic and dopaminergic mechanisms that may work in external areas of the hypothalamus to delay the onset of eating. A long-term follow-up (up to 4 years) using fenfluramine and phentermine in obese normotensive subjects demonstrated a statistically significant fall in systolic blood pressure without a change in heart rate. The positive effect on blood pressure in this study, however, was attributed to improved lifestyle factors, such as exercise, stress
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management, and weight In a 6-month follow-up treatment of obesity with dexfenfluramine, O’Connor and c011eagues~~ showed a significant decrease in systolic and diastolic blood pressure, a change related to lower insulin sensitivity and noradrenergic activity that may not be related to weight reduction. Some appetite suppressants may be viable adjunct pharmacotherapy for obesity and apparently are safe for hypertensive subjects, but additional long-term cooperative studies are necessary to support their safety and efficacy. SALT INTAKE AND HYPERTENSION
Earlier studies of large populations have shown a direct relationship between sodium consumption and the prevalence of hypertension as well as a low incidence of hypertension in populations with a low salt h1take.4~. Some of these studies, however, have been conducted on primitive societies and criticized for their failure to consider that such populations may be exposed to less stress and also may have lower incidences of obesity.82Today, clinicians are more inclined to -believe that patients with essential hypertension may be classified as salt sensitive and salt resistant, based on the absolute changes in arterial pressure that originate from dietary salt intake.34In a previous study, Weinberger and colleagues92showed that 51% of the hypertensive participants were salt sensitive, as a result, perhaps, of alterations in electrolyte transport across cell membranes and the concomitant alteration in intracellular concentrations of sodium and increased sympathetic activity; both alterations may have a genetic basis.6 The deficit in sodium ion transport across cell membranes (demonstrated in red blood cells) in patients with essential hypertension or in normotensive subjects with a family history of hypertension may alter the calcium/sodium ion exchange across vascular smooth muscle membrane.6These changes increase the concentration of calcium ions, which may increase vascular wall tension and smooth muscle contractibility, thereby increasing blood pressure.65 According to some investigators, changes in sodium excretion at tubular levels that are genetic in origin cause sodium and water retention, increase blood volume, and cause hemodynamic changes that may trigger hypertension? The increased sympathetic activity that may be induced by increased salt intake enhances vasoconstrictor tone and induces hyperten~ion.~~ Other studies have shown that a high salt intake in salt-sensitive individuals interacts with the renin-angiotensin system in the insulin-resistant state, changes that may increase systolic and glomerular capillary pressure.95Salt sensitivity predisposes individuals to renal injury, target organ damage that is common in hypertensive
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salt-sensitive individual^.^^ These patients also experience a higher incidence of left ventricular hypertrophy and cardiovascular complications than do non-salt-sensitive individual^.^
Effects of Salt Restriction
Population studies show poor adherence to sodium restriction," and some investigators have concluded that it has not been helpful in reducing either blood pressure25or the cardiovascular risks of hyperten~ i o nMacGregor .~ and co-workers,5°however, demonstrated that a reduction to 80 mmol of salt daily resulted in a significant drop (7 mm Hg) in mean blood pressure; the DISH study15 mentioned earlier demonstrated that when salt intake was reduced to 40 mmol daily, 46% of the patients remained normotensive. Compared with non-salt-sensitive individuals, salt-sensitive subjects had a better response or were the only responders to a low-salt diet.67Accordingly, some concern that salt restriction in non-salt-sensitive patients may have deleterious effects (an increase in serum creatinine, uric acid, and serum insulin and adverse alterations in serum lipids) exist^.^ A 6-month follow-up of hypertensive patients on a salt-restricted dieP9 demonstrated that restricted sodium intake did not show that systemic hemodynamic changes correlated with the drop in blood pressure. A low-sodium diet in salt-sensitive subjects induced lower plasma renin and aldosterone concentrations than it did in non-salt-sensitive individual^.^^
ALCOHOL INTAKE AND HYPERTENSION
Systolic and diastolic blood pressures are significantly related to alcohol intake and to drinking 39 and blood pressure levels were higher in subjects who drank daily than they were in those who drank heavily only on weekends.79Intriguing findings from large epidemiologic studies of alcohol intake and blood pressure suggested a Jshaped ass~ciation.~~ In these studies, subjects who reported having fewer than one drink a day had higher systolic and diastolic blood pressure (4 to 8 mm Hg and 3 to 5 mm Hg) than did participants who drank up to three drinks a Additionally, mortality owing to coronary artery disease was 17% lower in those individuals who consumed two to three drinks per day compared with those reporting fewer than one drink daily.I7,38, 51 The protective effects of alcohol may be mediated by the increase in high-density lipoprotein (HDL) cholesterol seen in subjects who drink
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up to three drinks a day74and by the decrease in lipoprotein Lp(a) that accompanies wine consumption.80Other beneficial cardiovascular characteristics described in lighter alcohol drinkers are those that reduce clotting, such as an increase in endogenous tissue plasminogen activator and a decrease in fibrinogen, as well as the antioxidants contained in wine that may protect against atheroma formation.”, 83 Acute alcohol administration raises blood pressure by increasing the discharge rate of the sympathetic vasoconstrictor nerves in the skeletal muscle vasculature. Other related mechanisms may be a direct effect on calcium transport into smooth muscle cells and a depletion of intracellular magnesium, which affects peripheral vasculature tone via vasospasm. Impaired insulin sensitivity was suggested as a causal mechanism of hypertension following acute alcohol intake.37Studies of the mechanisms of increased blood pressure as a result of the long-term consumption of alcohol in humans are lacking, but some of the mechanisms described include increased sympathetic activity, increased reninangiotensin levels, impaired baroreflex activity, impaired insulin sensitivity, magnesium depletion, or a direct effect on peripheral vascular t0ne.3~
Effects of Decreased Alcohol Intake \
In a study conducted over a 3-week period, a reduction in daily alcohol intake by half (from 56 to 26 mL/day) without salt restriction induced statistically significant lower systolic and diastolic pressure (decreases of up to 4.8 and up to 3 mmHg).88A long-term trial (1 year) of heavy drinkers who were encouraged to reduce their daily alcohol intake by 30% to 40% showed a statistically significant fall of 6.8 mm Hg in systolic blood pressure compared with a 4.7 mm Hg drop in the control group ( P <.05).9O The exact mechanisms underlying the drop in blood pressure that follows moderation of alcohol consumption remain unclear but were independent of changes in weight or salt intake. It appears that drinkers of not more than 30 mL of alcohol per day (three drinks) may have lower blood pressure and experience protective effects on cardiovascular morbidity and mortality than do heavy drinkers (more than three drinks daily). EXERCISE AND HYPERTENSION Acute dynamic exercise in normotensive subjects raises systolic blood pressure by 50 to 70 mm Hg, while diastolic blood pressure remains unchanged or decreases by 4 to 8 mm Hg. In hypertensive
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subjects, however, exercise increases systolic blood pressure to levels higher than 200 mm Hg and also increases diastolic blood pressure. This higher pressor response was also reported in normotensive subjects with a family history of hyperten~ion.~~ The elevated blood pressure that accompanies acute dynamic exercise has been attributed to a decrease in vagal tone, followed by an increase in sympathetic activity, heart rate, and stroke volume. The lower diastolic blood pressure in normotensive subjects is caused by peripheral vasodilation and decreased total peripheral resistance. In hypertensive subjects, however, peripheral resistance did not decrease; instead, these individuals responded with increased diastolic blood pressure. This elevated diastolic blood pressure in hypertensives is generally associated with a reduced ejection fraction and coronary artery disease.& Consequently, increased blood pressure induced by exercise is considered a stronger predictor of morbidity and mortality from myocardial infarction than is resting blood pressure, especially in subjects with underlying left ventricular hypertrophy.6*,
Effects of Endurance Exercise Extensive clinical data support the blood pressure-lowering effect of endurance dynamic exercise training in 75% of the patients studied.n In a meta-analysis of 48 investigations comprised chiefly of men, the subjects, aged 16 to 72, undertook heavy-intensity exercise training (i.e., between 50% and 85% of their qaximal exercise capacity) three times weekly for 15 to 90 minutes, for up to 16 months; in these subjects, Fagard19 demonstrated an average drop in systolic and diastolic blood pressure (by 5.3 mm Hg and 4.8 mm Hg). Fagard also noticed major flaws in those studies, however, among them an inadequate number of blind control studies, poor randomization techniques, failure to maintain a stable diet among study subjects, and poor adjustment of results for confounding variables such as concomitant weight loss or sodium restriction. The decrease in blood pressure that occurs with endurance exercise training may be explained by the following hemodynamic mechanisms: decreased stroke volume, cardiac output, and ejection fraction; additionally, fractional fiber shortening was reduced, as was the contractility index?, 36 These changes occurred after a decrease in limb vasculature resistance and lower vascular responsiveness to a-adrenergic receptors.8 Other metabolic changes induced by endurance exercise training are reduced levels of plasma renin activity and catecholamines,18with an increase in an endogenous ouabain-like substance that may enhance urinary sodium excretion by acting as a natriuretic hormone, thus having a favorable effect on blood pressure.35
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Exercise also reduces cardiovascular morbidity by lowering weight, serum cholesterol and triglyceride levels, and platelet aggregation and increasing HDLs and insulin sensitivity.61, An extended exercise program in hypertensive subjects has demonstrated statistically significant decreases in blood pressure, left ventricular mass, mass index, and thickness of intravascular Consequently, endurance exercise appears to be beneficial for hypertensive patients. Because of the previously described flaws in the investigations performed, however, exercise recommendations are still imprecise, and a number of issues remain to be resolved, among them the number of exercise sessions to be recommended per week, the duration and intensity of each session, and the best type of exercise to practice. The best advice currently appears to be to encourage exercise in sedentary hypertensives without serious end organ damage, beginning with low-intensity activity (expressed as a level of perceived exertion with no pain, respiratory distress, or other discomfort) and with a maximal heart rate based on subtracting the patient's age from 220.14 Exercise should be undertaken three to five times weekly for 30 to 45 minutes per session and maintained continuously because its cardiovascular benefits may disappear 2 weeks after cessation of physical a~tivity.'~ SMOKING AND HYPERTENSION Large epidemiologic studiesz4,78 have demonstrated that smokers have lower blood pressure than do nonsmokers, a finding that may stem from the confounding factor of obesity, which is more common in nonsmokers than in smokers. Other investigators have concluded th& nicotine use, alcohol consumption, and a sedentary lifestyle are frequently associated and that these three adverse habits contribute to the clustering of cardiovascular risk factors (i.e., lower HDLs, increased triglyceride levels, and high blood pressure).12 The metabolic and hemodynamic effects of smoking were investigated in subjects who were habitual smokers, and the results showed increased cardiac output, without changes in stroke volume-an effect that may continue for 90 minutes after the individual finished smoking and may be due to local nicotine stimulation of the adrenergic nervous system at the adrenergic axon terminals within the tissue.I3,6o Effects of Smoking Cessation Smoking cessation reduces systolic and diastolic blood pressure for at least 6 hours and decreases serum adrenaline and cortical levels for 6
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weeks?l Long-term cessation (an average of 2.5 years), however, did not change blood pressure levels when the results were adjusted for weight loss (70% of those individuals who quit smoking gained Although smoking cessation does not have a clear-cut long-term favorable effect on blood pressure, it may have positive effects on cardiovascular morbidity and mortality.56Consequently, smoking is still considered the most important preventable cause of premature mortality and morbidity in the United States.20 SUMMARY
Weight loss decreases blood pressure, and this change can be sustained over the long-term when the lower weight is maintained. Salt restriction may be effective in blood pressure control only in salt-sensitive individuals. Heavy drinkers (those who drink more than three drinks [30 mL] daily) experience deleterious effects such as hypertension and more cardiovascular risk factors. Consequently, they should be advised to reduce alcohol intake to less than 30 mL daily. Endurance training with dynamic exercise appears to be beneficial for hypertensive patients, although recommendation guidelines are still imprecise. Finally, smoking cessation has not been proven to decrease blood pressure levels but should nonetheless be recommended because of its favorable effects on cardiovascular morbidity and mortality. ACKNOWLEDGMENT Special thanks to Anne Compliment for her editorial review.
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58. Oparil S Sodium, the nervous system and hypertension. In Hunt JS, Dreihs LS, Dustan HI’, et a1 (eds): Hypertension Update 11: Pathophysiology of Hypertension. Lyndhurst, New Jersey, Health Learning System, 1985, p 15 59. Page LB, Danion A, Moellering RC: Antecedents of cardiovascular disease in six Solomon Island societies. Circulation 49:379, 1975 60. Perkins KA, Sexton JE, DiMarco A, et al: Subjective and cardiovascular response to nicotine combined with alcohol in male and female smokers. Psychopharmacology (Berl.) 119205, 1995 61. Prudhomme D, Despress JP, Landry JF, et a1 Systolic blood pressure during submaxima1 exercise: An important correlate of cardiovascular disease risk factors in normotensive obese women. Metabolism 43:18, 1994 62. Puddey IB, Cox K Exercise lowers blood pressure-sometimes? Or did Pheidippides have hypertension? J Hypertens 13:1229, 1995 63. Ramsey LE, Yeo WW, Chadwick IC: Non-pharmacological therapy of hypertension. Br Med Bull 50:494, 1994 64. Reid CM, Dart AM, Dewar EM, et al: Interactions between the effects of exercise and weight loss on risk factors, cardiovascular haemodynamics and left ventricular structure in overweight subjects. J Hypertens 12291, 1994 65. Reisin E: Sodium and obesity in the pathogenesis of hypertension. Am J Hypertens 3:164, 1990 66. Reisin E: Recommendations for the evaluation and treatment of high blood pressure: A review of six national and international reports. Drugs Today 31:427, 1995 67. Reisin E: Obesity hypertension: Non-pharmacologic and pharmacologic therapeutic modalities. In Laragh JH, Brenner BM (eds): Hypertension: Pathophysiology, Diagnosis and Management, ed 2. New York, Raven Press, 1995, p 2683 68. Reisin E, Abel R, Modan M, et a1 Effect of weight loss without salt restriction on the reduction of blood pressure in overweight hypertensive patients. N Engl J Med 298:1, 1978 69. Reisin E, Frohlich ED: Effects of weight reduction on arterial pressure. J Chronic Dis 35:887, 1982 70. Reisin. E, Frohlich E D Hemodynamics in obesity. In Tarazi RC, Zanchetti A (eds): Cardiovascular Aspects of Hypertension. Dordrecht, The Netherlands, Elsevier Science Publishers, 1989, p 105 71. Reisin E, Frohlich ED, Messerli FH, et al: Cardiovascular change after weight reduction in obesity hypertension. Ann Intern Med 98:315, 1983 72. Richards RJ, Thakur V, Reisin E: Obesity-related hypertension: Its physiological basis and pharmacological approaches to its treatment. J Hum Hypertens 10559, 1996 73. Ridker SC, Vaughn DE, Stampfer MJ, et al: Association of moderate alcohol consumption and plasma concentration of endogenous tissue-type plasminogen activator. JAMA 272:929, 1994 74. Rimm EB, Klatsky A, Grobbee D, et al: Review of moderate alcohol consumption and reduced risk of coronary heart disease: Is the effect due to beer, wine or sports? BMJ 312731, 1996 75. Rocchini AP, Key J, Bondie D, et al: The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 321:580, 1989 76. Scherrer U, Nussberger J, Torriani S, et al: Effect of weight reduction in moderately overweight patients on recorded ambulatory blood pressure and free cytosolic platelet calcium. Circulation 83:552, 1991 77. Schwartz RS, Hirth VA: The effects of endurance and resistance training on blood pressure. Int J Obes Relat Metab Disord 19:552, 1995 78. Seltzer CC: Effect of smoking on blood pressure. Am Heart J 87558, 1974 79. Seppa K, Laippala P, Sillanaukee F: Drinking pattern and blood pressure. Am J Hypertens 7249, 1994 80. Shaper AG, Phillips AN, Pocock SJ, et al: Alcohol and ischemic heart disease in middle aged British men. BMJ 294:733, 1987 81. Sharpe PC, McGrath LT, McClean E, et al: Effect of red wine consumption on lipoproteins (a) and other risk factors for atherosclerosis. QTM 88:101, 1996
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82. Simpson F O Salt and hypertension: A skeptical review of the evidence. Clin Sci 53S463, 1979 83. Sleight P: Short term and long term effects of alcohol on blood pressure, cardiovascular risk and all cause mortality. Blood Pressure 5:201, 1996 84. Sowers JA, NyBy M, Naftali BE, et al: Blood pressure and hormone changes associated with weight reduction in the obese. Hypertension 4:686, 1983 85. Sowers JR, Whitfield LA, Beck WJ, et al: Role of enhanced sympathetic nervous system activity and reduced Na-K dependent adenosine triphosphatase activity in maintenance of elevated blood pressure in obesity: Effect of weight loss. Clin Sci 63:1215, 1982 86. Stamler R, Stamler J, Riedlinger WF, et al: Weight and blood pressure findings in hypertension screening of 1 million Americans. JAMA 240:1607, 1978 87. Tuck MJ, Sowers J, Domfeld L, et al: The effect of weight reduction on blood pressure, plasma renin activity and plasma aldosterone levels obese patients. N Engl J Med 304930, 1981 88. Ueshima H, Mikawa K, Baba S, et a1 Effect of reduced alcohol consumption on blood pressure in untreated hypertensive men. Hypertension 21248, 1993 89. Umvik P, Myking DL Unchanged central hemodynamics after six months of moderate sodium restriction with or without potassium supplement in essential hypertension. Blood Pressure 4:32, 1995 90. Wallace P, Cutler S, Haines A: Randomized controlled trial of general practitioner intervention in patients with excessive alcohol consumption. BMJ 297:663, 1988 91. Ward MM, Swan GE, Jack LM, et al: Ambulatory monitoring of heart rate and blood pressure during the first week after smoking cessation. Am J Hypertens 8:630, 1995 92. Weinberger MH, Miller JZ, Luft FC, et a1 Definition and characteristics of sodium sensitivity and blood pressure resistance. Hypertension 8-11127, 1986 93. Weintraub M, Sundaresan PR, Modan M, et al: Long-term weight control study I (weeks 0-34). Clin Pharmacol Ther 51:586, 1992 94. Weintraub M, Sundaresan PR, Schuster 8, et al: Long-term weight control study 111 (weeks 104 to 156). Clin Pharmacol Ther 51:602, 1992 95. Weir MR, Dengel DR, Belhrens T, et a1 Salt induced increases in systolic blood pressure affect renal hemodynamics and proteinuria. Hypertension 25:1339, 1995 96. Wylie-Rosett J, Wassertheil-Smoller S, Blaufox MD, et a1 Trial of antihypertensive intervention and management Greater efficacy with weight reduction than with a sodium potassium intervention. J Am Diet Assoc 93:408, 1993
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NONPHARMACOLOGIC APPROACHES TO HYPERTENSION Weight, Sodium, Alcohol, Exercise, and Tobacco Considerations Efrain Reisin, MD
Several lifestyle modifications have been proposed as effective treatments for hypertension, and to date, one international and five national committees have issued recommendations on such treatment measures. These include weight reduction, salt and alcohol restriction, increased physical activity, and smoking cessation (Table 1).66Some of these nonpharmacologic approaches may control blood pressure without the concomitant use of antihypertensive^^^; they may reduce the frequency or or they may improve dosage levels of antihypertensive medicati~nsl~; cardiovascular morbidity and mortality. This article reviews the mechanisms that link obesity, increased salt or alcohol consumption, and smoking with hypertension. Also described are the changes that may occur in these mechanisms and in blood pressure levels when nonpharmacologic approaches, including exercise, are employed to treat hypertension.
From the Section of Nephrology, Department of Medicine, Louisiana State University School of Medicine, New Orleans, Louisiana
MEDICAL CLINICS OF NORTH AMERICA VOLUME 81 * NUMBER 6 * NOVEMBER 1997
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Table 1. NONPHARMACEUTICAL APPROACHES TO ANTIHYPERTENSIVE THERAPY Modalities Weight reduction
Salt restriction Decreased alcohol intake Endurance exercise
Smoking cessation
Mechanism of Action on Blood Pressure Improved insulin sensitivity; diminished sympathetic activity, plasma renin activity, and aldosterone; reverse hemodynamic alterations and left ventricular hypertrophy In salt-sensitive individuals, decreased reactivity of the reninangiotensin-aldosterone system Remains unclear but appears to be independent of changes in weight or salt intake Decreases cardiac output and vascular responsiveness to a-adrenergic receptors; may also reduce plasma renin activity and catecholamine levels Long-term cessation has no longterm favorable effects on blood pressure
Recommendation Weight loss of at least 10 kg
Salt intake of no more than 6 g daily, only in salt-sensitive patients Decrease alcohol intake to no more than 3 drinks (30 mL) daily Exercise 3-5 times weekly, for 30-45 minutes each session, at a level of perceived exertion with no distress May be indicated only to decrease premature cardiovascular morbidity and mortality
OBESITY AND HYPERTENSION
Several epidemiologic studies have linked obesity and hypertension, regardless of race or 86 and longitudinal studiesz9, 47 have described an increased prevalence of hypertension as weight and age increase. Various mechanisms have been suggested as explanations for the association between obesity and hypertension, among them dysregulation of the endocrine-metabolic systems and alterations in the fluid volume distribution with hemodynamic changes and cardiac morphologic alteration^.^^, 72 Some researchers consider insulin resistance and the consequent hyperinsulinemia to be the initial trigger in obesity-hyperten~ion.~~, 31, 44 however, cast some doubts about the long-term effect of hyperinsulinemia on hypertension because hypertension did not develop in obese dogs with chronic hyperins~linemia.~~ If insulin resistance is not an initial trigger of hypertension, it may nonetheless be related to other metabolic-endocrine associations with obesity-hyperten~ion.~~ For example, overfeeding may cause increased sympathetic activity and may enhance the aldosterone-to-plasma renin activity ratio-changes that may induce sodium and water retention.28Additionally the decreased
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Na +,K+-ATPase activity described in obese hypertensive patients may increase intracellular sodium content and decrease calcium efflux. These changes increase intracellular calcium concentration, smooth muscle tone, and vascular resistance.z,16,40 The author and other investigators', 3, 53, 69 have studied the hemodynamic characteristics and the cardiovascular adaptations that followed weight gain. The plasma and total blood volumes in obese hypertensive patients, compared with those in normotensive subjects, have been reported to increase when absolute values were ~ o n s i d e r e dFrohlich .~~ and colleaguesz2believe that this absolute increase in intravascular volume in obese hypertensives is the actual volume pumped by the heart; when redistributed centrally to the cardiopulmonary area, that volume increases venous return and cardiac output. Hypertension develops if systemic vascular resistance fails to decrease as cardiac output inand have shown that total peripheral c r e a s e ~ Messerli .~~ resistance was inappropriately normal in obese hypertensives compared with lean hypertensives. Using echocardiographic techniques in obese hypertensives, they also found an increase in left atrial, left ventricular, and aortic root diameters as well as in posterior wall and septa1 wall thickness and left ventricular mass.54These changes cause cardiac enlargement and impairment of left ventricular filling.55The myocardium adapts to chamber dilation by adding contractile elements in series'O and thickens as a result of the increased afterload by adding contractile elements in paralleLZ1This process results in the eccentric-concentric left ventricular hypertrophy that characterizes obesity-hyperten~ion.~~ The combined hemodynamic alterations of obesity and hypertension increase the risk of congestive heart failure.22 Effects of Weight Reduction
Numerous studies have demonstrated the positive effects of weight 69, 87 In the first study reduction on the management of hypertensi~n.~~, in which salt intake was not the author and colleagues reduced blood pressure to normal levels in 75% of the obese hypertensive patients treated with only a hypocaloric diet; their average weight loss was 10 kg. In a long-term follow-up (12 months) of the same 52% of those who had maintained their weight reduction also had systolic and diastolic blood pressure measurements under or equal to 140 mm Hg and 90 mm Hg. Investigators in the Dietary Intervention Study in Hypertension (DISH)&summarized their experience with obese hypertensives who were taken off their antihypertensive medications but encouraged to reduce their weight or to follow a sodium-restricted obese hypertensives remained normotendiet; in that study, 60% of
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sive without antihypertensive medications when they lost an average of 4.5 kg. In the same study, 46% of the patients remained normotensive when daily sodium intake was reduced to 40 mEq/day. The changes in blood pressure apparently followed a floor effect, or a degree of weight loss beyond which further reduction in blood pressure did not occur." The Trial of Antihypertensive Interventions and Management (TAIM) research a large cooperative intervention, compared the effect of weight loss to the effect of placebo, chlorthalidone (25 mg/ day), or propranolol (50 mg/day) treatments; by the end of the followup period, the investigators found that compared with the effects of placebo and the two antihypertensives, weight loss enhanced blood pressure control by 23%. Other investigators have shown that weight loss successfully reduced blood pressure and that when weight loss was added to the antihypertensive regimen blood pressure was better controlled in those patients who met the body mass index goal than it was in those who did not (95% versus 20%).15 Weight loss has reversed some of the previously discussed metabolic-endocrine-hemodynamicmechanisms that induce obesity-hypertension (Fig. l).67 For example, weight loss returned insulin levels to normal fasting levels and improved insulin sensitivity as a result of an apparent increase in the number of insulin-binding receptors in the
Weight Reduction Decreased lntravascular and Cardiopulmonary Blood Volume
Decreased Hyperinsulinemia
Decreased Cadiac Output
Decreased Adrenergic Activity
Alteration in Na+-K+and Ca++ lntracellular Distribution
/
-
Muscle lone and Vascular Resistance
Figure 1. Physiologic changes induced by weight reductions. (Adapted from Reisin E: Obesity hypertension: non-pharmacologic and pharmacologic therapeutic modalities. In Laragh JH, Brenner BM (eds): Hypertension: Pathophysiology, Diagnosis, and Management, ed 2. New York, Raven Press, 1995, p 2688; with permission.)
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target cells.67Levels of plasma norepinephrine also have been shown to drop after weight reduction, a change explained as one based on diminished sympathetic nervous system 85 Weight loss also may decrease plasma renin activity and aldosterone, changes that may be mediated by decreased sympathetic activity or by changes in the plasma renin Previous studies have reported the effects of a lowcalorie diet on Na+,K+-ATPaseactivity, with different res~lts,8~ but a more recent study showed a decrease in free cytolytic platelet calcium levels associated with reduction in forearm resistance and a consequent increase in blood The author and colleagues have shown that following a weight reduction of 10 kg, obese hypertensives experienced a statistically significant reduction in intravascular and cardiopulmonary volume when absolute values were ~onsidered.~", 71 Hemodynamic studies performed after weight loss of 10 kg have shown a reduction in oxygen consumption, cardiac output, and left ventricular stroke work without changes in peripheral resistance-changes that suggest improved cardiac function.67 Echocardiographic studies after weight loss have demonstrated a decrease in intraventricular, septal, posterior wall thickness, and left ventricular mass, but only the decrease in left ventricular hypertrophy was correlated with the decrease in systolic blood pressure.52 Appetite Suppressants and Hypertension
A major problem for obese hypertensives is dietary noncomplian~e,6~, 72 and because a large number of prescribed or over-the-counter appetite suppressants are used as adjunct treatment in obese subjects, the mechanisms of action and the effect on blood pressure of some of these medications are discussed briefly. Pharmacologic agents may affect the process of satiation (control of meal size) and satiety (control of postmeal interval^).^ Certain serotonergic agents may function as important satiety agents by antagonizing the consumption of fat, thereby causing selective avoidance of fat and reducing daily lipid b1take.4~ 93 seem to act in this way; both Fenfluramine and dexfenfl~ramine~~, drugs reduce food intake and increase satiety. Phente~mine~~ appears to suppress appetite through noradrenergic and dopaminergic mechanisms that may work in external areas of the hypothalamus to delay the onset of eating. A long-term follow-up (up to 4 years) using fenfluramine and phentermine in obese normotensive subjects demonstrated a statistically significant fall in systolic blood pressure without a change in heart rate. The positive effect on blood pressure in this study, however, was attributed to improved lifestyle factors, such as exercise, stress
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management, and weight In a 6-month follow-up treatment of obesity with dexfenfluramine, O’Connor and c011eagues~~ showed a significant decrease in systolic and diastolic blood pressure, a change related to lower insulin sensitivity and noradrenergic activity that may not be related to weight reduction. Some appetite suppressants may be viable adjunct pharmacotherapy for obesity and apparently are safe for hypertensive subjects, but additional long-term cooperative studies are necessary to support their safety and efficacy. SALT INTAKE AND HYPERTENSION
Earlier studies of large populations have shown a direct relationship between sodium consumption and the prevalence of hypertension as well as a low incidence of hypertension in populations with a low salt h1take.4~. Some of these studies, however, have been conducted on primitive societies and criticized for their failure to consider that such populations may be exposed to less stress and also may have lower incidences of obesity.82Today, clinicians are more inclined to -believe that patients with essential hypertension may be classified as salt sensitive and salt resistant, based on the absolute changes in arterial pressure that originate from dietary salt intake.34In a previous study, Weinberger and colleagues92showed that 51% of the hypertensive participants were salt sensitive, as a result, perhaps, of alterations in electrolyte transport across cell membranes and the concomitant alteration in intracellular concentrations of sodium and increased sympathetic activity; both alterations may have a genetic basis.6 The deficit in sodium ion transport across cell membranes (demonstrated in red blood cells) in patients with essential hypertension or in normotensive subjects with a family history of hypertension may alter the calcium/sodium ion exchange across vascular smooth muscle membrane.6These changes increase the concentration of calcium ions, which may increase vascular wall tension and smooth muscle contractibility, thereby increasing blood pressure.65 According to some investigators, changes in sodium excretion at tubular levels that are genetic in origin cause sodium and water retention, increase blood volume, and cause hemodynamic changes that may trigger hypertension? The increased sympathetic activity that may be induced by increased salt intake enhances vasoconstrictor tone and induces hyperten~ion.~~ Other studies have shown that a high salt intake in salt-sensitive individuals interacts with the renin-angiotensin system in the insulin-resistant state, changes that may increase systolic and glomerular capillary pressure.95Salt sensitivity predisposes individuals to renal injury, target organ damage that is common in hypertensive
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salt-sensitive individual^.^^ These patients also experience a higher incidence of left ventricular hypertrophy and cardiovascular complications than do non-salt-sensitive individual^.^
Effects of Salt Restriction
Population studies show poor adherence to sodium restriction," and some investigators have concluded that it has not been helpful in reducing either blood pressure25or the cardiovascular risks of hyperten~ i o nMacGregor .~ and co-workers,5°however, demonstrated that a reduction to 80 mmol of salt daily resulted in a significant drop (7 mm Hg) in mean blood pressure; the DISH study15 mentioned earlier demonstrated that when salt intake was reduced to 40 mmol daily, 46% of the patients remained normotensive. Compared with non-salt-sensitive individuals, salt-sensitive subjects had a better response or were the only responders to a low-salt diet.67Accordingly, some concern that salt restriction in non-salt-sensitive patients may have deleterious effects (an increase in serum creatinine, uric acid, and serum insulin and adverse alterations in serum lipids) exist^.^ A 6-month follow-up of hypertensive patients on a salt-restricted dieP9 demonstrated that restricted sodium intake did not show that systemic hemodynamic changes correlated with the drop in blood pressure. A low-sodium diet in salt-sensitive subjects induced lower plasma renin and aldosterone concentrations than it did in non-salt-sensitive individual^.^^
ALCOHOL INTAKE AND HYPERTENSION
Systolic and diastolic blood pressures are significantly related to alcohol intake and to drinking 39 and blood pressure levels were higher in subjects who drank daily than they were in those who drank heavily only on weekends.79Intriguing findings from large epidemiologic studies of alcohol intake and blood pressure suggested a Jshaped ass~ciation.~~ In these studies, subjects who reported having fewer than one drink a day had higher systolic and diastolic blood pressure (4 to 8 mm Hg and 3 to 5 mm Hg) than did participants who drank up to three drinks a Additionally, mortality owing to coronary artery disease was 17% lower in those individuals who consumed two to three drinks per day compared with those reporting fewer than one drink daily.I7,38, 51 The protective effects of alcohol may be mediated by the increase in high-density lipoprotein (HDL) cholesterol seen in subjects who drink
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up to three drinks a day74and by the decrease in lipoprotein Lp(a) that accompanies wine consumption.80Other beneficial cardiovascular characteristics described in lighter alcohol drinkers are those that reduce clotting, such as an increase in endogenous tissue plasminogen activator and a decrease in fibrinogen, as well as the antioxidants contained in wine that may protect against atheroma formation.”, 83 Acute alcohol administration raises blood pressure by increasing the discharge rate of the sympathetic vasoconstrictor nerves in the skeletal muscle vasculature. Other related mechanisms may be a direct effect on calcium transport into smooth muscle cells and a depletion of intracellular magnesium, which affects peripheral vasculature tone via vasospasm. Impaired insulin sensitivity was suggested as a causal mechanism of hypertension following acute alcohol intake.37Studies of the mechanisms of increased blood pressure as a result of the long-term consumption of alcohol in humans are lacking, but some of the mechanisms described include increased sympathetic activity, increased reninangiotensin levels, impaired baroreflex activity, impaired insulin sensitivity, magnesium depletion, or a direct effect on peripheral vascular t0ne.3~
Effects of Decreased Alcohol Intake \
In a study conducted over a 3-week period, a reduction in daily alcohol intake by half (from 56 to 26 mL/day) without salt restriction induced statistically significant lower systolic and diastolic pressure (decreases of up to 4.8 and up to 3 mmHg).88A long-term trial (1 year) of heavy drinkers who were encouraged to reduce their daily alcohol intake by 30% to 40% showed a statistically significant fall of 6.8 mm Hg in systolic blood pressure compared with a 4.7 mm Hg drop in the control group ( P <.05).9O The exact mechanisms underlying the drop in blood pressure that follows moderation of alcohol consumption remain unclear but were independent of changes in weight or salt intake. It appears that drinkers of not more than 30 mL of alcohol per day (three drinks) may have lower blood pressure and experience protective effects on cardiovascular morbidity and mortality than do heavy drinkers (more than three drinks daily). EXERCISE AND HYPERTENSION Acute dynamic exercise in normotensive subjects raises systolic blood pressure by 50 to 70 mm Hg, while diastolic blood pressure remains unchanged or decreases by 4 to 8 mm Hg. In hypertensive
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subjects, however, exercise increases systolic blood pressure to levels higher than 200 mm Hg and also increases diastolic blood pressure. This higher pressor response was also reported in normotensive subjects with a family history of hyperten~ion.~~ The elevated blood pressure that accompanies acute dynamic exercise has been attributed to a decrease in vagal tone, followed by an increase in sympathetic activity, heart rate, and stroke volume. The lower diastolic blood pressure in normotensive subjects is caused by peripheral vasodilation and decreased total peripheral resistance. In hypertensive subjects, however, peripheral resistance did not decrease; instead, these individuals responded with increased diastolic blood pressure. This elevated diastolic blood pressure in hypertensives is generally associated with a reduced ejection fraction and coronary artery disease.& Consequently, increased blood pressure induced by exercise is considered a stronger predictor of morbidity and mortality from myocardial infarction than is resting blood pressure, especially in subjects with underlying left ventricular hypertrophy.6*,
Effects of Endurance Exercise Extensive clinical data support the blood pressure-lowering effect of endurance dynamic exercise training in 75% of the patients studied.n In a meta-analysis of 48 investigations comprised chiefly of men, the subjects, aged 16 to 72, undertook heavy-intensity exercise training (i.e., between 50% and 85% of their qaximal exercise capacity) three times weekly for 15 to 90 minutes, for up to 16 months; in these subjects, Fagard19 demonstrated an average drop in systolic and diastolic blood pressure (by 5.3 mm Hg and 4.8 mm Hg). Fagard also noticed major flaws in those studies, however, among them an inadequate number of blind control studies, poor randomization techniques, failure to maintain a stable diet among study subjects, and poor adjustment of results for confounding variables such as concomitant weight loss or sodium restriction. The decrease in blood pressure that occurs with endurance exercise training may be explained by the following hemodynamic mechanisms: decreased stroke volume, cardiac output, and ejection fraction; additionally, fractional fiber shortening was reduced, as was the contractility index?, 36 These changes occurred after a decrease in limb vasculature resistance and lower vascular responsiveness to a-adrenergic receptors.8 Other metabolic changes induced by endurance exercise training are reduced levels of plasma renin activity and catecholamines,18with an increase in an endogenous ouabain-like substance that may enhance urinary sodium excretion by acting as a natriuretic hormone, thus having a favorable effect on blood pressure.35
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Exercise also reduces cardiovascular morbidity by lowering weight, serum cholesterol and triglyceride levels, and platelet aggregation and increasing HDLs and insulin sensitivity.61, An extended exercise program in hypertensive subjects has demonstrated statistically significant decreases in blood pressure, left ventricular mass, mass index, and thickness of intravascular Consequently, endurance exercise appears to be beneficial for hypertensive patients. Because of the previously described flaws in the investigations performed, however, exercise recommendations are still imprecise, and a number of issues remain to be resolved, among them the number of exercise sessions to be recommended per week, the duration and intensity of each session, and the best type of exercise to practice. The best advice currently appears to be to encourage exercise in sedentary hypertensives without serious end organ damage, beginning with low-intensity activity (expressed as a level of perceived exertion with no pain, respiratory distress, or other discomfort) and with a maximal heart rate based on subtracting the patient's age from 220.14 Exercise should be undertaken three to five times weekly for 30 to 45 minutes per session and maintained continuously because its cardiovascular benefits may disappear 2 weeks after cessation of physical a~tivity.'~ SMOKING AND HYPERTENSION Large epidemiologic studiesz4,78 have demonstrated that smokers have lower blood pressure than do nonsmokers, a finding that may stem from the confounding factor of obesity, which is more common in nonsmokers than in smokers. Other investigators have concluded th& nicotine use, alcohol consumption, and a sedentary lifestyle are frequently associated and that these three adverse habits contribute to the clustering of cardiovascular risk factors (i.e., lower HDLs, increased triglyceride levels, and high blood pressure).12 The metabolic and hemodynamic effects of smoking were investigated in subjects who were habitual smokers, and the results showed increased cardiac output, without changes in stroke volume-an effect that may continue for 90 minutes after the individual finished smoking and may be due to local nicotine stimulation of the adrenergic nervous system at the adrenergic axon terminals within the tissue.I3,6o Effects of Smoking Cessation Smoking cessation reduces systolic and diastolic blood pressure for at least 6 hours and decreases serum adrenaline and cortical levels for 6
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weeks?l Long-term cessation (an average of 2.5 years), however, did not change blood pressure levels when the results were adjusted for weight loss (70% of those individuals who quit smoking gained Although smoking cessation does not have a clear-cut long-term favorable effect on blood pressure, it may have positive effects on cardiovascular morbidity and mortality.56Consequently, smoking is still considered the most important preventable cause of premature mortality and morbidity in the United States.20 SUMMARY
Weight loss decreases blood pressure, and this change can be sustained over the long-term when the lower weight is maintained. Salt restriction may be effective in blood pressure control only in salt-sensitive individuals. Heavy drinkers (those who drink more than three drinks [30 mL] daily) experience deleterious effects such as hypertension and more cardiovascular risk factors. Consequently, they should be advised to reduce alcohol intake to less than 30 mL daily. Endurance training with dynamic exercise appears to be beneficial for hypertensive patients, although recommendation guidelines are still imprecise. Finally, smoking cessation has not been proven to decrease blood pressure levels but should nonetheless be recommended because of its favorable effects on cardiovascular morbidity and mortality. ACKNOWLEDGMENT Special thanks to Anne Compliment for her editorial review.
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