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HYPERTENSION HEMODYNAMICS
ESSENTIAL HYPERTENSION, PART I
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HYPERTENSION HEMODYNAMICS Fetnat M. Fouad-Tarazi, MD
Arterial blood pressure is determined by cardiac output and systemic vascular resistance so that pressure = flow x resistance. Various hemodynamic patterns, therefore, may lead to the same level of blood pressure. This information indicates that blood pressure measurement per se reflects the net effect of hemodynamic alterations, which may vary as the underlying adaptive cardiovascular changes take place. To that effect, the determinants of blood pressure level include factors that affect both cardiac output and arteriolar vascular physiology. Venous return, myocardial contractility and relaxation, circulating blood volume, heart rate, and adrenergic activity are known to influence cardiac outVascular resistance is affected by the autonomic nervous system and neurohormonal vasoconstrictors, including catecholamines, arginine vasopressin (AVP), endothelins, and tissue and circulating angiotensin II.lo0Modern hemodynamic understanding demonstrated the important role of the vascular endothelium in the regulation of the degree of vasoconstriction or vasodilation, including intrinsic and extrinsic mechanisms.18 The potential relevance of blood viscosity, vascular wall shear conditions (rate and stress), and blood flow velocity (mean and pulsatile components) on vascular endothelial function has been shown in hu56, 64, m,89 In addition, previous findings by Folkow28and KorneF5 man~.’~, indicated that vascular wall thickness participates in the amplification of changes in vascular resistance in hypertensive patients. Not to be forgotten are the effects of large arterial stiffness as well as the baroreflex resetting mechanisms producing neural feedback loops that regulate the cardiovascular dynamics and consequently blood pressure level.3*27* 37,41 From The Cleveland Clinic Foundation, Department of Cardiology/Molecular Cardiology, Cleveland, Ohio
MEDICAL CLINICS OF NORTH AMERICA
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VOLUME 81 * NUMBER 5 SEPTEMBER 1997
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Baro-reflexes were shown to be important not only in orthostatic blood 88, 93 but also in postexercise h y p ~ t e n s i o n . ~ ~ pressure reg~lation,8~, EARLY VERSUS ESTABLISHED ESSENTIAL HYPERTENSION
Early onset of hypertension is difficult to determine in humans. Various animal studies in the spontaneously hypertensive rat (SHR), a model close enough to human essential hypertension, however, have shown that the initiating hemodynamic disturbance in early hypertension is an increased flow and cardiac Many human studies have shown that borderline hypertension is characterized by increased cardiac output without change of peripheral resistance.59,60, 85, 97 The mechanism of this increased cardiac output has not been clearly identified. Julius and colleagues60pointed out the importance of the sympathetic nervous system in early hypertension as well as in borderline hypertension. High-output hypertensi~n~~ was described in early borderline essential hypertension, in some patients with long-standing hypertension, and in steroid-mediated hypertension. High-output hypertension has been classified into that dependent on peripheral factors (increased tissue demands or hypervolemia) and that related to cardiac stimulation (adrenergic hyperactivity or slight hypokalemia combined with hypercalcemia). Whether the sodium-calcium exchange cellular mechanism plays a role in this type of hypertension has not been confirmed.49Increased cardiac output may be associated with a short circulation time and rapid heart rate, reflecting a hyperkinetic circulation, or the increased cardiac output may occur alone, in which case it represents central translocation of blood volume. In its chronic established phase, essential hypertension is characterized by a normal (or reduced) cardiac output and elevated systemic vascular resistance, generally linked to a decreased diameter of the arteriolar lumen.97The exact mechanism of this excessive vasoconstriction in chronic essential hypertension and other types of established hypertension is not known but has been the subject of extensive studies and hypotheses. The increased systemic resistance was generally related either to an active process or to rarefaction of the vascular bed. Active vasoconstriction was attributed to increased production of vasoactive factors, to enhanced reactivity of the smooth muscle cells; or to structural changes in the vessel wall leading to a reduction in the lumen-towall ratio.28 It is not known if more than one factor may be present at one time or if an interchange between these various factors may occur at different phases of the hypertensive d i ~ e a s eThe . ~ theory of autoregulation has prevailed for a long time.57This theory postulated that the initial high cardiac output leads to overperfusion of tissues in excess of the metabolic needs of these tissues, and it is this overperfusion that triggers an increase in active tension of the vascular smooth muscles of the resistance vessels57;as a result, a secondary reactive increase in systemic
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vascular resistance occurs to counterbalance the increase in flow and eventually restore cardiac output to a normal value. This autoregulation theory has been strongly supported by Guyton and colleague^'^, 20, 21, 47 and by Ledingham and Pelling.6sSupport to this hypothesis came from studies in patients and animals with gross renal impairment. It was demonstrated that in renovascular hypertension fluid overload is associated with an initial increase in cardiac output, whereas sequential hemodynamic studies over 1 to 2 weeks demonstrated a later development of an increase of systemic vascular resistance in association with restoration of cardiac output.75Contrary to this adaptive hypothesis was the demonstration that actual pathologic changes in the peripheral vasculature mediate the increase of vascular resistance.28,29* 65, 90 Indeed, FolkowZsand Korner and showed the importance of hypertrophy of the muscles of the resistance vessels in amplifying the pressor stimuli. In experimental studies of renal hypertension, it was demonstrated that vascular hypertrophy occurs within the initial 10 to 20 days after applying the renal artery clip.72It was also demonstrated that in these hypertensive models, there was an accentuation of the vascular responsiveness to exogenous noradrenalin, angiotensin 11, and vasopressin as compared to normal controls.2 Also, Panza and co-workerss0 showed that patients with hypertension are predisposed to a more pronounced hypertensive response to any given vasoconstrictor agent. The mechanism of the accentuated hypertensive response to vasoconstrictive stimuli in hypertensive subjects was thought to be related not only to alterations in the structural and physical properties of resistance arteries, but also to the changes in endothelial function. In their study, Panza and co-workerss0 showed that normalization of blood pressure with conventional antihypertensive therapy for at least 5 years did not improve the blunted response to endothelium-dependent agents that was described in hypertensive patients. Therefore, it was suggested that the endothelial abnormality may play a primary role in the genesis of hypertension or may perpetuate the hypertensive process. An increased production of an endothelial dependent contracting factor102remains only speculative. The concept of vascular remodelinp has been further explored when the role of the vascular endothelium became well recognized; the vascular endothelium plays a major role in the initiation of vascular changes because of its direct interaction with the intraluminal physical forces and biochemical mediators as well as its ability to secrete endogenous vasoactive and growth regulating substances. The remodeling process of the vascular wall (vascular hypertrophy), therefore, appears to participate in the maintenance of increased vascular resistance in hypertension whatever the initial hemodynamic pattern. It was also demonstrated in vitro that the preexisting level of vascular tone is an important determinant of arterial autoregulatory responsi~eness.~~ Looking at the question in a different way, the author has examined the immediate, moment-to-moment, regulatory vascular functional changes that occur when blood pressure is altered acutely in hypertensive patients.% Data indicated that the acute change of blood
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pressure did not alter the changes in forearm vascular resistance induced by cold pressor stimulus or during postischemic reactive hyperemia. It was concluded that the magnitude of forearm vascular resistance is an inherent property of the vessel wall rather than a dynamic function that varies according to the initial level of blood pressure. GENETIC FACTORS IN PRIMARY HYPERTENSION
The new challenge is the finding of a genetic basis for these changes in human hyperten~ion.4~ The mode of inheritance of primary hypertension appears to be complex. Hypertension represents a polygenic trait that shows strong dependence on multiple environmental factors as well as a heterogeneity of genes that are or could be involved in the process.69 It is not yet clear if essential hypertension is related to an individual genetic factor or multiple genes may be involved. Animal experimentation allows a much more precise study of environmental factors as well as of genetic factors. Cosegregation and linkage analyses have been used for the investigation of inbred strains. Genetic analysis in human hypertension demonstrated positive linkage for the renin and angiotensin-converting enzyme (ACE) genes similar to that found in animal experiment^.^^, Studies from Hata and colleagues50and Caulfield and associates15 implicated a role for angiotensinogen in human hypertension. Several other genes have been investigated as candidate genes in hypertension, including angiotensin I1 receptor gene, and endothelial nitric oxide synthase gene and angiotensinogen gene.58The difficulties in such studies stem from the fact that negative results do not necessarily rule out the role of a particular gene because differences may exist among various families. ffi
SALT SENSITIVITY, AUTONOMIC NERVOUS SYSTEM, AND VOLUME FACTORS IN HYPERTENSION
A major unresolved issue in understanding the pathogenesis of hypertension is the sensitivity of some individuals to alterations in dietary sodium intake. The association between sodium consumption and arterial blood pressure has been the subject of extensive studies in humans as well as in experimental animals.*,22, 24, 49, 71, 91, 94 It is well recognized that certain patients with hypertension respond differently to a high sodium intake; some have an increase, whereas others have either unchanged or a decrease in blood pressure during salt loading. The mechanism by which sodium elevates blood pressure in some patients with hypertension remains unclear. Various hypotheses were examined, including genetic, pathologic, hemodynamic, and hormonal factors. Weinberger and colleagues''''' described a sluggish renal adaptation to dietary sodium restriction in salt-sensitive patients. Campese and as~ociates'~ suggested that the sympathetic nervous system may also
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contribute to the heterogeneity of blood pressure response to sodium intake. Hollenberg and Williams53 implicated the combined effect of altered renal vascular response to a salt load and a decreased aldosterone response to angiotensin I1 in nonrnodulators, who had blood pressure responses as salt-sensitive patients. Studies by the author have shown that this blood pressure sensitivity to salt intake is unrelated to the amount of salt retained or to the basal levels and responsiveness of plasma catecholamines, plasma renin activity, and aldosterone p r o d ~ c t i o n The . ~ ~ most consistent finding in these studies was the demonstration that salt-sensitive patients respond to a high salt diet by an increase in systemic vascular resistance, whereas in salt-resistant patients blood pressure remained essentially unchanged because changes in flow were negated by adaptive changes in systemic vascular resistance, indicating that salt-resistant patients were more able to adapt to salt loading by reducing the peripheral vascular resistance. It was also found that salt-sensitive patients had reduced sensitivity of low pressure receptors in response to a decrease of preload as compared to salt-resistant patients.’O, 11, 35 In addition, although responses to vasodilator stimuli were comparable in both salt-sensitive and salt-resistant patients, the salt-resistant group exhibited a higher sensitivity of the vascular resistance to direct a-adrenergic stimulation as compared to salt-sensitive ~atients.3~ This finding was again taken in favor of the higher adaptability of the cardiovascular system in salt-resistant patients. The geometric structure of the aorta and large vessels may also be important determinants in the blood pressure response to sodium intake. For example, low sodium intake was reported to reduce vascular wall stiffness in cross-sectional studies using pulse wave velocity measurement: and arterial compliance was found to be reduced in the carotid, brachial, and femoral arteries of salt-sensitive subjects with borderline hypertension.u, 67 These findings led to the suggestion that high salt intake in these subjects modifies the viscoelastic properties of the large arteries; this interesting assumption has not been proven by morphologic studies. HEMODYNAMICS OF ISOLATED SYSTOLIC HYPERTENSION
Mechanical principles regulate the function of large arteries.78Reduced aortic distensibility is well recognized particularly in advanced age groups. As a result, there is loss of the Windkessel function of the arterial tree, so that the relationship between stroke volume and arterial recoil is altered leading to a selective or predominant rise of systolic blood pressure.%In general, one may subdivide the cause of this systolic hypertension into remediable functional causes (such as increased stroke volume and increased adrenergic activity) and nonremediable structural causes (such as atherosclerotic changes of the vascular walls). In young people, isolated systolic hypertension is usually related to increased
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stroke volume.31Arterial compliance can be measured in humans by invasive and more recently by noninvasive validated method^.^ Changes induced by therapeutic interventions may therefore be assessed. Improvement of large arterial compliance should be a goal of antihypertensive therapy because systolic blood pressure is an important determinant of myocardial wall stress and myocardial oxygen requirement as well as of cerebral perfusion. Also, abnormal arterial compliance has been shown to be associated with abnormalities in baroreceptor function.16 Finally the mechanical effect of increased pulse pressure (increased oscillatory variations) that results from decreased arterial compliance may make the arterial wall more susceptible to pathologic changes affecting the physical properties of the intima and subintimal layers? Such a feature may suggest that changes in arterial compliance may indeed precede the occurrence of atherosclerosis at least in some patients.
LEFT VENTRICULAR HYPERTROPHY IN HYPERTENSION
The myocardium undergoes structural changes in response to the increased afterload. Because cardiac myocytes are terminally differentiated, they cannot replicate (hyperplasia),but they respond by hypertrophy. This remodeling process allows the heart to pump effectively against the elevated pressure. As a result, contractile performance of the left ventricle remains unaltered in hypertensive models (including humans) for a long time until decompensation takes place.99 In hypertension, amplification of dP/dt max (maximum rate of change of left ventricular pressure during isovolumetric phase of contraction) by the hypertrophied heart is analogous to the hemodynamic amplifying capacities of the peripheral arterioles. With continuing left ventricular hypertrophy, however, there is encroachment on the lumen of the ventricle and eventual limitation of diastolic filling and stroke volume.40Furthermore, coronary circulation was found to be altered because of rarefaction of microcirculatory architecture in the hypertrophied heart.74,lo5 Left ventricular hypertrophy in hypertension may be the phenotypic expression of genetic disturbances. Circulating neurohumoral factors (such as catecholamines) may stimulate an intracellular proto-oncogene (c-myc) and DNA-directed protein synthesis.9zOther proto-oncogenes have been also in~riminated.~~ Alterations in structural myocardial components may also involve changes in collagen composition of the myocardium.13Diastolic heart failure occurs particularly in the elderly with associated coronary artery disease.lol Because left ventricular diastolic filling is determined to a great extent by atrial contraction, the occurrence of atrial fibrillation in these patients results in further impairment of cardiac pump function.lo7
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LEFT VENTRICULAR DIASTOLIC FUNCTION IN HYPERTENSION
The decrease of diastolic function in hypertension appears to be genetically determined. Changes in gene expression of proteins that 48 Understandregulate intracellular calcium handling were described.26, ing calcium kinetics allows better understanding of the mechanism of these changes. When the cell is electrically excited and the sarcolemma membrane is depolarized, calcium enters the cell via the voltage-dependent slow calcium channels, triggering release of calcium from the sarcoplasmic reticulum into the cytosol. Cytosolic calcium allows myosin-actin interaction, cross-bridge cycling, and force development (systole). Then calcium is pumped out of the cytoplasm into the sarcoplasmic reticulum. This is an energy-requiring mechanism because calcium goes from low to high concentration gradient. In addition, calcium is pumped outside the cell across the sarcolemma. Therefore, the left ventricular diastolic tone is achieved (resting tone). Calcium-adenosine triphosphatase (ATPase) is a critical enzyme involved in myocardial relaxation. It causes hydrolysis of ATP and release of the energy needed to sequester calcium in the sarcoplasmic reticulum. In the hypertrophied heart, its density decreases relative to the increase in left ventricular muscle mass leading to a reduction in its capacity to sequester calcium rapidly. This was demonstrated in animal models and tissue from humans with severe heart failure. Also, sodium/calcium exchanger in sarcolemmal cell membrane (which is primed by the sodium/potassium-ATPdependent pump) was found to be altered in left ventricular hypertrophy. These two pumps are genetically determined. The effect of the renin-angiotensin system on diastolic left ventricular function has received extensive attention. The antihypertensive effects of ACE inhibitors correlate poorly with measurable plasma levels of plasma renin activity, ACE activity, and angiotensin 11. Cardiac models of experimental left ventricular hypertrophy owing to pressure overload (banded ascending aorta just above aortic valve) allowed studying the heart in the normal condition and during concentric left ventricular hypertrophy with normal systolic function. It was found that the cardiac renin-angiotensin system is activated in conjunction with increased expression of messenger RNA for ACE in the left ventricle but not in the right ventricle; this was associated with an increase in tissue ACE Others showed increased ACE by autoradiography of the isolated heart (from aortic banded models) infused with angiotensin I in the coronary arteries. This finding indicated intracardiac conversion of angiotensin I to angiotensin 11; indeed, angiotensin I1 measured in the coronary venous effluent increased two to three fold the normal. This effect was found to be mediated by ACE and blunted by ACE inhibitors. Angiotensin I1 is not only a cardiac and vascular growth factor (direct and via increased afterload), but also it regulates the coronary vascular flow via coronary vasoconstriction and seems to be playing a role in slowing left ventricular relaxation in left ventricular hypertrophy (the
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mechanism mediating this effect on left ventricular relaxation is still unclear). Schunkert and co-workersE7showed that infusion of angiotensin I at constant flow rate caused increased coronary perfusion pressure in both normal and hypertrophied hearts; parallel infusion of enalaprilat significantly diminished angiotensin I effects on coronary perfusion pressure. Eberli and associatesz5demonstrated an increase of left ventricular end diastolic pressure to a significantly higher level in hypertrophied hearts than nonhypertrophied hearts exposed to ischemic stimulus. Enalaprilat had no effect in nonhypertrophied hearts, but it attenuated the greater increase in left ventricular end diastolic pressure in the hypertrophied hearts (low-flow ischemia experiments). In addition, it was shown that repetitive ischemic reperfusion produced an elevation of left ventricular end diastolic pressure at the baseline and at the end of each reperfusion cycle and even at the end of 25 minutes of final reperfusion in both control rats and rats with left ventricular hypertrophy. The recovery of left ventricular end diastolic pressure in each reperfusion cycle was more incomplete and progressively deteriorated in the left ventricular hypertrophy group. Friedrich and colleagues38also showed in human studies that left ventricular end diastolic pressure declined significantly in response to 15 minutes of intracoronary enalaprilat infusion as compared to baseline in patients with aortic stenosis and in patients with dilated cardiomyopathy. The aortic stenosis patients with the highest elevation of left ventricular end diastolic pressure showed the greatest improvement with intracoronary enalaprilat. The reduction of left ventricular diastolic function in left ventricular hypertrophy is partly due to the abnormality of passive properties of the left ventricle. The left ventricular wall is not only thickened, but also it becomes more fibrotic, which results in poor distensibility.l2,77 Diastole consists of two time frames: the early diastolic period (filling and relaxation) and the late (atrial emptying) phase, which depends, to a great extent, on the left atrial pressure, left ventricular contractility, and the ability of the left ventricle to relax. When the left ventricle is unable to relax, its left ventricular end diastolic pressure increases, and its filling is achieved mainly by increased left atrial pressure as it exceeds left ventricular end diastolic pressure. This was recognized several years ago as an accentuation of the P-wave amplitude in the electrocardiogram of hypertensive patients.98 Studies of left ventricular diastolic function in hypertensive patients became possible with the advent of noninvasive techniques for the assessment of cardiac function in humans. It was demonstrated by various groups of investigators that diastolic filling rate is reduced in a proportion of hypertensive patients and that the diastolic filling abnormalities may even precede left ventricular hypertrophy or abnormalities of left ventricular systolic function.32Furthermore, left ventricular diastolic dysfunction was found to be correlated with left ventricular mass in hypertensive patients, and in general it improved during regression
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of left ventricular h y p e r t r ~ p h y .It~ ~was also found to be unaltered, however, in physiologic left ventricular h y p e r t r ~ p h y Thus, . ~ ~ the exact determinants of left ventricular diastolic dysfunction in hypertension are still unknown. There is suggestive evidence that it may be related to abnormalities of calcium kinetics, which perhaps explain why calcium channel blockers were frequently quoted as effective agents in improving left ventricular diastolic dysfunction in hypertension.8
Regional Left Ventricular Diastolic Function In real life, patients have several comorbid events. The presence of coronary artery disease leads to variations in perfusion in the different regions of the myocardium. The radionuclide method allows determination of the regional variations in diastolic function. This method is attractive because it is noninvasive and data are digital, which allows for rapid mathematical analysis.6Asynchronous regional left ventricular diastolic function is particularly interesting in the presence of ischemic myocardial changes. Several approaches were proposed to achieve this goal: (1) Sectional volume curves include septal, apical, and lateral sections.76(2) In the four-quadrant method? data are generated from the outer two thirds pixels in each quadrant of the left ventricle. Regional homogeneity in the time-to-peak filling rate is examined and used for comparisons. (3) Freeman and colleagues36reported on the second harmonic data defined on a pixel-by-pixel basis; an image is displayed that represents time from minimum counts to one half filling rather than peak filling. When they compared the diastolic images to abnormalities of coronary anatomy, they found that their diastolic images correlated better with potentially ischemic vascular beds than did visual systolic wall motion analysis. (4)Two harmonic time-activity curve96was used displaying time-to-peak filling rate for each pixel in the left ventricular region of interest; gaussian distribution characterized normal blood flow, whereas a bimodal distribution characterized coronary artery disease.
Ambulatory Monitoring of Left Ventricular Diastolic and Systolic Function Ambulatory monitoring of left ventricular diastolic and systolic function has become possible by the use of a special monitoring device, a portable nuclear VEST monitor. This device was initially described by Wilson and colleagues in 1983.’06Although its clinical applications have not reached an optimum at present, one may foresee important applications to various situations relevant to transient left ventricular dysfunction that occur during routine activity of patients with cardiovascular diseases.34
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PATHOPHYSIOLOGIC BASIS FOR THE USE OF INDIVIDUALIZED TREATMENT OF HYPERTENSION
Studies from different centers have proven the efficacy of standard stepped-care therapy in controlling blood pressure in hypertensive patients. The beneficial effect of this blood pressure reduction was shown to decrease hypertensive complications such as cerebrovascular accidents, congestive heart failure, and nephropathy. In particular, prolongation of life in treated patients with mild hypertension (diastolic blood pressure = 90 to 104 mm Hg) was shown by the HDFP study. Also the Australian National Blood Pressure Trial' showed fewer deaths from cardiovascular causes for treated hypertensive patients with diastolic blood pressure 95 to 109 mm Hg compared to a placebo-treated control group. More recently, the JNC V provided recommendations for treatment of hypertension based on outcomes of large trials in hypertensive patients, consideration of patients' medical conditions and needs, and consideration of cost of medications.61 Despite these satisfactory results, the stepped-care therapy does not take into account the heterogeneity of essential hypertension, including volume-dependent, renin-dependent, and cardiogenic varieties among others. The question remains as to whether the stepped-care therapy is the most advantageous and most cost-effective as compared to a more individualized treatment approach. An individualized approach could, at least theoretically, achieve the same goal of controlling blood pressure in a shorter time, with fewer medications, and maintain this blood pressure control for longer periods by targeting therapy to the underlying pathophysiologic mechanism that maintains hypertension. Individualization of therapy may be based on various approaches. The hemodynamic profile, however, provides accurate objective measures of the multiple cardiovascular indices prevailing in a particular subject. Recognition of these various hemodynamic disturbances associated with or leading to hypertension allows setting specific goals for their normalization. The minimum essential measurements should include cardiac output and systemic resistance because blood pressure is proportional to the product of these two indices. Other hemodynamic indices, however, should not be ignored, such as blood volume, cardiac function, myocardial perfusion, venous tone, speed of the circulation, presence of arrhythmias, and presence of ventricular hypertrophy. SUMMARY
The hemodynamic factors in hypertension should be evaluated in terms of early versus late stages, autoregulation versus amplifying mechanisms, and arterial compliance versus arteriolar vasoconstrictive responses. In addition, evaluation of hemodynamic changes in hypertension should include the role of vascular endothelium, genetic factors, volume factors, salt intake, vascular reactivity, presence or absence of
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left ventricular hypertrophy or left ventricular diastolic dysfunction, and finally the presence of left ventricular systolic failure. Whether therapy directed by knowledge of hemodynamic profiling will be more eficacious or more cost-effective than standard therapy in reducing morbidity and mortality of hypertension needs to be proven. ACKNOWLEDGMENT The author acknowledges Heidi Raynor for preparation of the manuscript.
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43. Ganten D, Takahashi S, Lindpaintner K, et a 1 Genetic basis of hypertension. Hypertension 18(suppl 3):109-114, 1991 44. Gibbons G, Dzau V: The emerging concept of vascular remodeling. N Engl J Med 3301431-1438, 1994 45. Granger CB, Karimeddini MK, Smith VE, et al: Rapid ventricular filling in left ventricular hypertrophy: I. Physiologic hypertrophy. J Am Coll Cardiol 5869-874, 1985 46. Gross-Sawicka E, Shehadeh A, Hanna M, et al: Influence of initial blood pressure on vascular reactivity. Am J Noninvas Cardiol 8:352-359, 1994 47. Guyton A, Hall J, Lohmeier T, et al: Position paper: The concept of whole body autoregulation and the dominant role of the kidneys for long-term blood pressure regulation. Front Hypertens Res 125-134, 1981 48. Gwathmey J, Morgan J: Altered calcium handling in experimental pressure overload in the ferret. Circ Res 57836, 1985 49. Haddy FJ, Pamani MB Role of dietary salt in hypertension. J Am Coll Nutr 14428438, 1995 50. Hata A, Namikawa C, Sasaki M, et a1 Angiotensinogen as a risk factor for essential hypertension in Japan. J Clin Invest 931285-1287,1994 51. Hayoz D, Bemardi L, No11 G, et al: Flow-diameter phase shift: A potential indicator of conduit artery function. Hypertension 26:20-25, 1995 52. Hilbert P, Lindpaintner K, Beckmann J, et al: Chromosomal mapping of two genetic loci associated with blood pressure regulation in hereditary hypertensive rats. Nature 353521-528, 1991 53. Hollenberg NK, Williams G H Abnormal renal sodium handling in essential hypertension. Am J Med 81:412418,1986 54. Jackson TR, Blair LAC, Marshal J, et a 1 The mas oncogene encodes an angiotensin receptor. Nature 355437440, 1988 55. Jacob H, Lindpaintner K, Lincoln S, et a1 Genetic mapping of a gene causing hypertension in the stroke prone spontaneously hypertensive rat. Cell 67213-224, 1991 56. Joannides R, Richard V, Haefeli W, et al: Role of basal and stimulated release of nitric oxide in the regulation of radial artery caliber in humans. Hypertension 26327-331, 1995 57. Johnson P:Autoregulation of blood flow. Circ Res 59:483-495, 1986 58. Johnston C: Tissue angiotensin converting enzyme in cardiac and vascular hypertrophy, repair, and remodeling. Hypertension 23958-268, 1994 59. Julius S, Conway J: Hemodynamic studies in patients with borderline blood pressure elevation. Circulation 38:282-288, 1968 60. Tulius S, Randall 0, Esler, et a 1 Altered cardiac responsiveness and regulation in the normal cardiac output type of borderline hypertension. Circ Res 3qsuppl 1):199207. 1975 61. Kaplan NM, Gifford RW Jr: Choice of initial therapy for hypertension. JAMA 275~1577-1580, 1996 62. Kawasaki T, Delea CS, Bartter FC, et al: The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am J Med 64:193-198, 1978 63. Kenney M, Seals D: Postexercise hypotension: Key features, mechanisms, and clinical significance. Hypertension 23:653-664, 1993 64. Koller A, Huang A Shear stress-induced dilation is attenuated in skeletal muscle arterioles of hypertensive rats. Hypertension 25(pt 2):758-763, 1995 65. Komer P: Causal and homeostatic factors in hypertension. Clin Sci 63:5~-26s,1982 66. Komer P, Bobik A, Oddie C, et a1 Sympathoadrenal system is critical for structural changes in genetic hypertension. Hypertension 22243-252,1993 67. Laurent S, Caviezel B, Beck L, et al: Carotid artery distensibility and distending pressure in hypertensive humans. Hypertension 23(pt 2):878-883, 1994 68. Ledingham J, Pelling D: Hemodynamic and other studies in the renoprival hypertensive rat. J Physiol 210235253, 1970
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69. Lindpainter K Blood pressure and heredity: Is it all in the genes, or not? Blood Press Hered 22:147-149, 1993 70. Lindpainter K, Takahashi S, Ganten D: Structural alterations of the renin gene in stroke-prone spontaneously hypertensive rats: Examination of genotype-phenotype correlations. J Hypertens 8763-773, 1990 71. Luft FC, Rankin LI, Henry DP, et al: Plasma and urinary norepinephrine values at extremes of sodium intake in normal man. Hypertension 1:261-266, 1979 72. Lundgren Y, Hallback M, Weiss L, et al: Rate extent of adaptive cardiovascular changes in rats during experimental renal hypertension. Acta Physiol Scand 91:103115, 1974 73. MacGregor GA: Sodium is more important than calcium in essential hypertension. Hypertension 7628-640, 1985 74. Marcus M, Mueller T, Gascho J, et a1 Effects of cardiac hypertrophy secondary to hypertension on the coronary circulation. Am J Cardiol 44:1023-1028, 1979 75. McGrath B, Tiller D, Bune A, et a1 Autonomic blockade and the Valsalva maneuver in patients on maintenance dialysis: A hemodynamic study. Kidney Int 12294-302,1997 76. Miller T, Goldman K, Sampathkumaran K, et al: Analysis of cardiac diastolic function: Application in coronary artery disease. J Nucl Med 24:2-7, 1983 77. Mukherjee D, Sen S: Collagen phenotype during development and regression of myocardial hypertrophy in spontaneously hypertensive rats. Circ Res 6714751480, 1990 78. ORourke M Mechanical principles in arterial disease (United States). Hypertension 26:2-9, 1995 79. Osol G, Halpem W Pre-existing level of tone is an important determinant of cerebral artery autoregulatory responsiveness. Hypertension 767s-69s, 1989 80. Panza J, Casino P, Kilcoyne C, et al: Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 871468-1474, 1993 81. Panza JA, Quyyimi AA, Callahan TS, et al: Effect of antihypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertension. J Am Coll Cardiol21:1145-1151, 1993 82. Rossi GP, Belloni AS, Albertin G, et al: Endothelin-1 and its receptors A and B in human aldosterone-producing adenomas. Hypertension 25S42-847, 1995 83. Rutan G, Hermanson 8, Bild D, et al: Orthostatic hypotension in older adults. Hypertension 19:508-519, 1992 84. Safar M, Frohlich E: The arterial system in hypertension. Hypertension 2610-14, 1995 85. Safar M, Weiss Y, Levenson J, et al: Hernodynamic study of 85 patients with borderline hypertension. Am J Cardiol 31:315-319, 1973 86. Samani N, Brammar W, Swales J: A major structural abnormality in the renin gene of the spontaneously hypertensive rat. J Hypertens 7249-254, 1989 87. Schunkert H, Jackson B, Tang S, et al: Distribution and functional significance of cardiac angiotensin converting enzyme in hypertrophied rat hearts. Circulation 871328-1339, 1993 88. Schutzman J, Jaeger F, Maloney JD, et al: Head-up tilt and hemodynamic changes during orthostatic hypotension in patients with supine hypertension. J Am Coll Cardiol 24:454-461, 1994 89. Simon A, Levenson J: Abnormal wall shear conditions in the brachial artery of hypertensive patients. Hypertension 8:109-114, 1990 90. Sivertsson R: The hemodynamic importance of structural vascular changes in essential hypertension. Acta Physiol Scand (suppl 343):l-56, 1970 91. Sowers JR, Zemel MB, Zemel P, et al: Salt sensitivity in blacks: Salt intake and natriuretic substances. Hypertension 12:485490, 1988 92. Starksen NF, Simpson PC, Bishopric N, et al: Cardiac myocyte hypertrophy is associated with c-myc proto-oncogene expression. Proc Natl Acad Sci USA 83:8348-8350, 1986 93. Streeten D Orthostatic hypotension and hypertension. In Izzo J, Black H, Taubert K, et a1 (eds): Hypertension Primer. Council on High Blood Pressure Research, Dallas, TX, Heart Association, 1993, pp 224-225
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94. Sullivan JM, Ratts TE, Taylor JC, et al: Hemodynamic effects of dietary sodium in man: A preliminary report. Hypertension 2:50&514, 1980 95. Takeshita A, Mark A L Decreased vasodilator capacity of forearm resistance vessels in borderline hypertension. Hypertension 2610-616, 1980 96. Tamaki N, Yasuda T, Moore R, et al: Continuous monitoring of left ventricular function by an ambulatory radionuclide detector in patients with coronary artery disease. J Am Coll Cardiol 126694579, 1988 97. Tarazi R, Gifford R Jr: Systemic arterial pressure. In Sodeman, Sodeman (eds): Pathologic Physiology: Mechanisms of Disease. Philadelphia, WB Saunders, 1985, pp 228260 98. Tarazi R, Miller A, Frohlich E, et al: Electrocardiographic changes reflecting left atrial abnormality in hypertension. Circulation 34818-822, 1996 99. Tarazi RC, Fouad FM: Assessment of cardiac status in hypertensive patients. J Hypertens 3(suppl):S27-31, 1985 100. Ting C, Yang T, Chen J, et al: Arterial hemodynamics in human hypertension. Hypertension 22839446, 1993 101. Topol EJ, Trail1 TA, Fortuin NJ: Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 312277-283, 1985 102. Vanhoutte PM: Endothelium and control of vascular function. Hypertension 13:658667, 1989 103. Weinberger MH, Fineberg NS: Sodium and volume sensitivity of blood pressure: Age and blood pressure change over time. Hypertension 18:67-71, 1991 104. Weinberger MH, Stegner JE, Fineberg N S A comparison of two tests for the assessment of blood pressure responses to sodium. Am J Hypertens 6:179-184, 1993 105. Wicker P, Tarazi RC, Kobayashi K Coronary blood flow during the development and regression of left ventricular hypertrophy in renovascular hypertensive rats. Am J Cardiol51:1744-1749, 1983 106. Wilson R, Sullivan P, Moore R, et al: An ambulatory ventricular function monitor: Validation and preliminary clinical results. Am J Cardiol 52601, 1983 107. Yellin EL, Sonnenblick EH, Frater RWM: Dynamic determinants of left ventricular filling: An overview. In Baan J, Amtzenius AC, Yellins EL (eds): Cardiac Dynamics. The Hague, Martinus Nijhoff, 1980, pp 145158
Address reprint requests to Fetnat M. Fouad-Tarazi, MD The Cleveland Clinic Foundation Research Institute 1 Clinic Center 9500 Euclid Ave. Cleveland, OH 44195-5069
0025-7125/97 $0.00
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HYPERTENSION HEMODYNAMICS Fetnat M. Fouad-Tarazi, MD
Arterial blood pressure is determined by cardiac output and systemic vascular resistance so that pressure = flow x resistance. Various hemodynamic patterns, therefore, may lead to the same level of blood pressure. This information indicates that blood pressure measurement per se reflects the net effect of hemodynamic alterations, which may vary as the underlying adaptive cardiovascular changes take place. To that effect, the determinants of blood pressure level include factors that affect both cardiac output and arteriolar vascular physiology. Venous return, myocardial contractility and relaxation, circulating blood volume, heart rate, and adrenergic activity are known to influence cardiac outVascular resistance is affected by the autonomic nervous system and neurohormonal vasoconstrictors, including catecholamines, arginine vasopressin (AVP), endothelins, and tissue and circulating angiotensin II.lo0Modern hemodynamic understanding demonstrated the important role of the vascular endothelium in the regulation of the degree of vasoconstriction or vasodilation, including intrinsic and extrinsic mechanisms.18 The potential relevance of blood viscosity, vascular wall shear conditions (rate and stress), and blood flow velocity (mean and pulsatile components) on vascular endothelial function has been shown in hu56, 64, m,89 In addition, previous findings by Folkow28and KorneF5 man~.’~, indicated that vascular wall thickness participates in the amplification of changes in vascular resistance in hypertensive patients. Not to be forgotten are the effects of large arterial stiffness as well as the baroreflex resetting mechanisms producing neural feedback loops that regulate the cardiovascular dynamics and consequently blood pressure level.3*27* 37,41 From The Cleveland Clinic Foundation, Department of Cardiology/Molecular Cardiology, Cleveland, Ohio
MEDICAL CLINICS OF NORTH AMERICA
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Baro-reflexes were shown to be important not only in orthostatic blood 88, 93 but also in postexercise h y p ~ t e n s i o n . ~ ~ pressure reg~lation,8~, EARLY VERSUS ESTABLISHED ESSENTIAL HYPERTENSION
Early onset of hypertension is difficult to determine in humans. Various animal studies in the spontaneously hypertensive rat (SHR), a model close enough to human essential hypertension, however, have shown that the initiating hemodynamic disturbance in early hypertension is an increased flow and cardiac Many human studies have shown that borderline hypertension is characterized by increased cardiac output without change of peripheral resistance.59,60, 85, 97 The mechanism of this increased cardiac output has not been clearly identified. Julius and colleagues60pointed out the importance of the sympathetic nervous system in early hypertension as well as in borderline hypertension. High-output hypertensi~n~~ was described in early borderline essential hypertension, in some patients with long-standing hypertension, and in steroid-mediated hypertension. High-output hypertension has been classified into that dependent on peripheral factors (increased tissue demands or hypervolemia) and that related to cardiac stimulation (adrenergic hyperactivity or slight hypokalemia combined with hypercalcemia). Whether the sodium-calcium exchange cellular mechanism plays a role in this type of hypertension has not been confirmed.49Increased cardiac output may be associated with a short circulation time and rapid heart rate, reflecting a hyperkinetic circulation, or the increased cardiac output may occur alone, in which case it represents central translocation of blood volume. In its chronic established phase, essential hypertension is characterized by a normal (or reduced) cardiac output and elevated systemic vascular resistance, generally linked to a decreased diameter of the arteriolar lumen.97The exact mechanism of this excessive vasoconstriction in chronic essential hypertension and other types of established hypertension is not known but has been the subject of extensive studies and hypotheses. The increased systemic resistance was generally related either to an active process or to rarefaction of the vascular bed. Active vasoconstriction was attributed to increased production of vasoactive factors, to enhanced reactivity of the smooth muscle cells; or to structural changes in the vessel wall leading to a reduction in the lumen-towall ratio.28 It is not known if more than one factor may be present at one time or if an interchange between these various factors may occur at different phases of the hypertensive d i ~ e a s eThe . ~ theory of autoregulation has prevailed for a long time.57This theory postulated that the initial high cardiac output leads to overperfusion of tissues in excess of the metabolic needs of these tissues, and it is this overperfusion that triggers an increase in active tension of the vascular smooth muscles of the resistance vessels57;as a result, a secondary reactive increase in systemic
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vascular resistance occurs to counterbalance the increase in flow and eventually restore cardiac output to a normal value. This autoregulation theory has been strongly supported by Guyton and colleague^'^, 20, 21, 47 and by Ledingham and Pelling.6sSupport to this hypothesis came from studies in patients and animals with gross renal impairment. It was demonstrated that in renovascular hypertension fluid overload is associated with an initial increase in cardiac output, whereas sequential hemodynamic studies over 1 to 2 weeks demonstrated a later development of an increase of systemic vascular resistance in association with restoration of cardiac output.75Contrary to this adaptive hypothesis was the demonstration that actual pathologic changes in the peripheral vasculature mediate the increase of vascular resistance.28,29* 65, 90 Indeed, FolkowZsand Korner and showed the importance of hypertrophy of the muscles of the resistance vessels in amplifying the pressor stimuli. In experimental studies of renal hypertension, it was demonstrated that vascular hypertrophy occurs within the initial 10 to 20 days after applying the renal artery clip.72It was also demonstrated that in these hypertensive models, there was an accentuation of the vascular responsiveness to exogenous noradrenalin, angiotensin 11, and vasopressin as compared to normal controls.2 Also, Panza and co-workerss0 showed that patients with hypertension are predisposed to a more pronounced hypertensive response to any given vasoconstrictor agent. The mechanism of the accentuated hypertensive response to vasoconstrictive stimuli in hypertensive subjects was thought to be related not only to alterations in the structural and physical properties of resistance arteries, but also to the changes in endothelial function. In their study, Panza and co-workerss0 showed that normalization of blood pressure with conventional antihypertensive therapy for at least 5 years did not improve the blunted response to endothelium-dependent agents that was described in hypertensive patients. Therefore, it was suggested that the endothelial abnormality may play a primary role in the genesis of hypertension or may perpetuate the hypertensive process. An increased production of an endothelial dependent contracting factor102remains only speculative. The concept of vascular remodelinp has been further explored when the role of the vascular endothelium became well recognized; the vascular endothelium plays a major role in the initiation of vascular changes because of its direct interaction with the intraluminal physical forces and biochemical mediators as well as its ability to secrete endogenous vasoactive and growth regulating substances. The remodeling process of the vascular wall (vascular hypertrophy), therefore, appears to participate in the maintenance of increased vascular resistance in hypertension whatever the initial hemodynamic pattern. It was also demonstrated in vitro that the preexisting level of vascular tone is an important determinant of arterial autoregulatory responsi~eness.~~ Looking at the question in a different way, the author has examined the immediate, moment-to-moment, regulatory vascular functional changes that occur when blood pressure is altered acutely in hypertensive patients.% Data indicated that the acute change of blood
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pressure did not alter the changes in forearm vascular resistance induced by cold pressor stimulus or during postischemic reactive hyperemia. It was concluded that the magnitude of forearm vascular resistance is an inherent property of the vessel wall rather than a dynamic function that varies according to the initial level of blood pressure. GENETIC FACTORS IN PRIMARY HYPERTENSION
The new challenge is the finding of a genetic basis for these changes in human hyperten~ion.4~ The mode of inheritance of primary hypertension appears to be complex. Hypertension represents a polygenic trait that shows strong dependence on multiple environmental factors as well as a heterogeneity of genes that are or could be involved in the process.69 It is not yet clear if essential hypertension is related to an individual genetic factor or multiple genes may be involved. Animal experimentation allows a much more precise study of environmental factors as well as of genetic factors. Cosegregation and linkage analyses have been used for the investigation of inbred strains. Genetic analysis in human hypertension demonstrated positive linkage for the renin and angiotensin-converting enzyme (ACE) genes similar to that found in animal experiment^.^^, Studies from Hata and colleagues50and Caulfield and associates15 implicated a role for angiotensinogen in human hypertension. Several other genes have been investigated as candidate genes in hypertension, including angiotensin I1 receptor gene, and endothelial nitric oxide synthase gene and angiotensinogen gene.58The difficulties in such studies stem from the fact that negative results do not necessarily rule out the role of a particular gene because differences may exist among various families. ffi
SALT SENSITIVITY, AUTONOMIC NERVOUS SYSTEM, AND VOLUME FACTORS IN HYPERTENSION
A major unresolved issue in understanding the pathogenesis of hypertension is the sensitivity of some individuals to alterations in dietary sodium intake. The association between sodium consumption and arterial blood pressure has been the subject of extensive studies in humans as well as in experimental animals.*,22, 24, 49, 71, 91, 94 It is well recognized that certain patients with hypertension respond differently to a high sodium intake; some have an increase, whereas others have either unchanged or a decrease in blood pressure during salt loading. The mechanism by which sodium elevates blood pressure in some patients with hypertension remains unclear. Various hypotheses were examined, including genetic, pathologic, hemodynamic, and hormonal factors. Weinberger and colleagues''''' described a sluggish renal adaptation to dietary sodium restriction in salt-sensitive patients. Campese and as~ociates'~ suggested that the sympathetic nervous system may also
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contribute to the heterogeneity of blood pressure response to sodium intake. Hollenberg and Williams53 implicated the combined effect of altered renal vascular response to a salt load and a decreased aldosterone response to angiotensin I1 in nonrnodulators, who had blood pressure responses as salt-sensitive patients. Studies by the author have shown that this blood pressure sensitivity to salt intake is unrelated to the amount of salt retained or to the basal levels and responsiveness of plasma catecholamines, plasma renin activity, and aldosterone p r o d ~ c t i o n The . ~ ~ most consistent finding in these studies was the demonstration that salt-sensitive patients respond to a high salt diet by an increase in systemic vascular resistance, whereas in salt-resistant patients blood pressure remained essentially unchanged because changes in flow were negated by adaptive changes in systemic vascular resistance, indicating that salt-resistant patients were more able to adapt to salt loading by reducing the peripheral vascular resistance. It was also found that salt-sensitive patients had reduced sensitivity of low pressure receptors in response to a decrease of preload as compared to salt-resistant patients.’O, 11, 35 In addition, although responses to vasodilator stimuli were comparable in both salt-sensitive and salt-resistant patients, the salt-resistant group exhibited a higher sensitivity of the vascular resistance to direct a-adrenergic stimulation as compared to salt-sensitive ~atients.3~ This finding was again taken in favor of the higher adaptability of the cardiovascular system in salt-resistant patients. The geometric structure of the aorta and large vessels may also be important determinants in the blood pressure response to sodium intake. For example, low sodium intake was reported to reduce vascular wall stiffness in cross-sectional studies using pulse wave velocity measurement: and arterial compliance was found to be reduced in the carotid, brachial, and femoral arteries of salt-sensitive subjects with borderline hypertension.u, 67 These findings led to the suggestion that high salt intake in these subjects modifies the viscoelastic properties of the large arteries; this interesting assumption has not been proven by morphologic studies. HEMODYNAMICS OF ISOLATED SYSTOLIC HYPERTENSION
Mechanical principles regulate the function of large arteries.78Reduced aortic distensibility is well recognized particularly in advanced age groups. As a result, there is loss of the Windkessel function of the arterial tree, so that the relationship between stroke volume and arterial recoil is altered leading to a selective or predominant rise of systolic blood pressure.%In general, one may subdivide the cause of this systolic hypertension into remediable functional causes (such as increased stroke volume and increased adrenergic activity) and nonremediable structural causes (such as atherosclerotic changes of the vascular walls). In young people, isolated systolic hypertension is usually related to increased
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stroke volume.31Arterial compliance can be measured in humans by invasive and more recently by noninvasive validated method^.^ Changes induced by therapeutic interventions may therefore be assessed. Improvement of large arterial compliance should be a goal of antihypertensive therapy because systolic blood pressure is an important determinant of myocardial wall stress and myocardial oxygen requirement as well as of cerebral perfusion. Also, abnormal arterial compliance has been shown to be associated with abnormalities in baroreceptor function.16 Finally the mechanical effect of increased pulse pressure (increased oscillatory variations) that results from decreased arterial compliance may make the arterial wall more susceptible to pathologic changes affecting the physical properties of the intima and subintimal layers? Such a feature may suggest that changes in arterial compliance may indeed precede the occurrence of atherosclerosis at least in some patients.
LEFT VENTRICULAR HYPERTROPHY IN HYPERTENSION
The myocardium undergoes structural changes in response to the increased afterload. Because cardiac myocytes are terminally differentiated, they cannot replicate (hyperplasia),but they respond by hypertrophy. This remodeling process allows the heart to pump effectively against the elevated pressure. As a result, contractile performance of the left ventricle remains unaltered in hypertensive models (including humans) for a long time until decompensation takes place.99 In hypertension, amplification of dP/dt max (maximum rate of change of left ventricular pressure during isovolumetric phase of contraction) by the hypertrophied heart is analogous to the hemodynamic amplifying capacities of the peripheral arterioles. With continuing left ventricular hypertrophy, however, there is encroachment on the lumen of the ventricle and eventual limitation of diastolic filling and stroke volume.40Furthermore, coronary circulation was found to be altered because of rarefaction of microcirculatory architecture in the hypertrophied heart.74,lo5 Left ventricular hypertrophy in hypertension may be the phenotypic expression of genetic disturbances. Circulating neurohumoral factors (such as catecholamines) may stimulate an intracellular proto-oncogene (c-myc) and DNA-directed protein synthesis.9zOther proto-oncogenes have been also in~riminated.~~ Alterations in structural myocardial components may also involve changes in collagen composition of the myocardium.13Diastolic heart failure occurs particularly in the elderly with associated coronary artery disease.lol Because left ventricular diastolic filling is determined to a great extent by atrial contraction, the occurrence of atrial fibrillation in these patients results in further impairment of cardiac pump function.lo7
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LEFT VENTRICULAR DIASTOLIC FUNCTION IN HYPERTENSION
The decrease of diastolic function in hypertension appears to be genetically determined. Changes in gene expression of proteins that 48 Understandregulate intracellular calcium handling were described.26, ing calcium kinetics allows better understanding of the mechanism of these changes. When the cell is electrically excited and the sarcolemma membrane is depolarized, calcium enters the cell via the voltage-dependent slow calcium channels, triggering release of calcium from the sarcoplasmic reticulum into the cytosol. Cytosolic calcium allows myosin-actin interaction, cross-bridge cycling, and force development (systole). Then calcium is pumped out of the cytoplasm into the sarcoplasmic reticulum. This is an energy-requiring mechanism because calcium goes from low to high concentration gradient. In addition, calcium is pumped outside the cell across the sarcolemma. Therefore, the left ventricular diastolic tone is achieved (resting tone). Calcium-adenosine triphosphatase (ATPase) is a critical enzyme involved in myocardial relaxation. It causes hydrolysis of ATP and release of the energy needed to sequester calcium in the sarcoplasmic reticulum. In the hypertrophied heart, its density decreases relative to the increase in left ventricular muscle mass leading to a reduction in its capacity to sequester calcium rapidly. This was demonstrated in animal models and tissue from humans with severe heart failure. Also, sodium/calcium exchanger in sarcolemmal cell membrane (which is primed by the sodium/potassium-ATPdependent pump) was found to be altered in left ventricular hypertrophy. These two pumps are genetically determined. The effect of the renin-angiotensin system on diastolic left ventricular function has received extensive attention. The antihypertensive effects of ACE inhibitors correlate poorly with measurable plasma levels of plasma renin activity, ACE activity, and angiotensin 11. Cardiac models of experimental left ventricular hypertrophy owing to pressure overload (banded ascending aorta just above aortic valve) allowed studying the heart in the normal condition and during concentric left ventricular hypertrophy with normal systolic function. It was found that the cardiac renin-angiotensin system is activated in conjunction with increased expression of messenger RNA for ACE in the left ventricle but not in the right ventricle; this was associated with an increase in tissue ACE Others showed increased ACE by autoradiography of the isolated heart (from aortic banded models) infused with angiotensin I in the coronary arteries. This finding indicated intracardiac conversion of angiotensin I to angiotensin 11; indeed, angiotensin I1 measured in the coronary venous effluent increased two to three fold the normal. This effect was found to be mediated by ACE and blunted by ACE inhibitors. Angiotensin I1 is not only a cardiac and vascular growth factor (direct and via increased afterload), but also it regulates the coronary vascular flow via coronary vasoconstriction and seems to be playing a role in slowing left ventricular relaxation in left ventricular hypertrophy (the
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mechanism mediating this effect on left ventricular relaxation is still unclear). Schunkert and co-workersE7showed that infusion of angiotensin I at constant flow rate caused increased coronary perfusion pressure in both normal and hypertrophied hearts; parallel infusion of enalaprilat significantly diminished angiotensin I effects on coronary perfusion pressure. Eberli and associatesz5demonstrated an increase of left ventricular end diastolic pressure to a significantly higher level in hypertrophied hearts than nonhypertrophied hearts exposed to ischemic stimulus. Enalaprilat had no effect in nonhypertrophied hearts, but it attenuated the greater increase in left ventricular end diastolic pressure in the hypertrophied hearts (low-flow ischemia experiments). In addition, it was shown that repetitive ischemic reperfusion produced an elevation of left ventricular end diastolic pressure at the baseline and at the end of each reperfusion cycle and even at the end of 25 minutes of final reperfusion in both control rats and rats with left ventricular hypertrophy. The recovery of left ventricular end diastolic pressure in each reperfusion cycle was more incomplete and progressively deteriorated in the left ventricular hypertrophy group. Friedrich and colleagues38also showed in human studies that left ventricular end diastolic pressure declined significantly in response to 15 minutes of intracoronary enalaprilat infusion as compared to baseline in patients with aortic stenosis and in patients with dilated cardiomyopathy. The aortic stenosis patients with the highest elevation of left ventricular end diastolic pressure showed the greatest improvement with intracoronary enalaprilat. The reduction of left ventricular diastolic function in left ventricular hypertrophy is partly due to the abnormality of passive properties of the left ventricle. The left ventricular wall is not only thickened, but also it becomes more fibrotic, which results in poor distensibility.l2,77 Diastole consists of two time frames: the early diastolic period (filling and relaxation) and the late (atrial emptying) phase, which depends, to a great extent, on the left atrial pressure, left ventricular contractility, and the ability of the left ventricle to relax. When the left ventricle is unable to relax, its left ventricular end diastolic pressure increases, and its filling is achieved mainly by increased left atrial pressure as it exceeds left ventricular end diastolic pressure. This was recognized several years ago as an accentuation of the P-wave amplitude in the electrocardiogram of hypertensive patients.98 Studies of left ventricular diastolic function in hypertensive patients became possible with the advent of noninvasive techniques for the assessment of cardiac function in humans. It was demonstrated by various groups of investigators that diastolic filling rate is reduced in a proportion of hypertensive patients and that the diastolic filling abnormalities may even precede left ventricular hypertrophy or abnormalities of left ventricular systolic function.32Furthermore, left ventricular diastolic dysfunction was found to be correlated with left ventricular mass in hypertensive patients, and in general it improved during regression
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of left ventricular h y p e r t r ~ p h y .It~ ~was also found to be unaltered, however, in physiologic left ventricular h y p e r t r ~ p h y Thus, . ~ ~ the exact determinants of left ventricular diastolic dysfunction in hypertension are still unknown. There is suggestive evidence that it may be related to abnormalities of calcium kinetics, which perhaps explain why calcium channel blockers were frequently quoted as effective agents in improving left ventricular diastolic dysfunction in hypertension.8
Regional Left Ventricular Diastolic Function In real life, patients have several comorbid events. The presence of coronary artery disease leads to variations in perfusion in the different regions of the myocardium. The radionuclide method allows determination of the regional variations in diastolic function. This method is attractive because it is noninvasive and data are digital, which allows for rapid mathematical analysis.6Asynchronous regional left ventricular diastolic function is particularly interesting in the presence of ischemic myocardial changes. Several approaches were proposed to achieve this goal: (1) Sectional volume curves include septal, apical, and lateral sections.76(2) In the four-quadrant method? data are generated from the outer two thirds pixels in each quadrant of the left ventricle. Regional homogeneity in the time-to-peak filling rate is examined and used for comparisons. (3) Freeman and colleagues36reported on the second harmonic data defined on a pixel-by-pixel basis; an image is displayed that represents time from minimum counts to one half filling rather than peak filling. When they compared the diastolic images to abnormalities of coronary anatomy, they found that their diastolic images correlated better with potentially ischemic vascular beds than did visual systolic wall motion analysis. (4)Two harmonic time-activity curve96was used displaying time-to-peak filling rate for each pixel in the left ventricular region of interest; gaussian distribution characterized normal blood flow, whereas a bimodal distribution characterized coronary artery disease.
Ambulatory Monitoring of Left Ventricular Diastolic and Systolic Function Ambulatory monitoring of left ventricular diastolic and systolic function has become possible by the use of a special monitoring device, a portable nuclear VEST monitor. This device was initially described by Wilson and colleagues in 1983.’06Although its clinical applications have not reached an optimum at present, one may foresee important applications to various situations relevant to transient left ventricular dysfunction that occur during routine activity of patients with cardiovascular diseases.34
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PATHOPHYSIOLOGIC BASIS FOR THE USE OF INDIVIDUALIZED TREATMENT OF HYPERTENSION
Studies from different centers have proven the efficacy of standard stepped-care therapy in controlling blood pressure in hypertensive patients. The beneficial effect of this blood pressure reduction was shown to decrease hypertensive complications such as cerebrovascular accidents, congestive heart failure, and nephropathy. In particular, prolongation of life in treated patients with mild hypertension (diastolic blood pressure = 90 to 104 mm Hg) was shown by the HDFP study. Also the Australian National Blood Pressure Trial' showed fewer deaths from cardiovascular causes for treated hypertensive patients with diastolic blood pressure 95 to 109 mm Hg compared to a placebo-treated control group. More recently, the JNC V provided recommendations for treatment of hypertension based on outcomes of large trials in hypertensive patients, consideration of patients' medical conditions and needs, and consideration of cost of medications.61 Despite these satisfactory results, the stepped-care therapy does not take into account the heterogeneity of essential hypertension, including volume-dependent, renin-dependent, and cardiogenic varieties among others. The question remains as to whether the stepped-care therapy is the most advantageous and most cost-effective as compared to a more individualized treatment approach. An individualized approach could, at least theoretically, achieve the same goal of controlling blood pressure in a shorter time, with fewer medications, and maintain this blood pressure control for longer periods by targeting therapy to the underlying pathophysiologic mechanism that maintains hypertension. Individualization of therapy may be based on various approaches. The hemodynamic profile, however, provides accurate objective measures of the multiple cardiovascular indices prevailing in a particular subject. Recognition of these various hemodynamic disturbances associated with or leading to hypertension allows setting specific goals for their normalization. The minimum essential measurements should include cardiac output and systemic resistance because blood pressure is proportional to the product of these two indices. Other hemodynamic indices, however, should not be ignored, such as blood volume, cardiac function, myocardial perfusion, venous tone, speed of the circulation, presence of arrhythmias, and presence of ventricular hypertrophy. SUMMARY
The hemodynamic factors in hypertension should be evaluated in terms of early versus late stages, autoregulation versus amplifying mechanisms, and arterial compliance versus arteriolar vasoconstrictive responses. In addition, evaluation of hemodynamic changes in hypertension should include the role of vascular endothelium, genetic factors, volume factors, salt intake, vascular reactivity, presence or absence of
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left ventricular hypertrophy or left ventricular diastolic dysfunction, and finally the presence of left ventricular systolic failure. Whether therapy directed by knowledge of hemodynamic profiling will be more eficacious or more cost-effective than standard therapy in reducing morbidity and mortality of hypertension needs to be proven. ACKNOWLEDGMENT The author acknowledges Heidi Raynor for preparation of the manuscript.
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