(Hypertension. 1999;34:782-789.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
From the Alton Ochsner Medical Foundation, New Orleans, La.
Correspondence to Edward D. Frohlich, MD, Alton Ochsner Distinguished Scientist, Vice President for Academic Affairs, Alton Ochsner Medical Foundation, 1516 Jefferson Hwy, New Orleans, LA 70121.
| Abstract |
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Key Words: left ventricular hypertrophy coronary heart disease coronary hemodynamics fibrosis sudden death risk
| Introduction |
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| Earlier-Described Mechanisms Underlying LVH Risk |
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Still highly attractive as an underlying pathophysiological mechanism of risk is impaired coronary hemodynamics, most effectively explained and accepted as being manifested by inadequate coronary flow reserve.28 29 30 31 32 Indeed, this alteration of coronary hemodynamics could very well explain the increasing prevalence of cardiac dysrhythmias, silent ischemia, and sudden cardiac death associated with LVH. Compounding the increasing complexity of this problem is the relatively recent concept of endothelial dysfunction and other altered coronary hemodynamic factors in hypertension. Thus, a defect in the local generation of nitric oxide relating to endothelial dysfunction has also been offered to explain impaired coronary blood flow and relaxation of human coronary resistance vessels.33 34 35 Other factors have been suggested for impaired coronary hemodynamics, including coronary arteriolar compression by the hypertrophied and stiffer LV with a fibrosed ventricular wall (see below); occlusive epicardial coronary arterial disease by an atherosclerotic lesion, which has long been known to be exacerbated by hypertension36 ; increased arteriolar wall thickening and arteriolar wall-to-lumen diameter associated with hypertensive vascular disease37 38 ; inadequate sizing of coronary vessels39 ; increased blood viscosity in hypertension40 41 42 ; and an increased left ventricular chamber diameter reflecting not only myocytic hypertrophy but also collagen deposition and an increased protein matrix.8 12 43 44 45 46 47
Perhaps better appreciated are the underlying functional mechanisms that have been emphasized clinically over the past several decades. Of these, the most accepted alteration of coronary hemodynamics is the increased coronary arteriolar resistance associated with hypertension in all organ circulations.48 49 50 However, this need not be associated with reduced resting coronary blood flow,49 50 51 52 53 although resting ischemia may be important, particularly if associated with occlusive atherosclerotic epicardial coronary arterial disease. However, reduced coronary flow reserve in patients with LVH can be demonstrated relatively early in the asymptomatic stage of the disease by estimating coronary blood flow before and after certain physiological and pharmacological interventions that promote increased demand for coronary flow.29 32 54 55 These alterations in coronary hemodynamics may now be assessed more completely (clinically as well as experimentally) to explain coronary insufficiency and silent ischemia. In this respect, impairment of coronary arteriolar dilation may be engendered not only by the coronary arteriolar constriction of hypertension but also by the endothelial dysfunction.34 35
The remainder of this discussion will focus on some of the newer and current issues related to the intrinsic cardiac alterations associated with hypertensive heart disease: a clear definition of coronary heart disease (CHD), coronary insufficiency, diastolic dysfunction and cardiac failure, ventricular fibrosis, and perhaps the long-standing controversial concern of salt excess (Table). Each of these factors is intimately and directly related to the underlying pathophysiology of hypertensive heart disease and the risk associated with LVH. Some have been summarized before19 20 ; some should be reassessed into our current base of knowledge; several have recently emerged into our thinking; and, no doubt, all may be readapted to our future thinking of risk mechanisms as they, too, evolve.
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| Coronary Heart Disease |
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Most important for consideration is the definition used for CHD. Thus, deaths attributable to CHD by the epidemiologists in these multicenter studies included more end points than just myocardial infarction. Myocardial infarction did not explain all deaths from CHD; other CHD deaths resulted from unstable angina pectoris or unremitting chest pain unconfirmed by autopsy, lethal cardiac dysrhythmias, cardiac failure, or sudden cardiac death. Furthermore, after publication of that meta-analysis, reports appeared relating sudden cardiac death to the higher doses of hydrochlorothiazide (or its equivalents) used for treatment of hypertension and use of potassium-sparing agents to prevent hypokalemia.57 In addition, shortly after completion of the initial 14 multicenter trials in which the thiazides were used in daily doses equivalent to 100 mg hydrochlorothiazide, national recommendations advocated reduction of the initial diuretic dose to 12.5 or 25 mg with subsequent increases to 50 mg as the full doses58 ; this recommendation has persisted.59 60 Thus, when a subsequent meta-analysis was reported, involving elderly hypertensive patients (a population certainly with higher prevalence of atherosclerotic CHD), the actual reduction of CHD was precisely what was predicted originally, 26%; and reduction of deaths from stroke was 40%.61 Hence, the issue raised of failure of therapy to protect from CHD has not been supported. In addition, subsequent studies have demonstrated significant reduction of deaths from CHD as well as from stroke.
| Left Ventricular Hypertrophy |
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| Coronary Insufficiency |
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Endothelial Dysfunction
Whereas this new concept of endothelial
dysfunction is not intended to be the primary focus of the present
discussion, it has become an extremely important mechanism underlying
many aspects of hypertensive cardiovascular disease and
related complicating comorbid disorders. Endothelial
dysfunction has been shown experimentally76 77 78 and
clinically33 34 35 to be a major component of the vascular
disease in hypertension. Other cardiovascular risk
factors, diseases, and conditions that have been implicated in
producing endothelial dysfunction include aging,
menopause, tobacco abuse, diabetes mellitus,
hyperlipidemia, atherosclerosis,
hyperhomocysteinemia, vessel injury, and cardiac
failure.77 Intrinsic to this concept is impaired synthesis
of nitric oxide from its amino acid precursor L-arginine by
the endothelium of the coronary vasculature as
well as by the myocytic endothelium in
hypertension.79 80 Many studies have focused on involved
potentially related mechanisms, including a defect in the gene nitric
oxide synthase, increased symmetrical dimethyl arginine,
enhanced local participation (ie, autocrine, paracrine, or intracrine)
of the renin-angiotensin system, or conversely, diminished
participation of the local bradykinin-kinin system. With respect to the
latter 2 local autocrine/paracrine (and even intracrine) peptide
systems, it is well known that angiotensin II inhibits
nitric oxide synthesis and that bradykinin promotes local nitric acid
synthesis in the endothelium.81 82
Most exciting are recent observations, experimental as well as clinical, that ACE inhibition and probably angiotensin II type 1 receptor inhibition, which have already been discussed, reduce LV mass and improve LV coronary flow reserve in older SHR.83 These findings suggest augmented local endothelial production of nitric acid synthesis and improvement of endothelial dysfunction of the coronary circulation. Furthermore, we have recently reported that prolonged L-arginine administration also induces similar improvement in intra-coronary hemodynamics and other pathophysiological alterations induced by hypertensive coronary vascular disease as well as by agents chronically administered experimentally that inhibit nitric oxide synthase endothelially.84 Furthermore, recent clinical studies have shown that prolonged administration of L-arginine to patients with hypertensive or atherosclerotic vascular disease improve the clinical and hemodynamic alterations associated with these diseases.85 86
| Ventricular Fibrosis: Diastolic Dysfunction and Cardiac Failure |
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Ventricular Fibrosis
One distinct and striking factor associated with LVH and
hypertensive heart disease that is not present in exercise-induced
(ie, physiological) LVH is the presence of collagen
deposition and ventricular fibrosis.97
Although this aspect of hypertensive heart disease is now well
accepted,8 9 12 43 44 it had been relatively neglected in
the past. Not only is LV collagen deposition increased in hypertension,
but it is also increased with aging. In this respect, our recent
experimental studies involving the SHR and normotensive Wistar-Kyoto
rats of increasing ages have shed new light on these LV
coronary hemodynamic and structural changes.
These studies have demonstrated a striking and progressive impairment
not only in LV coronary blood flow and flow reserve but also of
the right ventricle with advancing age from 23 to 80 weeks in the SHR
as well as in their normotensive and age- and gender-matched
controls.98 Moreover, these alterations in
ventricular hemodynamics were associated
with a parallel increasing deposition of collagen (ie, hydroxyproline)
in both ventricles. These findings in LVH of the SHR have been
confirmed in human beings, in whom hypertrophied myocytes have been
directly correlated with collagen deposition.99
Furthermore, these hemodynamic and structural
alterations that have been associated with aging and with hypertension
do not appear to be fixed and uncorrectable by therapeutic
interventions. Thus, our earliest studies demonstrated that LV mass
could be reduced by most antihypertensive agents. Specifically, LV mass
has been reduced within 3 weeks, as demonstrated by studies from our
laboratory using an identical protocol and in short courses of therapy
in patients with a centrally acting adrenergic
inhibitor,100 101 ß-adrenergic receptor
inhibitors,102 103 104 calcium
antagonists,105 106 107 108 109 or with ACE
inhibitors or an angiotensin II (type 1)
receptor antagonist alone or in
combination.71 110 111 112 113 114 115 Furthermore, associated with ACE
inhibitorinduced or calcium
antagonistinduced reductions in LV muscle mass was a
concomitant reduction in LV collagen; however, there was a concurrent
increase in right ventricular mass only with calcium
antagonists.105 109 This early (within 3
weeks) development of increased right ventricular mass was
confirmed clinically by demonstrating increased wall
thickness.114 When the ACE inhibitor was
administered together with the calcium antagonist, the
increased RV mass resulting from collagen deposition in the SHR was
prevented even though there was no further decrease in LV
mass.116 117 Thus, the RV mass increase was related solely
to increased RV collagen (or hydroxyproline concentration).
More recently, we have reported increased coronary flow reserve and reduced hydroxyproline concentration (and content) associated with reduction in arterial pressure, LV afterload, and LV mass after prolonged treatment with an ACE inhibitor or a type 1 angiotensin II receptor antagonist (alone or in combination).83 In support of these findings, another report, by Varo et al,118 demonstrated reversal of fibrosis and suggested that prolonged type 1 angiotensin II blockade diminished the posttranscriptional synthesis of fibril-forming collagen type 1 molecules in adult SHRs receiving the agent from 16 to 30 weeks of age. Furthermore, we reported similar decreases in arterial pressure, total peripheral resistance, and LV mass after prolonged L-arginine treatment associated with a reduction in LV collagen (ie, hydroxyproline), although right ventricular collagen was not as markedly decreased.84 These improvements in LV structure and function with L-arginine were observed only in the hypertensive (SHR) rats, suggesting that the alterations related to endothelial dysfunction responding to L-arginine may have been more related to the hypertensive disease rather than to aging. However, it must be emphasized that all antihypertensive drug classes reduce LV mass (and occasionally RV mass) and that these changes frequently occurred with certain agents in normotensive rats. Hence, the mechanisms involved require much further biochemical and biological study and should not be ascribed simply to regression of LVH.
A current report from the Framingham Heart Study indicated that there has been a very real and significant decrease in the prevalence of hypertension in that community as well as a coincident reduction in the prevalence of severely elevated pressures and LVH.119 A cause-effect relationship for these associations may appear to be a logical assumption. However, rather than concluding that effective control of blood pressure elevation reversed the incidence of LVH by regressing LVH, it is also reasonable to conclude that with more widespread recognition of patients having elevated arterial pressure, the prevalence of LVH diminished through prevention of development of LVH. Thus, with early recognition of hypertension in patients, there was a reduced prevalence in the progression of the disease that resulted in fewer patients with more severe stages of blood pressure elevation as well as in the incidence of LVH.119 Indeed, as suggested in our earlier report concerning prevention of LVH, to my way of thinking, the best means of treating LVH is the early recognition of patients with hypertension, prompt institution of a rigorous and effective antihypertensive treatment program that is designed to prevent development of LVH, and hence, prevention of the consequences of the risk from LVH in the first place.2 However, once LVH has been recognized in a hypertensive patient, an equally vigorous antihypertensive therapy is a necessity designed to control the elevated systolic and diastolic goal pressures to levels <140 and <90 mm Hg, respectively. In these patients, prevention of cardiac dysrhythmias by taking specific precautions to protect the patient from developing and reversing hypokalemia and hypomagnesemia is essential. Of course, agents that provide increased coronary blood flow and flow reserve and, if possible, reduce ventricular fibrosis should protect the patient against other mechanisms of risk associated with the LVH.
It is appropriate to comment at this point on the effects of excessive dietary sodium intake on LV structure. Several years ago, we observed that increased dietary salt intake in the SHR was associated with increased LV mass even when the salt excess did not increase arterial pressure or total peripheral resistance.120 The LV and total cardiac mass increased further with a higher salt intake; this was associated with a further rise in arterial pressure and total and regional vascular resistances in most organ circulations. More recently, others have reported that, with similar salt excess, an increased LV mass was associated with severe ventricular fibrosis as well as perivascular fibrosis in the coronary and renal circulations.121 We believe that these findings have particularly important implications for our developing concepts concerning hypertensive heart disease, sudden cardiac death, CHF, and perhaps the persistently increasing incidence of end-stage renal disease in patients with hypertension in recent years.21 60
| Concluding Hypothesis |
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Received May 8, 1999; first decision July 1, 1999; accepted July 2, 1999.
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