Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Evaluation of Subclinical Target Organ Damage for Risk Assessment and Treatment in the Hypertensive Patients: Left Ventricular Hypertrophy
Enrico Agabiti-Rosei,
Maria Lorenza Muiesan and
Massimo Salvetti
Internal Medicine, University of Brescia, Brescia, Italy
Address correspondence to: Prof. Enrico Agabiti-Rosei, Internal Medicine, Medical and Surgical Sciences, University of Brescia, c/o 2a Medicina Spedali Civili di Brescia, Piazza Spedali Civili 1, 25100 Brescia, Italy. Phone: +30-396044; Fax: +30-3388147; E-mail: agabiti{at}med.unibs.it
At some point in the natural history of hypertension, the compensatoryincrease in left ventricular mass ceases to be beneficial. Leftventricular hypertrophy (LVH) becomes a preclinical diseaseand an independent risk factor for congestive heart failure,ischemic heart disease, arrhythmia, sudden death, and stroke.In addition to elevated BP, several mechanisms are involved,including body size, age, gender, race, fibrogenic cytokines,and neurohumoral factors, notably angiotensin II, which favorinterstitial collagen deposition and perivascular fibrosis.These tissue changes are responsible for the insidious contractiledysfunction that is associated with LVH, consequent to decreasedcoronary reserve and altered diastolic ventricular filling andrelaxation. The cardinal investigations are echocardiographyand electrocardiography. All antihypertensive drugs regressLVH, notably those that act on the renin-angiotensin-aldosteronesystem, which also could target the detrimental tissue changes.Regression enhances systolic midwall performance, normalizesautonomic function, and restores coronary reserve. The resultingimprovement in prognosis has enshrined the detection, prevention,and reversal of LVH in the current guidelines of hypertensionmanagement.
At some point in the natural history of hypertension, the compensatoryincrease in left ventricular mass (LVM) is not beneficial anymore.In fact, it becomes a preclinical disease and an independentrisk factor for congestive heart failure, ischemic heart disease,arrhythmia, sudden death, and stroke (1).
Determinants of Hypertensive Left Ventricular Hypertrophy
The high prevalence of LV hypertrophy (LVH) in hypertensionreflects the increased afterload imposed on the left ventricle,although other important determinants are demographic characteristics(e.g., age, gender, race), neurohumoral and growth factors,and underlying genetic factors. Hypertension is the fundamentaltrigger to the sequence of biologic events that lead to thedevelopment of LVH. LVM is more closely related to average 24-hBP (2–4). Volume load, inotropy, and arterial compliancealso are important determinants of the development and the degreeof LVH. Other contributing factors include stage of hypertensivedisease, genetics, demographic factors, comorbid diseases (e.g.,diabetes, obesity, coronary artery disease), possibly mediatedvia cardiac load. Obesity, which compounds hemodynamic loadindependent of a clear-cut increase in BP, is a major determinantof LVM, because it is associated with increased plasma volumeand cardiac output (5). It has been suggested that consideringthese measurable factors and hemodynamic load, echocardiographicLVM could be assessed in the individual patient as deviationfrom the value that is appropriate for a given cardiac workload,corrected for gender and body size. LVM that overcompensatesfor hemodynamic load tends to cluster with metabolic risk factorsand is associated with high cardiovascular risk (6,7). The definitionand the clinical evaluation of "inappropriate" LVM require furtherstudy.
Among the main nonhemodynamic factors that may contribute tothe development of LVH, a variety of neurohumoral and growthfactors (e.g., catecholamines, angiotensin II [AngII], aldosterone,endothelins) are included. The effect of sympathetic nervoussystem activity is evident in experimental models but less clear-cutin humans: in pheochromocytoma LVH prevalence is relativelylow and LVM seems to increase proportionately to BP, then inessential hypertension, LVH is associated with altered autonomicactivity and a blunted response to -adrenoceptor stimulation(8–10). Experimental studies also highlighted the roleof the renin-angiotensin-aldosterone system (RAAS) in mediatingLVH (11,12). AngII induces hypertrophy and hyperplasia in myocytesand vascular smooth muscle cells and may regulate collagen synthesis.Excess AngII production may regulate the expression of fibrogeniccytokine TGF-1 and favor perivascular and interstitial fibrosis.In addition, AngII may interfere with the process of collagendegradation, modulating the activity of metalloproteinases (afamily of zinc-containing proteins that include stromelysins,collagenases, and gelatinases) and their inhibitors (12). Aldosteronealso may stimulate extracellular collagen deposition and myocardialfibrosis.
The pathogenic role of the RAAS in the development of hypertensiveLVH requires confirmation, although LVM is significantly increasedin renovascular hypertension and primary aldosteronism comparedwith essential hypertension (13,14). Increased activity of theRAAS and sympathetic nervous system, hypervolemia, and anemiaall may influence the increase of LVM in patients with renaldisease.
Hypertensive LVH often is associated with insulin resistanceand high insulin levels (15). The involvement of IGF- I couldclarify the link among obesity, BP elevation, LVH, and the metabolicsyndrome. Leptin is another possible neuroendocrine determinant.LVH in an animal model of leptin deficiency (the ob/ob mouse)reversed rapidly in response to exogenous leptin, thereforeindicating the involvement of myocardial leptin receptors incardiac remodeling (16). Other major metabolic cardiovascularrisk factors, notably hypercholesterolemia and hyperglycemia,also may have an influence on LVM and the prevalence of LVH(17).
Several studies have suggested that approximately 30% of LVMvariance is genetically determined (18). Studies of geneticinfluence on LVM have focused mainly and are ongoing on therole of candidate genes, including those that are related tothe RAAS, - and -adrenoceptors, and components of the signaltransduction mechanisms involved in cardiac hypertrophy.
As recommended by the European Society of Hypertension and EuropeanSociety of Cardiology (19), LVH is diagnosed most commonly usingelectrocardiography (ECG) and M-mode and two-dimensional echocardiography.New ECG criteria in addition to repolarization abnormalitiesand increased voltage have been proposed, the Cornell methodprobably being the most sensitive (20). The ECG also can beused to detect patterns of ventricular overload ("strain") orischemia, which indicate higher cardiovascular risk. ECG andechocardiographic LVH both predict mortality independent ofeach other and other cardiovascular risk factors, thus conveying,at least in part, different prognostic information (21,22).Echocardiography has some advantages because it provides comprehensivewall, chamber, and LVM measures, together with systolic anddiastolic performance indices, while remaining reasonably cheap,widely available, and wholly noninvasive. The relation betweenLVM and cardiovascular risk is continuous, although the thresholdof 125 g/m2 for men and 110 g/m2 for women currently is usedmost widely for conservative estimates of LVH, according tothe recent European Society of Hypertension–European Societyof Cardiology guidelines (19). Despite its advantages, echocardiographymay entail a possible technical error as a result of the methoditself, the quality of the examination, or observer inexperience.It has been established that a biologic significance can beattributed to changes in LVM that exceed 10 to 15% (23).
Echocardiography also is useful in assessing the different typesof LV geometric adaptation to increased cardiac load (24), evaluatingthe increase in mass and/or in relative wall thickness. Moreaccurate and sophisticated techniques, such as magnetic resonanceimaging or cine computerized tomography, are more expensiveor time-consuming and are still of limited availability.
Methods have been developed to quantify tissue composition.Studies in animals and humans have shown that LV acoustic propertiesunder physiologic and pathologic conditions are influenced byseveral tissue components (myocardium, contractile and elastictissue, collagen and inelastic tissue, arteries, veins, myocytes,and sarcomeres). Results with videodensitometry and integratedbackscatter to characterize tissue in several diseases thatare associated with abnormal myocardial tissue, including hypertensiveLVH and diabetes, indicate that these techniques can complementclinical evaluation by revealing preclinical end-organ damage(25,26). Further reproducibility and feasibility studies arerequired to assess the clinical applications of these techniques.
Whether assessed by ECG or echocardiography, LVH is a well-documentedharbinger of morbidity and mortality. In several studies, theadjusted risk for cardiovascular morbidity associated with baselineLVH ranges from 1.5 to 3.5 with a weighted risk ratio of 2.3for all studies combined (27). Concentric hypertrophy seemsto carry the highest risk and eccentric hypertrophy an intermediaterisk, whereas concentric remodeling is probably associated witha smaller, albeit noteworthy, risk.
The structural remodeling of cardiomyocytes, nonmyocytes, andfibroblasts that occurs in cardiac hypertrophy contributes toperivascular fibrosis, initially around intramural coronaryarteries and thereafter in the interstitial space, leading toprogressive abnormalities of diastolic ventricular filling andrelaxation, systolic dysfunction, arrhythmias, and conductiondisturbances, thereby greatly compounding the risk that is associatedwith LVH (1).
The resulting pathophysiologic and clinical changes that accountfor increased risk in hypertensive LVH include both diastolicand systolic dysfunction. LVH and failure are frequently associatedwith coronary artery disease, and hypertension is a major riskfactor for coronary atherosclerosis. In ECG LVH, use of a "definiteLVH" pattern that comprises ST-segment and T-wave abnormalitieswas strongly associated with an increased incidence of acutemyocardial infarction and sudden death (3–6), suggestingthat altered repolarization reflects reduced coronary perfusion.
LVH is associated with structural and functional changes inboth large (28,29) and small (14,30,31) arteries. These structuralchanges are particularly evident in concentric LVH. The associationbetween LVH and extracranial carotid atherosclerosis also mightexplain the increased risk for cerebrovascular events. The vascularchanges that consistently are observed in LVH are also responsiblefor the reduced coronary reserve. Concomitant atherosclerosisin epicardial coronary vessels and structural alterations andrarefaction of small coronary vessels (32) limit blood supplywhen oxygen demand is increased. Compensatory angiogenesis isinadequate during the development of adult LVH. Decreased subendocardialcoronary perfusion leads to myocyte necrosis and reparativefibrosis, favoring the progression to heart failure. Other extravascularmechanisms that compound the impairment of coronary reserveinclude changes of oxygen demand related to wall tension, heartrate, and contractility. Functional changes further weaken thevasodilator response of the coronary microcirculation. In fact,endothelial dysfunction precedes morphologic changes in thevascular wall and triggers remodeling. In summary, LVH is astate of potential or actual myocardial ischemia.
There is a predisposition to ventricular arrhythmia in hypertensiveLVH, explaining the risk for sudden death. Impaired ventricularfilling, left atrial enlargement, and slowing of atrial conductionvelocity all encourage atrial fibrillation, increasing the riskfor thromboembolism. In addition, in patients with LVH (andabnormal LV geometry), higher urinary albumin excretion hasbeen observed, suggesting that cardiac and glomerular vasculardamage may parallel, independent of the hemodynamic load. Becausehypertensive LVH is an independent risk factor for cardiovascularmorbidity and mortality, the possibility of reversal or evenprevention by lowering BP and modifying other pathogenetic factorsis a major goal of antihypertensive therapy.
LVM can be decreased by nonpharmacologic intervention, notablyweight loss, which is effective in obese hypertensive patientsindependent of BP changes. As shown by the multicenter Treatmentof Mild Hypertension Study (TOMHS), lifestyle intervention mayreduce BP significantly and decrease LVM substantially in 30%of patients. However, there is still no hard evidence of anindependent effect by dynamic exercise, dietary sodium, or alcoholrestriction.
Multiple studies have shown that BP reduction reverses LVH.The main determinants are treatment duration and degree of BPreduction, in particular of average 24-h BP; subsequent evidencealso has shown the importance of homogeneity, or minimal dailyfluctuation, in BP control, as expressed in the "smoothnessindex" (33,34).
Because BP is not the sole determinant of LVH and fibrosis,the differing response of LVM to various classes of antihypertensivedrugs can be ascribed to interference with nonhemodynamic factorssuch as the RAAS and sympathetic nervous system. Several meta-analyseshave been conducted, including the main studies demonstratingreversal of echocardiographic LVH using various antihypertensivedrugs, and they have shown that baseline LVM and the degreeof BP reduction are the main determinants of LVH regression;in addition angiotensin-converting enzyme inhibitors, AngIIreceptor blockers, and calcium channel blockers have been moreeffective than blockers and diuretics given the same decreasein BP (35). Large, randomized, blinded studies that have comparedtwo or more different antihypertensive drugs have provided furtherdata, confirming, at least in large part, the results of meta-analyses.
However, it should be kept in mind that interdrug differencestend to fade with time, because treatment duration is associatedwith progressive BP control and decrease in LVM. In addition,most major intervention trials that have compared the effectsof single antihypertensive drugs on LVM in fact largely havebeen comparisons of combination therapies, because most patientswere taking more than one drug.
There is increasing interest in the effect of antihypertensivetreatment on myocardial tissue composition, particularly onperivascular and interstitial fibrous tissue. Recent experimentaland human evidence suggests that angiotensin-converting enzymeinhibitors and AngII antagonists are particularly effectivein inducing regression of myocardial fibrosis.
Clinical and Prognostic Significance of LVH Regression
Because LVH is such an important independent risk factor inhypertension, there is consensus as to the desirability of itsregression and prevention. Regression is associated with numerousbenefits, such as improved systolic midwall performance, normalizedautonomic function, enhanced coronary reserve, and, possibly,improved diastolic filling and decreased ventricular arrhythmia.It remains to be assessed extensively whether LVM changes mayimprove parallel vascular and/or renal damage modifications.
The improved prognosis associated with LVH regression has beendemonstrated in several studies using ECG measures. The largelong-term Losartan Intervention for Endpoint (LIFE) study showedthat the greater regression of LVH with losartan was associatedwith fewer cardiovascular events (36).
Further observations using the more sensitive echocardiographictechnique have shown that patients who achieve LVH regressionduring follow-up are much less likely to experience morbid eventsas compared with those with persistence of LVH (odds ratio 0.41)(37). In the echocardiographic substudy of the LIFE trial thatincluded 960 patients who were followed for >4 yr, the betterprognosis that was associated with the significant decreasein LVM from baseline to end of study was due mainly to a decreasein the incidence of stroke (38).
These cumulative findings highlight the prognostic value ofthe LVM response to treatment. BP was not significantly associatedwith the incidence of cardiovascular events in these studies,although it cannot be excluded that the changes that were observedin the LVM index at least partially reflected BP control.
Whereas complete regression significantly reduces cardiovascularrisk, an increase in echocardiographic LVM during antihypertensivetherapy or a failure to decrease confers a worse prognosis.In addition, the response of LV geometry to treatment may haveprognostic significance, independent of changes of LVM (39).
Focuses of future interest will include the biochemistry ofthe adaptive changes in energy metabolism and contractile proteins,notably the role of transmitters and transductional factors,as well as the timing of these responses to BP changes, neurohumoralactivation, and the development of structural alterations inother organs. Techniques such as tissue characterization andnoninvasive quantitative analysis of coronary flow will describethe respective contributions of perivascular and intraventricularfibrosis and myocardial ischemia to the mechanisms of LVH riskand, hopefully, indicate ways in which these advances can betranslated into the individual patient benefit. However, wealready know more than enough to realize that a major goal inthe management of hypertension is the detection, prevention,and reversal of LVH.
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Abstract
Introduction
-adrenoceptor stimulation (8–10). Experimental studies also highlighted the role of the renin-angiotensin-aldosterone system (RAAS) in mediating LVH (11,12). AngII induces hypertrophy and hyperplasia in myocytes and vascular smooth muscle cells and may regulate collagen synthesis. Excess AngII production may regulate the expression of fibrogenic cytokine TGF-
- and 
