Prognostic Impact
P. VERDECCHIA, F. ANGELI, M.G. SARDONE, R. GATTOBIGIO
Introduction
Among the several adverse changes in cardiovascular morphology and func- tion that may occur in hypertension, increased left ventricular (LV) mass is of the utmost importance. Increased LV mass is a major predictor of cardiac and cerebrovascular events independently of the traditional cardiovascular risk factors such as blood pressure, diabetes, cholesterol levels, and smoking status [1–5]. The prevalence of ventricular arrhythmias is also substantially higher in hypertensive patients with LV hypertrophy than in those with no evidence of cardiac remodelling [6–8].
Although the mechanisms of the association between LV mass and prog- nosis are not completely clear, LV mass is generally considered a biological assay that reflects and integrates the long-term cumulative effect of several risk factors for cardiovascular disease.
LV hypertrophy can be schematically divided into three main types: con- centric, eccentric, and asymmetric. Longitudinal studies have suggested that the definition of LV geometry may be used to refine cardiovascular risk stratification in hypertensive subjects [9–13]. Such studies have found that, overall, the risk of developing cardiovascular disease was greater in patients with concentric remodelling than in those with normal LV geometry, and greater in patients with concentric LV hypertrophy than in those with eccen- tric LV hypertrophy [10–13]. However, since LV mass was greater in subjects with concentric remodelling than in those with normal geometry, and also greater in subjects with concentric LV hypertrophy than in those with eccen- tric LV hypertrophy, the independent prognostic impact of LV geometry was reduced or abolished completely due to the overwhelming prognostic value of the LV mass itself [9–13].
Ospedale R. Silvestrini, Dipartimento Malattie Cardiovascolari, Perugia, Italy
Regression of LV Hypertrophy
The Framingham Heart Study [14] has shown that subjects with electrocar- diographic (ECG) evidence of LV hypertrophy at entry and serial increase in the ECG voltages over time are twice as likely to suffer a major cardiovascu- lar event over the subsequent years as are those with serial decrease in the voltages. Moreover, in the Heart Outcomes Prevention Evaluation (HOPE) study [15], the primary study end-point (cardiovascular death, myocardial infarction, or stroke) occurred in 12.3% of subjects with absence or regres- sion of LV hypertrophy during the study, compared with 15.8% of subjects with new development or persistence of LV hypertrophy over the same time.
In the PIUMA study (Progetto Ipertensione Umbria Monitoraggio Ambulatoriale) [16], the rate of cardiovascular events was higher in patients who had not achieved regression of LV hypertrophy compared with those with persistently normal LV mass. Event rates did not differ between the group with regression of LV hypertrophy and the group with persistently normal LV mass.
The mechanisms by which serial changes in LV mass parallel the risk of major cardiovascular events in hypertensive subjects are still elusive. There is abundant evidence that several factors may induce parallel changes in LV mass and atherosclerotic lesions. Elevated blood pressure (BP) stimulates both LV hypertrophy [17, 18] and atherosclerosis [19]. In hypertensive sub- jects, LV mass and intima–media thickness seem to progress in parallel, gen- erally in association with BP [20, 21]. Several non-haemodynamic factors may influence LV mass and atherosclerosis, such as insulin and insulin growth factors [22–27]. Furthermore, angiotensin II promotes the activation of intracellular reactions, which may lead both to cardiac hypertrophy [28–30] and progression of atherosclerotic lesions [31] through proliferation of vascular smooth muscle cells and production of extracellular matrix pro- tein [31]. AT1-receptor activation also play a well-established role in the pathogenesis of atherosclerosis [32, 33]. Endothelin, a potent vasoconstric- tor, stimulates both vascular cell migration and growth [34, 35] and cardiac muscle hypertrophy [36]. Studies have also reported that HDL cholesterol, a powerful determinant of atherosclerosis, shows an inverse association, inde- pendent of BP, with LV mass [37, 38]. In hypertensive subjects, plasma vis- cosity has been associated with both LV hypertrophy [39] and increased inti- ma–media thickness [40].
The above considerations support the hypothesis that serial changes in LV mass in treated hypertensive subjects may reflect the long-term level of activity of several haemodynamic and non-haemodynamic factors potential- ly active on atherosclerosis. On the one hand, the favourable prognostic impact of regression of LV hypertrophy might reflect slower progression of
atherosclerosis because of blunting of a variety of mechanisms not limited to BP overload. On the other hand, lack of regression of LV hypertrophy may be a marker of more advanced progression of atherosclerosis.
Serial Changes in LV Mass and Antihypertensive Treatment
Experimental studies [41, 42] suggested that afterload reduction is the main mechanism leading to a reduction in myocyte volume, while inhibition of the renin–angiotensin–aldosterone system is most effective in reducing interstitial enlargement and improving diastolic filling.
In patients with hypertensive LV hypertrophy, regression of hypertrophy is usually associated with reduction in BP [43, 44]. In clinical trials, as in everyday practice, it is difficult to establish whether a given antihypertensive drug is superior to another in inducing regression of LV hypertrophy. This is because hypertensive subjects often have to combine several drugs with dif- ferent mechanisms of action in order to achieve adequate BP control.
Subjects with LV hypertrophy, who generally have higher BP than those without, also frequently need treatment with multiple drugs. As a result, the merit of LV hypertrophy regression cannot really be attributed with any cer- tainty to any specific drug class in clinical trials [45]. However, whatever the differences between antihypertensive drugs in the degree of regression of LV hypertrophy, systolic BP is the major determinant of the development and regression of LV hypertrophy in subjects with essential hypertension.
A recent analysis of the PIUMA study [46] showed that the degree of reduction in LV mass during treatment is associated more closely with the reduction in 24-h ambulatory systolic BP than with that in clinical BP, proba- bly because 24-h ambulatory systolic BP better reflects the BP load to which the left ventricle is chronically exposed. The fundamental role of systolic BP in the basic mechanisms leading to LV hypertrophy is supported by several experimental data. The immediate cardiac consequence of a rise in SBP is an increase in end-systolic wall stress that triggers cellular reactions, ultimately leading to an increase in the volume of each cardiac myocyte. This process is mostly due to addition of sarcomeres in parallel, and the resulting increase in the cardiac mass tends to progressively normalise end-systolic wall stress.
This pattern is typical of prevalent or near-pure pressure overload states such as hypertension and aortic stenosis.
Overview
A recent meta-analysis [47] of studies which were quite small in size, but similar in their design and experimental procedures, investigated the prog-
nostic impact of serial changes in LV mass. In all these studies, hypertensive subjects were examined by echocardiography before and during antihyper- tensive treatment, before occurrence of major cardiovascular events. Patients were subsequently followed up for a further period of several years in order to establish the association between prior changes in LV mass and subse- quent events. Overall, these studies included 1064 hypertensive subjects (41% women) aged 45–51 years, and 106 cardiovascular events. The echocar- diographic study was carried out before the beginning of treatment and after 3–10 years of follow-up. Compared to subjects with lack of regression or new development of LV hypertrophy, those who achieved regression of LV hyper- trophy showed a 59% lower risk of subsequent cardiovascular disease [95%
confidence interval (CI): 22–79; P = 0.007]. The lower risk of events associ- ated with regression of LV hypertrophy was consistent across the individual studies. Compared to subjects with regression of LV hypertrophy, those with persistently normal LV mass showed a similar risk of subsequent events (odds ratio 0.64, 95% CI: 0.31–1.30; P = 0.21). Since the event risk was 36%
lower among the subjects who never experienced LV hypertrophy compared to those with regression and the confidence intervals were wide, our study could not provide conclusive evidence that regression of LV hypertrophy reduces the risk of subsequent events to the same level as that of subjects who never experienced LV hypertrophy (Fig. 1).
Fig. 1.Cardiovascular events in hypertensive subjects with regression vs. persistence or new development of left ventricular hypertrophy (data from [47])
Lesser Risk with LVH regression
Lesser Risk with LVH persistence/New
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