Hypertensive patients may develop a variety of cardiac structural and functional changes, including an increased left ventricular mass, left ventricular systolic and diastolic dysfunction, impairment of coronary reserve, arrhythmias and enlargement of left atrial and aortic root .
Of the several adverse changes in cardiovascular morphology and function that occur in association with hypertension, most attention has been focused on left ventricular hypertrophy for its detrimental contribution to survival and cardiovascular events .
There is a wealth of literature that links left ventricular hypertrophy to increased cardiovascular risk: in long-term epidemiological studies, the presence of left ventricular hypertrophy detected by electrocardiography or echocardiography has been shown to be an independent and robust prognostic factor for intermediate endpoints and clinical outcomes such as major cardiovascular events and mortality, total mortality and sudden death [2–7].
With the advent of echocardiography, it has also been recognized that electrocardiography may be relatively insensitive for detecting prognostically important increases in left ventricular mass [8,9]. In particular, milder increases in left ventricular mass could be easily detected, and additional epidemiological data have demonstrated that a strong gradient exists between increased echocardiographic left ventricular mass and increased cardiovascular risk [3,10,11]. Levy et al.  demonstrated a progressive increase in risk associated with left ventricular mass, even at levels not considered as ‘hypertrophic’; more recently, in a subset of 1925 Italian hypertensive patients , cardiovascular disease increased monotonically with more than a four-fold increase in risk between the lowest and highest left ventricular mass quintiles. Notably, clinically relevant increment in cardiovascular risk was identified in patients with left ventricular mass below the limits usually employed for left ventricular hypertrophy definition. These findings have been subsequently confirmed in a prespecified analysis of the Losartan Intervention For End-point reduction (LIFE) study , carried out in patients with essential hypertension, electrocardiographic evidence of left ventricular hypertrophy at entry and availability of left ventricular echocardiographic study at randomization and during follow up. In that study, lower values of left ventricular mass during treatment were associated with lower rates of cardiovascular disease, and such an effect was additional to the benefit provided by blood pressure (BP) lowering and treatment modality .
The observation that a decrease of left ventricular mass in hypertensive patients may result in improved survival rates attracted a great interest from researchers as well as from clinicians.
However, health professionals need to consider some critical issues in the echocardiographic estimation of left ventricular mass, definition of the cut-off values for diagnosis of left ventricular hypertrophy and clinical implications of serial changes in left ventricular mass.
In this context, the analysis by Gosse et al.  published in the current issue of the journal adds further data, which need to be combined with the extensive previous literature on left ventricular mass in hypertension.
Echocardiography is one of the most important noninvasive imaging methods in the evaluation of cardiac morphology and dynamics. However, the apparent simplicity in left ventricular mass evaluation by echocardiography conceals several critical aspects that may limit its clinical validity.
In particular, variability in left ventricular mass estimation, its reproducibility and body size indexing and other adjustments may influence both the clinical and epidemiologic use of echocardiography in the investigation of the left ventricular structure.
Although left ventricular mass calculations derived from the available formulas [15–22] (Table 1) are strictly and linearly correlated, the final crude estimations may differ by more than 20% . In addition, different formulas may yield distinct cut point values for the diagnosis of left ventricular hypertrophy.
Another issue that may be a source of great confusion is the diverse normalization and indexes currently used to adjust left ventricular mass for lean body mass, obesity and sex.
Several indexes for body size correction have been proposed, such as height, allometric height adjustments, weight, body surface area (BSA), BMI and free-fat mass (Table 1). The best way for normalization of left ventricular mass is still controversial and different adjustment criteria and their standard cut points may result in different prevalence of left ventricular hypertrophy . Furthermore, it is not clear whether different criteria for left ventricular hypertrophy may impact interventional strategies on the basis of cardiovascular risk stratification.
Addressing this aspect, Liao et al.  compared the predictive value of echocardiographic left ventricular hypertrophy using various methods of indexation for left ventricular mass. They observed that an increase in any left ventricular mass index was associated with a similar risk of death from all causes and cardiac diseases. Although left ventricular hypertrophy assessed by mass indexed for BSA using conventional partition values provided somewhat better prediction, the adjusted relative risk was in general not significantly different from left ventricular hypertrophy on the basis of other indexes .
Similar results are reported by Gosse et al. . In their analysis, they document that different indexations of left ventricular mass (height, height2.7 or BSA) have similar predictive values for cardiovascular complications .
Although left ventricular mass has been shown to be an independent prognostic marker for intermediate endpoints and clinical outcomes, some longitudinal studies analysed the definition of left ventricular geometry as a potential factor to refine cardiovascular risk stratification in hypertension. Usually, four distinct geometric patterns are considered to stratify patients: normal geometry, concentric remodelling, concentric hypertrophy and eccentric hypertrophy (Fig. 1).
Although this classification permits identification of determined adaptive processes, cohort studies evaluating geometric patterns impact in the incidence of cardiovascular events provided mixed results showing that the additional prognostic role of geometric patterns over left ventricular hypertrophy was lesser than initially supposed [11,24–26] (Fig. 1).
Koren et al.  found a 10-year incidence of cardiovascular events of 31% in patients with concentric hypertrophy compared with 11% in those with normal geometry; an Italian study  found a relative risk of 2.6 in patients with concentric remodelling compared with normal geometry patients; Krumholz et al.  showed a relative risk of 2.1 for all-cause mortality with concentric hypertrophy, but not additional risk in those classified as concentric remodelling.
Continuing our considerations on the role of left ventricular hypertrophy detected by echocardiography in cardiovascular disease management, the analysis by Gosse et al.  highlights the prognostic implications of serial changes in left ventricular mass during pharmacological treatment for hypertension. In their registry, a prospective substudy cohort was assembled in which echocardiography was obtained at baseline and after an average follow-up of 5 years. Increasing reductions in echocardiographic left ventricular mass were associated with greater reductions in cardiovascular event rates, independently of the baseline left ventricular mass. In addition, patients with left ventricular hypertrophy regression showed similar survival than patients with persistence of normal left ventricular mass. Nonetheless, it is important to recognize that a second measurement of left ventricular mass was obtained in only 436 out of the 763 patients initially recruited .
The results of this substudy by Gosse et al. are impressive for the concordance with other echocardiographic prospective studies (Fig. 2) [27–31], with respect to the link between regression of left ventricular hypertrophy and reduction of major cardiovascular events in essential hypertension. In a long-term Italian study , hypertensive patients underwent a left ventricular echocardiographic study before therapy and after 10 years of treatment. The rate of cardiovascular events was higher in the patients who had not achieved regression of left ventricular hypertrophy at follow-up than in those with persistently normal left ventricular mass. Furthermore, patients with regression of left ventricular hypertrophy showed an event rate similar to those with persistently normal left ventricular mass . In a subsequent analysis of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study , the lesser cardiovascular risk associated with regression of left ventricular hypertrophy (1.58 events per 100 person-years in patients with left ventricular hypertrophy regression vs. 6.27 in those with persistent left ventricular hypertrophy) remained significant in a multivariable analysis, which included BP changes as assessed by 24-h ambulatory monitoring.
In a study from France , the incidence of cardiovascular events was 4.8% in hypertensive patients without left ventricular hypertrophy, 9.6% in those with regression of left ventricular hypertrophy and 15% in those without regression of left ventricular hypertrophy.
Similar data have been reported by Koren et al.. Cardiovascular event rate during a 5-year follow-up was 9.2 and 28.6% for patients with regression of left ventricular hypertrophy (or persistence of normal left ventricular mass) and with new development (or persistence of left ventricular hypertrophy), respectively.
The pooled analysis of these four studies  showed that when compared with patients who failed to achieve regression of left ventricular hypertrophy or development of new left ventricular hypertrophy, those who achieved regression of left ventricular hypertrophy showed a 59% lesser risk of subsequent cardiovascular events (P = 0.007; Fig. 2).
As suggested by Gosse et al. , commenting the effects of the regression of left ventricular hypertrophy on the prognosis, it is worth mentioning that the mechanisms through which serial changes in left ventricular mass parallel the risk of major cardiovascular events in hypertensive patients remain to be assessed . Regression is associated with numerous cardiac benefits such as improved systolic midwall performance, normalized autonomic function, enhanced coronary reserve and improved diastolic filling and decreased ventricular arrhythmia [33,34]. However, there is also evidence that many biological factors, haemodynamic (BP) and nonhaemodynamic (insulin, insulin growth factors, angiotensin II, endothelin, plasma viscosity), are able to induce progression and destabilization of atherosclerotic lesions and, in the same time, to increase left ventricular mass [1,35–38].
From an epidemiological standpoint, the association between left ventricular hypertrophy and acute cerebrovascular events, independent of BP, strengthens the potential role of left ventricular mass as an integrated marker of atherosclerosis [39,40]. Indeed, in the LIFE study, left ventricular mass was greater in hypertensive patients with evidence of coronary artery disease than in those without this evidence .
The above considerations support the hypothesis that the favourable prognostic impact of left ventricular hypertrophy regression might reflect a lesser progression of atherosclerosis because of blunting of a variety of mechanisms not limited to BP overload and that the lack of regression of left ventricular hypertrophy may be a marker of a more advanced progression of atherosclerosis.
This study was funded in part by the Fondazione Umbra Cuore e Ipertensione – ONLUS, Perugia, Italy.
Conflicts of interest
None of the authors of this study has financial or other reasons that could lead to a conflict of interest.
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