Myocardial Remodeling in Hypertension

REVIEW Myocardial remodeling in hypertension

W Nadruz

Left ventricular (LV) hypertrophy and remodeling are frequently seen in hypertensive subjects and result from a complex interaction of several hemodynamic and non-hemodynamic variables. Although increased blood pressure is considered the major determinant of LV structural alterations, ethnicity, gender, environmental factors, such as salt intake, obesity and diabetes mellitus, as well as neurohumoral and genetic factors might influence LV mass and geometry. The conventional concept of hypertensive LV remodeling has been that hypertension leads to concentric hypertrophy, as an adaptive response to normalize wall stress, which is then followed by chamber dilation and heart failure. However, several lines of evidence have challenged this dogma. Concentric hypertrophy is not the most frequent geometric pattern and is less usually seen than eccentric hypertrophy in hypertensive subjects. In addition, data from recent studies suggested that transition from LV concentric hypertrophy to dilation and systolic dysfunction is not a common finding, especially in the absence of coronary heart disease. LV hypertrophy is also consistently associated with increased cardiovascular morbidity and mortality, raising doubts whether this phenotype is an adaptive response. Experimental evidence exists that a blunting of load-induced cardiomyocyte hypertrophy does not necessarily result in LV dysfunction or failure. Furthermore, the hypertrophic myocardium shows fibrosis, alterations in the coronary circulation and cardiomyocyte apoptosis, which may result in heart failure, myocardial ischemia and arrhythmias. Overall, this body of evidence suggests that LV hypertrophy is a complex phenotype that predicts adverse cardiovascular outcomes and may not be necessarily considered as an adaptive response to systemic hypertension.

Journal of Human Hypertension (2015) 29, 1–6; doi:10.1038/jhh.2014.36; published online 8 May 2014

INTRODUCTION concentric LV remodeling (normal LV mass and increased relative 5 Cardiac remodeling is defined as alterations in size, geometry, wall thickness). shape, composition and function of the heart resulting from cardiac load or injury.1 Left ventricular (LV) remodeling is frequently seen in hypertensive subjects and has been CELLULAR AND HISTOPATHOLOGICAL FEATURES considered an adaptive response to hemodynamic overload Hypertrophic growth of cardiomyocytes is the main mechanism imposed by systemic hypertension. This compensatory response by which the heart reduces LV wall stress imposed by pressure is assumed to be explained by the Laplace law, T ¼ P Â r/2h, where overload. It involves stimulation of an intricate web of intracellular tension or stress in the LV wall (T) is directly related to LV pressure signaling cascades that activate gene expression and promote (P) and radius (r) and is inversely related to LV wall thickness (h) protein synthesis and stability, with consequent increases in (Figure 1).2 Sustained elevated blood pressure leads to increases in protein content, in the number of force-generating units LV wall stress, which is a major determinant of myocardial oxygen (sarcomeres) and in the size of individual cardiomyocytes. demand. In response to increased LV wall stress, LV wall thickens Concentric hypertrophy is characterized by an increase in the and LV mass increases, thus resulting in normalization of wall width of cardiomyocytes caused by the parallel addition of new stress and the development of a structural pattern known as sarcomeres, whereas in eccentric hypertrophy there is an increase concentric hypertrophy. Alternatively, increases in blood volume in cardiomyocyte length due to the addition of new sarcomeres in would lead to an increase in the chamber radius, resulting in series.2,6 Adult cardiomyocytes were traditionally considered to be eccentric hypertrophy. terminally differentiated cells unable to divide. However, the LV structure and mass are complex phenotypes that may be paradigm that the adult heart is a postmitotic organ has been influenced by several factors other than chronic hemodynamic challenged by reports that cardiomyocytes may be able to overload. It is extensively acknowledged that non-hemodynamic proliferate in rat hearts as well as in severely hypertrophic, post- variables, such as ethnicity, gender, neurohumoral, environmental infarcted and end-stage-failing human hearts. Thus, it has been and genetic factors, modulate the myocardial hypertrophic suggested that the increased cardiac mass in LV hypertrophy may response.3,4 Therefore, distinct cardiac structural adaptations are be a result from a combination of hypertrophy and hyperplasia of seen in hypertensive subjects. LV geometry can be described both cardiomyocytes and non-cadiomyocytic cells.1,2 based on the LV mass (hypertrophy) and the relative wall Besides cardiomyocyte hypertrophy, several alterations of the thickness. Four LV geometric patterns have been identified: cardiomyocyte and the non-cardiomyocyte components (includ- normal LV geometry (normal LV mass and lower value of ing apoptosis, fibrosis and changes in the coronary circulation) are relative wall thickness), eccentric LV hypertrophy (increased LV also seen and seem to explain the increased risk of mass and lower value of relative wall thickness), concentric LV adverse cardiovascular outcomes related to LV hypertrophy.7 hypertrophy (increased LV mass and relative wall thickness) and Cardiomyocytes exhibit increased rates of cell death, especially

Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil. Correspondence: Professor W Nadruz, Departamento de Clıńica Me´dica, Faculdade de Cieˆncias Me´dicas, Universidade Estadual de Campinas, Cidade Universita´ria ‘Zeferino Vaz’, Campinas, Saõ Paulo 13081-970, Brazil. E-mail: [email protected] Received 16 January 2014; revised 25 March 2014; accepted 2 April 2014; published online 8 May 2014 Heart and hypertension W Nadruz 2 hypertrophy usually have the highest stroke volume and cardiac output and the lowest systemic vascular resistance levels compared with those with other geometric patterns. In such individuals, increased volemia seems to be a major determinant of wall stress and LV hypertrophy. On the other hand, hypertensive subjects with concentric remodeling usually have a lower cardiac output and intravascular volume.4 Differences in LV shape are also described among the LV geometric patterns. Noticeably, higher stroke volumes have been coupled with more spherical LV chambers. Therefore, subjects with eccentric hypertrophy usually exhibit the most spherical LV cavities, whereas those with concentric remodeling generally show the most elliptic shape.4 The notion that cardiomyocytes grow in response to hemodynamic load indicates that the mechanical stimulus is transduced into a biochemical event, thus modifying gene transcription. Attractive candidates for such a transducer are the components of the focal adhesion complex, through which the cytoskeleton of a cell connects to the extracellular matrix.13 Furthermore, Figure 1. The Laplace law and how it may explain the development mechanical stress may be coupled to intracellular signals that of concentric and eccentric LV hypertrophy in response to pressure are responsible for the hypertrophic response via phospholipases, and volume overload, respectively. T, tension or stress in the LV wall; P, LV pressure; r, radius of the chamber; h, LV wall thickness. ion channels and ion exchangers or may induce the release of growth-promoting factors (for example, angiotensin II, endothelin- 1 and transforming growth factor-beta), thus providing alternative pathways of growth induction.9,13 apoptosis, which may result in reduced contractile mass and affect In addition to raised blood pressure and variation in volemic contractility.1,6 Fibroblasts proliferate and there is exaggerated status, non-hemodynamic factors have been also implicated in the accumulation of collagen type I and type III fibers within the pathogenesis of hypertensive LV remodeling. For instance, interstitium and perivascular regions. These events induce the impaired suppression of the renin–angiotensin axis or increased development of fibrosis, which predisposes to diastolic and sensitivity to angiotensin II may act as stimuli for LV hypertrophy systolic LV dysfunction, diminished coronary flow reserve and in hypertensive patients. Likewise, increased plasma renin activity ventricular arrhythmias. Furthermore, there are changes in the levels have been related to hypertensive LV hypertrophy and data coronary circulation, such as hyperplasia and hypertrophy of derived from clinical trials suggested that agents targeting the intramyocardial arteries and a relative decrease in arteriolar and renin–angiotensin system may offer beneficial effects on LV mass capillary density, which predispose to inadequate myocardial beyond blood pressure reduction.10 In contrast, the role of the perfusion.6 Conversely, experimental evidence exists that a renin–angiotensin–aldosterone system in LV geometry is more blunting of cardiomyocyte hypertrophy does not necessarily controversial. Although some lines of evidence have suggested result in dysfunction or failure, even in the presence of pressure that low-renin states are coupled with eccentric hypertrophy and overload.8 These findings seem to challenge the dogma that load- high-renin states are related to concentric hypertrophy,3,4 data induced cardiomyocyte hypertrophy is an adaptive process. In from the Framingham Offspring Study showed that an increased fact, at the cellular level, hypertrophy of cardiomyocytes is aldosterone-to-renin ratio was associated with both concentric accompanied by derangements in energy metabolism, and eccentric hypertrophy in multivariable models.14 These latter contractile cycle, excitation–contraction coupling and autocrine findings raise doubts whether the renin–angiotensin–aldosterone functions that, in turn, may provide additional basis for LV system is a major factor in the modulation of LV geometry in dysfunction.6,9 hypertension. Further, non-hemodynamic factors, such as sympathetic drive and endothelin-1, have been also suggested to have a role in the hypertrophic response to systemic hypertension, HEMODYNAMIC AND NON-HEMODYNAMIC FACTORS although the clinical relevance of these factors on hypertensive LV Despite the concept that pressure overload is the major remodeling remains to be established.4,13 In particular, conflicting determinant of LV hypertrophy and remodeling in hypertensive results have been reported regarding the relationship between LV subjects, casual brachial blood pressure levels usually does not geometric patterns and biomarkers of sympathetic drive in show a close relationship with LV mass.10,11 Nevertheless, the hypertensive subjects.4 impact of blood pressure on LV mass should not be Data derived from clinical trials may also contribute to explain underestimated, as isolated brachial blood pressure measure- the mechanisms related to the development of distinct geometric ments are usually not representative of the hemodynamic load patterns in hypertensive subjects. The LIFE study evaluated LV imposed by systemic hypertension. In this regard, hypertension- geometry in 937 hypertensive subjects at baseline and after 4.8 related LV hypertrophy is more closely associated with 24-h blood years of treatment with losartan or atenolol.15 At baseline, 70% of pressure averages and blood pressure variation assessed by the studied subjects exhibited either eccentric or concentric ambulatory blood pressure monitoring than with clinic blood hypertrophy. Of the patients with LV hypertrophy at baseline, 52% pressure readings.10 Furthermore, alternative measures, such as had normal geometry at final study echocardiogram. In addition, central aortic and leg blood pressure, were also reported to show concentric LV hypertrophy was reduced by 84%, whereas 82% of better correlations with LV mass in comparison with casual the patients with concentric remodeling at baseline had normal brachial blood pressure.11,12 geometry at the end of the study. On the other hand, 47% of Intravascular volume is another hemodynamic variable that patients with eccentric hypertrophy experienced no changes may affect the LV structure in hypertensive subjects. The role of during follow-up. Even though the losartan arm exhibited a higher volemic status in LV remodeling is suggested by the distinct reduction in LV mass in comparison with the atenolol arm,15 hemodynamic profiles observed among the patterns of LV these data suggest that activation of the renin–angiotensin geometry. For instance, hypertensive patients with eccentric system and sympathetic drive might be more involved in the

Journal of Human Hypertension (2015) 1 – 6 & 2015 Macmillan Publishers Limited Heart and hypertension W Nadruz 3 development of concentric hypertrophy and concentric remodel- contrary to conventional knowledge, concentric hypertrophy is ing rather than of eccentric hypertrophy. neither the only one pattern of LV adaptation nor the most frequent one. In a subset of studies of the aforementioned review (n ¼ 20 656), normal LV geometry was the most common pattern ASSESSMENT OF LV MASS AND STRUCTURE detected.20 Furthermore, almost 25% of the patients presented Hitherto echocardiography and in a lesser extent magnetic eccentric LV hypertrophy, whereas a smaller fraction (E18%) resonance imaging are the best-documented procedures used exhibited concentric LV hypertrophy. These latter results suggest to evaluate LV mass. Regarding echocardiography, LV mass may that volume load might be a major mechanism of LV remodeling be assessed using M-mode, two-dimensional (2D) or three- in a substantial part of the hypertensive population. The same dimensional (3D) techniques, although robust long-term follow- review also showed that LV hypertrophy prevalence was not up information using 2D or 3D echocardiography estimations of significantly different between genders (prevalence rates ranged LV mass as cardiovascular event predictors is still lacking.16 Strong from 36 to 44% in men and from 38 to 46% in women). This correlations between LV mass measurements assessed with finding, however, should be taken with caution because of the echocardiography and magnetic resonance imaging have been heterogeneity of diagnostic criteria (gender- and non-gender- reported; however, there are significant differences in absolute specific) used to define LV hypertrophy in the various studies. In values of LV mass between these modalities. Thus, estimates with addition, in 66% of the included studies, LV hypertrophy echocardiography and magnetic resonance imaging may not be prevalence was higher in women. On the other hand, eccentric used interchangeably in the evaluation of LV mass.16 Although LV hypertrophy prevalence tended to be higher in women than in mass determined with magnetic resonance imaging is more men, whereas concentric hypertrophy had a similar range in both accurate, echocardiography has lower cost and is a more versatile, genders.20 feasible and available technique in comparison with magnetic resonance imaging. These practical issues have supported the use of M-mode echocardiography as the standard clinical method for ETHNICITY assessment of LV mass and diagnosis of LV hypertrophy.5,10 Ethnicity influences the epidemiology of LV hypertrophy. The With the advance of cardiac imaging techniques, the ability to prevalence of LV hypertrophy and concentric hypertrophy is evaluate structural features other than LV mass and geometry has higher in blacks than in whites.3,10 Nevertheless, it is uncertain increased. For instance, echocardiography and magnetic reso- whether this represents an effect independent of blood pressure, nance imaging have been used to quantify myocardial fibrosis as blacks exhibit a higher risk of hypertension and higher blood noninvasively. Echocardiography with integrated backscatter pressure levels among hypertensive subjects.21 shows good correlation with collagen volume fraction. Never- theless, less than half of patients may have appropriate backscatter signal for analysis, which can limit the use of this approach SALT INTAKE in practical settings.17 Cardiac magnetic resonance imaging with Salt intake as assessed with 24-h urinary sodium excretion was late gadolinium enhancement has become a more robust method found to be an independent determinant of LV mass and to detect myocardial fibrosis, yet this approach may provide only a remained significantly related to LV mass even after correcting partial measure of fibrosis extent and burden, as it relies on a for 24-h blood pressure in hypertensive but not normotensive difference in signal intensity that may not exist in the case of individuals. Furthermore, a reduction in dietary sodium was shown diffuse and generalized fibrosis.18 In this regard, myocardial to reduce LV hypertrophy. The mechanisms underlying the extracellular volume fraction quantified using myocardial T1 relationship between salt intake and LV remodeling are not fully mapping has gained increased attention as a valuable established, although some explanations have been proposed. complement to late gadolinium enhancement to quantificate High dietary sodium may lead to cardiac hypertrophy by fibrosis more accurately.17,18 Recent evidence also showed that promoting increases in blood pressure and intravascular volume magnetic resonance imaging may assess cardiomyocyte size. or by exerting direct effects on myocardial cells. In addition, salt Estimation of intracellular lifetime of water by contrast-enhanced intake may be associated with myocardial fibrosis by stimulating cardiac magnetic resonance was reported to exhibit a strong aldosterone synthesis and increases in AT1 receptors in the correlation with cardiomyocyte volume,19 and may be a promising myocardium.22 approach for quantification of cardiomyocyte hypertrophy. However, large prospective studies are needed to evaluate the prognostic value of indirect fibrosis and cardiomyocyte size OBESITY measurements and whether improvements in prediction may be Obesity has a significant impact on cardiac structure and is gained by adding these parameters to current LV mass and associated with LV hypertrophy independent of blood pressure relative wall thickness measurements. levels and hypertension. This increase in LV mass has been traditionally explained by obesity-associated hemodynamic alterations and is particularly linked to central fat distribution. In EPIDEMIOLOGY response to the metabolic demand of increased fat mass, obese LV hypertrophy prevalence varies with severity of hypertension, subjects exhibit increased systemic blood volume and cardiac ranging from o20% in mild to almost 100% in severe or output, a redistribution of circulating volume to the cardiopul- complicated hypertension.10 The analysis of 30 studies published monary area and reduced peripheral vascular resistance. In in the last decade, including a hypertensive population of 37 700 addition, the expanding circulating volume in obesity may be individuals, showed that prevalence rates of echocardiographic LV also a consequence of increased water retention due to high salt hypertrophy were lowest in population-based studies (10–19%), intake associated with food overload. The LV then dilates and, for intermediate (19–48%) in untreated hypertensive cohorts and this reason, obesity has been predominantly associated with greatest in high-risk hypertensive patients (58–77%), who eccentric hypertrophy.23,24 comprised individuals with electrocardiographic LV hypertrophy, Non-hemodynamic factors, which involve inflammatory factors, severe hypertension, history of previous cardiovascular events and epicardial fat deposition, insulin resistance, adipokines, lipotoxi- refractory hypertension.20 city, sympathetic overdrive and activation of renin–angiotensin– Great heterogeneity has been also reported in the prevalence of aldosterone axis, have been also reported to have a role in LV geometric patterns among hypertensive subjects. Interestingly, obesity-associated LV remodeling. Therefore, other structural

& 2015 Macmillan Publishers Limited Journal of Human Hypertension (2015) 1 – 6 Heart and hypertension W Nadruz 4 modifications, such as fibrosis and epicardial fat accumulation, are that the hypertrophic response of the failing heart, although frequently seen in the heart of obese individuals, which may result initially compensatory, is followed by progressive worsening of in thicker LV walls and even concentric geometry.24 symptoms that ends with the death of the patient due to When arterial hypertension develops in obese subjects, pressure ‘degeneration and weakening of the heart muscle.’ Furthermore, overload is added and exerts an exponential effect on the this scenario has been consistently reproduced in animal models prevalence of LV hypertrophy. This issue is clinically relevant, as of pressure overload due to aortic banding as well as in humans systemic hypertension and obesity frequently coexist.21 LV with aortic stenosis and hypertrophic cardiomyopathy.3 hypertrophy has been reported to range between 13% in However, some lines of evidence have raised uncertainties normotensive obese individuals and over 75% in hypertensive whether this natural history is indeed typical in hypertensive individuals with morbid obesity, whereas the analysis of a cohort humans. First, as previously shown, concentric LV hypertrophy is of 4176 hypertensive patients showed that normal weight, not the most frequent geometric pattern and is less commonly overweight and obese subjects exhibited prevalence rates of LV seen than eccentric hypertrophy in studies enrolling hypertensive hypertrophy of 12%, 25% and 48%, respectively.24 In addition, subjects.20 Second, recent reports suggested that transition from results of autopsy and prospective clinical studies showed that a LV concentric hypertrophy to dilation and systolic dysfunction is combination of concentric-eccentric LV hypertrophy is commonly not a common finding, especially in the absence of coronary heart seen when obesity and hypertension coexist.23 disease. For instance, the analysis of 1024 patients with concentric LV hypertrophy and normal ejection fraction revealed that only 13% of patients progressed to systolic dysfunction during B3 DIABETES MELLITUS years of follow-up. Remarkably, this transition occurred after an Accumulating data from experimental, pathologic, epidemiologic interval myocardial infarction in 42.5% of patients.29 In another and clinical studies have shown that diabetes mellitus itself results study, 20% of 220 subjects with concentric LV hypertrophy in structural and functional cardiac changes, independent of developed reduced LV ejection fraction after a median follow-up hypertension and coronary heart disease.25 Common findings in of 7.5 years. Among those who developed systolic dysfunction, biopsies of the diabetic heart are interstitial fibrosis, 29% had an interval myocardial infarction.30 Third, recent data cardiomyocyte hypertrophy and increase in contractile protein from the Framigham Heart Study revealed that heart failure risk glycosylation. Proposed mechanisms underlying these alterations varied by LV geometric pattern, with eccentric and concentric involve hyperglycemia, hyperinsulinemia, oxidative stress and hypertrophy predisposing to heart failure with reduced and activation of the renin–angiotensin–aldosterone system. Com- preserved ejection fraction, respectively, after a mean follow-up of pared with nondiabetic subjects, diabetic individuals usually 21 years.31 Interestingly, concentric LV remodeling was not exhibit higher LV mass and wall thickness, even after adjusting independently associated with heart failure risk after adjustment for body mass index and blood pressure.3,25 However, the exact for confounding variables. Although the prevalence of impact of diabetes mellitus on LV geometry remains uncertain hypertension was not high (hypertension was detected at because either concentric or eccentric remodeling was reported in baseline in 24% and 40% of subjects with eccentric and diabetic individuals.3 concentric hypertrophy, respectively), these results raise the The coexistence of diabetes mellitus and systemic hypertension assumption that hypertensive subjects might evolve toward usually results in additive effects in LV mass. The analysis of a dilated heart failure without developing prior concentric population-based sample of 1950 hypertensive adults showed hypertrophy. Furthermore, they strengthen the idea that that the likelihood of LV hypertrophy was 32% higher in diabetic concentric hypertrophy is more related to heart failure with than in nondiabetic hypertensives independent of most common preserved rather than with reduced ejection fraction. Overall, this clinically assessed conditions, such as sex, blood pressure and body of evidence indicates that the progression of LV remodeling obesity. In addition, concentric LV hypertrophy seems to be the may follow various pathways among hypertensive subjects most frequent geometric pattern in hypertensive diabetic (Figure 2). patients.26 PROGNOSIS GENETIC FACTORS LV hypertrophy is consistently identified as an independent risk LV hypertrophy is considered a complex disease, resulting from factor for cardiovascular morbidity and mortality. The analysis of the interaction of several genes with the environment. The 20 prospective studies (with 48 545 participants) published heritability of LV mass, measured as a quantitative trait, has been between 1960 and 2000 showed that subjects with LV hyper- estimated between 30 and 70% in different populations. In this trophy had a 2.3 times increased risk of cardiovascular morbidity regard, genes encoding proteins involved in LV structure, blood and a 2.5 times increased risk of cardiovascular mortality.3 pressure control, cell signal transduction, calcium homeostasis and Furthermore, data from the Massa Ventricolare Sinistra substrate metabolism, as well as genes encoding cell hormones nell’Ipertensione (MAVI) study, which evaluated 1033 subjects and growth factors, are potential candidates for the development with uncomplicated hypertension, demonstrated that for every of LV hypertrophy.27 Various reports, including candidate gene 39 g m À 2 increase in LV mass there was an independent 40% rise association studies and genome-wide association studies, have in the risk of major adverse cardiovascular events.32 On the other attempted to identify common genetic variants associated with hand, consistent evidence showed that regression of LV cardiac structure.3 However, the yielded results are far from being hypertrophy secondary to pharmacological control of blood translated into the clinical arena. Conversely, available data have pressure improves cardiovascular outcome and long-term suggested that multiple variants, each with modest effect size, prognosis. This can be exemplified by results of a meta-analysis may be involved in the modulation of LV mass.27 including 1064 hypertensive subjects, which demonstrated that LV hypertrophy regression was associated with a 59% reduction in the risk of cardiovascular events when compared with persistence PROGRESSION OF LV REMODELING or new development of LV hypertrophy.33 The conventional concept of hypertensive LV remodeling has Several mechanisms may mediate the prognostic value of LV been that hypertension leads to concentric hypertrophy, which is hypertrophy. On one side, many hemodynamic and non- then followed by chamber dilation and heart failure. This view was hemodynamic factors that stimulate increases in LV mass may described more than 120 years ago by William Osler28, who noted also induce progression and destabilization of atherosclerotic

Journal of Human Hypertension (2015) 1 – 6 & 2015 Macmillan Publishers Limited Heart and hypertension W Nadruz 5

Figure 2. Pathways of LV remodeling progression secondary to systemic hypertension. EF, ejection fraction; MI, myocardial infarction. lesions. For this reason, LV hypertrophy is considered a marker for hypertrophy is consistently associated with cardiovascular mor- future events, such as stroke and myocardial infarction. On the bidity and mortality, raising doubts whether this phenotype is other hand, LV hypertrophy may be also a mediator of events, by indeed an adaptive response. In this regard, LV hypertrophy is inducing myocardial dysfunction and ischemia, thus predisposing acknowledged not only as a marker but also as a mediator of to arrhythmias and heart failure.34 Noticeably, hypertension cardiovascular events. Therefore, prevention and diagnosis of LV precedes the development of heart failure in B90% of patients hypertrophy should be a priority in patients with systemic and increases risk for heart failure by twofold.21 hypertension. Epidemiological data have also shown that the LV geometric pattern has prognostic value. In this context, subjects with concentric hypertrophy are predisposed to the highest cardiovas- CONFLICT OF INTEREST cular risk, whereas those with eccentric hypertrophy and The author declares no conflict of interest. concentric remodeling are at an intermediate risk between concentric hypertrophy and normal geometry.34 The reasons by which concentric hypertrophy is coupled with worse prognosis are REFERENCES not entirely clear, although some explanations have been 1 Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling–concepts and clinical implica- proposed. As LV mass tends to be greater in patients with tions: a consensus paper from an international forum on cardiac remodeling. concentric than in those with eccentric geometry, it is possible Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol 2000; that the prognostic impact of concentric hypertrophy may be a 35: 569–582. 2 Frohlich ED, Susic D. Pressure overload. Heart Fail Clin 2012; 8: 21–32. consequence of the overwhelming prognostic value of LV mass 34 3 Drazner MH. The progression of hypertensive heart disease. Circulation 2011; 123: itself. Conversely, it can be also speculated that subjects with 327–334. concentric hypertrophy were exposed to antecedent hypertension 4Da´vila DF, Donis JH, Odreman R, Gonzalez M, Landaeta A. Patterns of left ven- 4 of higher severity, which would also lead to increased prevalence tricular hypertrophy in essential hypertension: should echocardiography guide rates of other end-organ damage and therefore to a higher risk of the pharmacological treatment? Int J Cardiol 2008; 124: 134–138. cardiovascular events. In addition, increased relative wall thickness 5 Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ven- has been independently associated with reduced flow reserve in tricular mass and geometry to morbidity and mortality in uncomplicated essential hypertensive patients, which may contribute to explain the excess hypertension. Ann Intern Med 1991; 114: 345–352. ´ cardiovascular event rate associated with concentric LV 6Dıez J. Towards a new paradigm about hypertensive heart disease. Med Clin North 35 Am 2009; 93: 637–645. hypertrophy. 7 Vakili BA, Okin PM, Devereux RB. Prognostic implications of left ventricular hypertrophy. Am Heart J 2001; 141: 334–341. 8 Samuel JL, Swynghedauw B. Is cardiac hypertrophy a required compensatory CONCLUSION mechanism in pressure-overloaded heart? J Hypertens 2008; 26: 857–858. LV remodeling is frequently seen in hypertensive subjects and 9 Sadoshima J, Izumo S. The cellular and molecular response of cardiac myocytes to results from a complex interaction of several hemodynamic and mechanical stress. Annu Rev Physiol 1997; 59: 551–571. non-hemodynamic variables. Although increased blood pressure 10 Ruilope LM, Schmieder RE. Left ventricular hypertrophy and clinical outcomes in is considered the major determinant of LV structural alterations, hypertensive patients. Am J Hypertens 2008; 21: 500–508. ethnicity, gender, environmental factors, such as salt intake, 11 Norton GR, Majane OH, Maseko MJ, Libhaber C, Redelinghuys M, Kruger D et al. Brachial blood pressure-independent relations between radial late systolic shoulder- obesity and diabetes mellitus, as well as genetic factors, might derived aortic pressures and target organ changes. Hypertension 2012; 59: 885–892. influence LV mass and geometry. Increases in LV mass have 12 Gemignani T, Matos-Souza JR, Franchini KG, Nadruz Jr W. Leg blood pressure been traditionally considered as a compensatory response to measured in orthostatic posture is associated with left ventricular mass in hemodynamic overload in hypertensive patients. However, LV normotensive subjects. Am J Hypertens 2012; 25: 1083–1087.

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Journal of Human Hypertension (2015) 1 – 6 & 2015 Macmillan Publishers Limited