**2. The progression of cardiac remodeling in hypertension**

Hypertension-induced cardiac remodeling is an initial adaptive response of the heart in order to compensate the increased left ventricle wall stress induced by an augmented hemodynamic load. This remodeling is named adaptive hypertrophy, which is featured by growing inwards of the left ventricle and septum wall, resulting in a reduction in left ventricle chamber (**Figure 1**) [2, 3]. The structural changes may occur due to additional contractile-protein units within the cardiomyocytes leading to an expansion in the myocyte width. In parallel to the cellular growth, the cardiac extracellular matrix is also hypertrophied. An important hallmark in chronic hypertension is the intensive turnover from the extracellular matrix, resulting in a progressive collagen deposition [3]. Amount evidences have shown that the cardiac fibrosis could contribute to initial diastolic dysfunction harming the re-lengthening of myocytes during diastole [2, 8, 9]. Thus, despite being called "adaptive", this hypertrophy generates several maladaptive molecular and/or cellular mechanisms triggered in the initial remodeling.

**1. Introduction**

52 Renin-Angiotensin System - Past, Present and Future

output [2, 3].

failure, stroke, etc.

Cardiac remodeling is generally triggered due to cardiovascular diseases, such as myocardial infarction, pressure overload, idiopathic dilated cardiomyopathy or volume overload [1]. Cardiac remodeling is also the most common factor in heart failure progress, a chronic disease defined as a complex syndrome. In this sense, heart failure is associated with intensive and progressive cardiac structural and functional modifications, leading to impaired cardiac

More than 23 million people worldwide are affected by heart failure. In the United States, approximately 5 million patients have heart failure and this number increases by more than half a million cases per year [4]. It is estimated that an increase in the 46% in the prevalence of

There are several criteria to diagnose heart failure as revised by Roger VL [6]. These criteria are important to determine the kind of heart failure treatment and also contribute to improving the accuracy of epidemical data. Despite the progress of the heart failure treatment, mortality rates are still high. Nowadays, the available treatments for heart failure improve the survival rates but raise hospitalizations as well as hospital readmissions. Among these treatments, there are angiotensin-converting enzyme inhibitors (ACEi) and beta-adrenoceptors blockers that alleviate the symptoms in individuals with advanced heart failure and depressed ejection fraction in end-stage disease [7]. Therefore, heart failure is a growing public health problem, in which a projection from 2012 to 2030 heart failure will account more than \$69 billion in

health-care cost in the United States. It will be a significant increase from 127% [5].

**2. The progression of cardiac remodeling in hypertension**

Several risk factors are associated with heart failure, such as smoking, obesity, diabetes mellitus, coronary heart disease and hypertension among others. Hypertension—chronic elevation of blood pressure—is the most prominent human health problem, and it is the main comorbidity linking obesity, cardiovascular and metabolic diseases. According to Framingham study, hypertension is considered the major risk factor attributed to heart failure, and its prevalence in hypertension exceeds 50% [6, 8]. Hereupon, hypertension is the cause of deaths because it often coexists with heart failure and also places individuals at a higher risk for kidney

Hypertension-induced cardiac remodeling is an initial adaptive response of the heart in order to compensate the increased left ventricle wall stress induced by an augmented hemodynamic load. This remodeling is named adaptive hypertrophy, which is featured by growing inwards of the left ventricle and septum wall, resulting in a reduction in left ventricle chamber (**Figure 1**) [2, 3]. The structural changes may occur due to additional contractile-protein units within the cardiomyocytes leading to an expansion in the myocyte width. In parallel to the cellular growth, the cardiac extracellular matrix is also hypertrophied. An important hallmark in

heart failure from 2012 to 2030 in people with 18-year old or more [5].

**Figure 1.** The hypertension induced progression from adaptive hypertrophy to maladaptive hypertrophy. Cardiac remodeling is progressive in hypertension. Initially, an adaptive hypertrophy occurs in the left ventricle that grows inwards reducing the left ventricle chamber. The cardiac remodeling may progress to maladaptive hypertrophy. The left ventricular chamber is dilated and left ventricle and septum wall are thinned. The strength of cardiac contraction may be reduced mainly due the loss of contractile proteins. The heart is therefore considered decompensated, which may result in heart failure. Both, adaptive and maladaptive hypertrophies are characterized by increased heart size and weight. RV: right ventricle and LV: left ventricle.

Hypertensive patients may progress from adaptive to maladaptive hypertrophy, which is characterized by increased left ventricle chamber accompanied by thinning of a left ventricle and septum wall (**Figure 1**). The myocytes are still hypertrophied, but the length is increased [1–3, 9]. The mechanisms involved in the transitions from adaptive to maladaptive hypertrophy are poorly understood. Nonetheless, some studies point out to the excessive matrix extracellular degradation during maladaptive hypertrophy disrupting the cellular organization [2], which could contribute to myocytes lengthening and left ventricular chamber dilatation. It has been also accepted that cell death is associated with this alteration in myocytes [2, 10].

Pathogenic cellular and interstitial changes in hypertension-induced cardiac remodeling are orchestrated by several molecular mechanisms that may be transduced from mechanical force into myocardial growth. In this regard, renin-angiotensin system (RAS) is activated in hypertension and may be involved in cardiac hypertrophy and failure. Clinical and experimental studies have shown significant benefit conferred by pharmacological blockade of RAS [7, 11–13] arousing interest by mechanisms underlying the action of angiotensin II (Ang II).
