Cardiovascular changes during chronic hypertensive states

The European Society of Hypertension and the European Society of Cardiology have published the Guidelines for the Management of Arterial Hypertension. In adult populations the stratification of CV risk is based on BP level, risk factors, subclinical organ damage (SOD) and established CV disease (CVD) and kidney disease. The categories are clearly defined. The main risk factors include systolic and diastolic blood pressure (DBP) levels, age (man >55 years, women >65 years), smoking, dyslipidemia, fasting plasma glucose of 5.6–6.9 mmol/l, abnormal glucose tolerance test, abdominal obesity and family history of premature CVD (man at age <55 years, women at age <65 years). Despite the presence of one out of the major risk factors (HTN, hypercholesterolemia, smoking), the vast majority of young and middle-aged adults will not experience an adverse CV event. In contrast, an adult patient with HTN grade 1 or 2 and one to two risk factors has a moderate CV risk, while evidence of three or more risk factors, metabolic syndrome, SOD or diabetes stratifies the patient into the high risk group.

Risk stratification using the SCORE (the Systemic Coronary Risk Evaluation) Project risk charts is recommended for each adult hypertensive patient [10]. The SCORE risk charts can be used to estimate the 10-year risk of fatal CVD by gender, age, SBP, total cholesterol and smoking status. Risk charts based on SCORE were developed for both low- and high-risk countries. In individuals at low or moderate risk (SCORE 1–4 %) the search for SOD is encouraged. Sehestedt et al. showed the role of detecting SOD in the estimation of CV risk [11]. In healthy subjects the assessment of SOD includes increased pulse wave velocity (a marker of increased arterial stiffness), presence of atherosclerotic plaques, increased urine albumin/creatinine ratio (a marker of vascular damage) and increased LV mass (LVM), which predicts CV death independent of SCORE [11].

The presence of an established CVD or renal disease carries a very high CV risk, even in patients with normal or high-normal BP. HTN is the main CV risk factor, however patients with chronic kidney disease (CKD) also have many other uremia-related risk factors, such as inflammation, oxidative stress, increased renin–angiotensin–aldosterone system (RAAS) activity, increased Ca × P product, hyperphosphatemia, hyperparathyroidism, decreased Fetuin-A, elevated asymmetric dimethylarginine plasma concentrations, fluid overload and anemia [12]. These risk factors are why patients with renal diseases in the adult population are considered to be at very high CV risk—even those with high normal BP. A panel of experts has included CKD among the eight high-risk pediatric diagnoses associated with premature CV risk. Moreover, intervention strategies for children with CKD should be similar to the secondary prevention guidelines for adults with established coronary disease [13].

This cluster of different risk factors multiplies the CV risk. The coexisting risk factors differ depending upon age. In a study by Flynn et al. involving a group of 351 children with HTN, 44 % were obese. The authors reported that the hypertensive children under 6 years were less likely to be obese or to have elevated cholesterol than school-age children or adolescents, but they were more likely to have secondary HTN and a lower glomerular filtration rate (GFR) [14]. Wilson et al. [15] studied children with CKD and found that the incidence of different CV risk factors increased with increasing body mass index. The patient group in this study comprised obese children with HTN, dyslipidemia and abnormal glucose metabolism [15]. The prevalence of CV risk factors was very high in children on RRT. In a Turkish study 44 % patients on peritoneal dialysis had uncontrolled HTN and 39 % had dyslipidemia [16].

CKD as well as essential HTN and obesity/metabolic syndrome are characterized by enhanced activity of the RAAS and the sympathetic nervous system [17]. These systems not only regulate BP but also contribute to CV abnormalities.

HTN in adults is defined as a SBP of >140 mm Hg and/or a DBP of >90 mm Hg [4]. Evidence from randomized controlled trials demonstrates that treatment-induced reductions in BP are beneficial in patients with such BP values. A large number of observational studies have demonstrated that CV morbidity and mortality have a continuous relationship with both SBP and DBP [18]. In adults, each 20-mm Hg increase in SBP or 10-mm Hg increase in DBP doubles the death rates from stroke and other CV causes. A meta-analysis of individual data for one million adults revealed that the relationship between BP and vascular mortality decreases steeply downwards, at least as far as the normal SBP of 115 mm Hg and DBP of 75 mm Hg.

In children, BP increases with age and body size. Normative values for defining HTN have been determined on the basis of BP measurements in a large reference population [19]. In that study, the cut-off point for detecting HTN in children was defined as the 95th percentile for gender, age and height. To date, there have been no multicenter long-term studies assessing the impact of childhood BP level on clinically apparent CV complications in adulthood. However, in youth a graded increase in SOD parameters [carotid IMT (cIMT), arterial stiffness, LVM index (LVMI) and decrease in diastolic function] from normotension to pre-HTN and to HTN, has been found [20].

Research conducted on adults and children has revealed that LVM is significantly determined by fat-free mass (FFM). To avoid any incorrect interpretation of results when body surface area in obese patients is used, it was suggested that height raised to an exponential power of 2.7 should be used as an equivalent of FFM. The Fourth Report recommends using a single cut-off point (38 g/m^2.7) to define LVH in children [30]. Khoury et al. performed M-mode echocardiography in 2,273 non-obese healthy children and established percentile charts for LVM and LVMI depending on sex and age. The 95th percentile for LVMI ranged from 80 g/m^2.7 for newborns to 40 g/m^2.7 for 11 year olds. These researchers recommended the identification of LVH based on the 95th percentile for LVMI in children under 9 years of age, and in older children the accepted cut-off point was an LVMI of >40 g/m^2.7 in girls and LVMI of >45 g/m^2.7 in boys [31]. Foster et al. demonstrated that the 95th percentile LVMI depends on the height distribution of the reference population and proposed LVM-for-height percentiles as a superior means of normalizing LVM for body size [32]. In young children, the correct diagnosis of LVH is difficult to arrive at due to the small reference samples and rapid changes in body size and heart mass. In CKD, children suffer from growth retardation and body composition changes (malnutrition, overhydration). Borzych et al. proposed using height age instead of chronological age to calculate the LVMI [33].

LVH is an important SOD in hypertensive subjects and an independent CV risk factor both in children and adult populations [34]. In several studies the relationship between LVM and subsequent CV risk was found to persist after adjustment for traditional risk factors. In the MAVI study, LVH doubled the risk of CV events. The following events developed during follow-up in a group of uncomplicated subjects with essential HTN: sudden cardiac death, MI, stroke, transient ischemic attack, heart failure, new onset unstable angina, arterial occlusive disease and progressive renal failure [34].

Left ventricle geometry can be classified into four categories: normal geometry, concentric remodeling [normal LVM, increased relative wall thickness (RWT)], concentric hypertrophy (elevated LVM and RWT) and eccentric hypertrophy (elevated LVM and normal RWT) [35]. Adult patients with concentric remodeling and hypertrophy have the highest peripheral resistance, and those with eccentric hypertrophy have a supernormal cardiac index, thereby demonstrating the role of pressure and volume overload as mechanisms involved in developing LVH. Moreover, in the group with concentric remodeling, the highest peripheral resistance was accompanied by reduced LV end-diastolic dimension, which suggests that pressure overload is balanced by a decreased volume load. In adults, concentric hypertrophy was found to be associated with the highest risk of CVD. In concentric hypertrophy, the degree of impaired LV filling (left atrial afterload) increases with increases in LV stiffness, which results in an increase in the size and function of the left atrium.

Concentric and eccentric LVH have been detected in children with primary HTN and in various studies in patients with CKD at different stages of the disease [36‐38]. In a group of 128 children on peritoneal dialysis followed by the International Pediatric Network (IPPN) Registry, SBP was significantly lower in children with normal cardiac geometry than in patients progressing to LVH or with persistent LVH [39]. In the multivariate analysis, obesity and HTN were independent risk factors for persistent or de novo LVH. In the study performed by Lurbe et al., LVH, defined as an LVMI of >95th percentile, was detected only in patients with masked HTN and not in the normotensive controls [40]. In another study involving CKD patients, masked HTN (defined as normal clinical BP but elevated in ambulatory BP measurements) was also linked to a significant increase in the risk of LVH [41]. These results highlight the need for performing regular ambulatory BP measurements in children with CKD. As shown by the results of the Escape study, concentric LVH is connected with subclinical systolic dysfunction (impaired fractional shortening at the midwall level) in children with CKD [42].

The treatment of HTN can result in the regression of LVH, as shown in the Life study [43], which also showed that losartan was more efficient than atenolol. In a meta-analysis by Fagard et al., the regression of LVM was significantly less with β-blockers (9.8 %) than with angiotensin receptor blockers (12.5 %) [44]. Another important finding from this meta-analysis was that all indices of systolic (LV fractional shortening and ejection fraction) and diastolic function (LV inflow ratio of early to late diastolic filling) improved in response to antihypertensive treatment. In children with CKD, treatment with fixed high-dose ACE inhibition led to reduction in LVH prevalence and improvement in systolic function. The association between an increase in midwall fractional shortening and a reduction in BP has been discovered [45].

Prospective studies performed in adult hypertensive subjects have found that LVH regression is associated with risk reduction of major CV morbid events, such as stroke, MI, CV death, atrial fibrillation, heart failure and even new-onset diabetes mellitus [46, 47].

In adults, the brain is an early target for organ damage by elevated BP. HTN causes vascular brain injury directly [small-vessel disease (SVD)] or by promoting atherosclerosis or cardiac damage. HTN results in increased brain vascular resistance and the loss of the physiological mechanism of autoregulation. Hypertensive SVD is thought to be the main cause of silent brain infarcts, which, by definition, lack clinically overt stroke-like symptoms; rather, they are associated with subtle deficits in physical and cognitive function. Moreover, the presence of silent infarcts more than doubles the risk of subsequent stroke and dementia. In the adult population 75 % of strokes occur in patients aged >65 years. In a study in 6,105 individuals with previous stroke or transient ischemic attack carried out by the PROGRESS Collaborative Group, combination therapy with perindopril and indapamid reduced systolic/diastolic BP by 12/5 mm Hg and stroke risk by 43 %. A similar reduction in the risk of stroke in both hypertensive and non-hypertensive subgroups was found [52].

In children, ischemic and hemorrhagic strokes occur at an equally frequent rate, but their incidence is much lower than that in adults, namely 1.2 to 13 cases per 100,000 children under 18 years of age [53]. Clinical presentation in adolescents is similar to that in adults, it mimics another disease in younger children. The lack of awareness of a stroke in a child is responsible for the longer time to diagnosis this event in children than in adults, even in hospitalized patients. In adults, age is the most important non-modifiable risk factor and HTN the most important modifiable risk factor. The etiology of stroke in children is mostly multifactorial and varied: congenital and acquired heart disease, arteriovenous malformations and sickle cell disease, thrombophilias and infectious diseases such as varicella, sepsis, meningitis and even minor infection [54]. Arteriovenous malformations, cavernous malformations and aneurysms are the most common causes of pediatric hemorrhagic stroke. HTN is also counted among hemorrhagic stroke risk factors, yet since it rarely occurs in children it is considered to be a less important risk factor. The most sensitive method to diagnose acute ischemic stroke is brain magnetic resonance imaging, which requires sedation in younger children. Nephrologic pediatric patients with vasculitis are at a high risk of stroke. HTN, connective tissues diseases, a recent infection and/or migraine headaches increase the risk of vertebral artery dissection and cervical artery dissection, both of which are a common cause of strokes in young adults after injuries.

In children, an association has been reported between elevated SBP and reduced scores on the digit span test, which is a neuropsychological measure of attention and concentration [55]. Single-center studies provide preliminary evidence that hypertensive children manifest deficits on measures of neurocognition, have an increased prevalence of learning difficulties and have altered cerebrovascular reactivity (decreased ability to enhance cerebral blood flow in response to increased neuronal activity) [56, 57].

Long-term follow-up multicenter studies are necessary to assess CV risk stratification in children and adolescents with HTN and to develop standards for diagnostic and treatment procedures. An addition point which should also be examined is whether the application of screening tests for CV risk factors and the implementation of adequate treatment will result in a decrease of CV risk in adulthood. Randomized controlled trials are required to assess the safety and efficacy of different antihypertensive drugs in reducing SOD in children. Modern RRT results in lengthening the life expectancy of children and adolescents with ESRD. Coexistence of many traditional and uremia-related risk factors increases CV morbidity and mortality. New research to understand the impact of specific uremia-related factors on cardiac and vasculature remodeling/injury is needed. Future studies to assess the efficacy and safety of statin treatment in different cases of secondary hypercholesterolemia, for example CKD and obesity, are needed.

Hypertension is currently the biggest single contributor to death around the world. Elevated BP represents an important risk factor for CV diseases, such as coronary heart disease, heart failure, stroke, peripheral artery disease and renal failure, in adults. It is well established that subclinical target organ damage (LVH, increased IMT, cognitive dysfunction, microalbuminuria) is already present in childhood. A special group of patients is that comprising children and adolescents with CKD. In observational and multicenter studies, subclinical target organ damage has been detected at early stages of CKD; however, regression and progression of LVH or IMT changes are possible. Ambulatory BP measurements and echocardiography should be performed in children with CKD on a regular basis in order to detect HTN and to monitor therapy. The results of the European Escape trial show that decreasing the BP to the low-normal range is associated with slowing the progression of CKD in children. The goal of antihypertensive treatment should not only be to normalize the BP but also to prevent target organ damage. The major concern in the management of hypertensive patients remains the heightened rate of late consequences.

The impact of HTN on CV damage has been extensively studied in large groups of adults—both in the general population and the adult CKD population. Based on observational and interventional studies, specific recommendations have been developed for the treatment of HTN and other risk factors (e.g. hypercholesterolemia) with the aim of reducing global CV risk. Long-term follow-up multicenter studies are necessary to assess CV risk stratification in children and adolescents with HTN and to work out standards for diagnostic and treatment procedures. New research to investigate the impact of specific uremia-related factors on cardiac and vasculature remodeling/injury are needed. The lack of comorbidities in children allows us to study the influence of HTN on early stages of organ damage—endothelial dysfunction in particular.

Children with CKD are at high risk of CV events, and preventive strategies should be started early in the course of renal disease.