*5.1.2 Age*

The mean age of participants in the present study (45.3 years) was similar to that of subjects in the study by Ntuli et al. [54] (44.2 years). Gupta et al. [52] did not report a mean age for their population which was limited to the working age-group under 58 years, while Huang et al. [53] carried out their investigation on participants in the 35–74 age group [52, 53]. The bulk of studies on ISHC have been focused on specific age groups, usually the young (under 35 years of age) or the old (over 50 years old) [27, 49, 59, 60] unlike our population which included all consenting persons over the age of 18. While several studies in recent years have shown that the condition is not at all restricted to the older population [25–27], the relatively high average age associated with ISH (especially the conventional subtype) in our study is consistent with the findings of a number of researchers and with the widely accepted notion that ISH is predominant and naturally occurring in the elderly population [1, 16, 18, 30, 61]. A study by Huang et al. [53] also showed an increase in ISHC with age.

Martins et al. [62] observed an increase in PP and SBP from the age of 45 upward in their analysis of data from the NHANES. Indeed, the most commonly described pathophysiological mechanism for ISH involves changes occurring to the large arteries owing to ageing [13]. With age progression, elastin in the media decreases, leading to a fragmented media [13, 18] which is susceptible to calcium and lipid accumulation. Along with this media calcification occurs the accumulation of smooth muscle cells within the intima, collagen cross linking occurs and all this leads to the thickening and fibrosis of the arterial wall [13, 18, 43]. These changes culminate in arterial stiffness, an increased wall-to-lumen ratio and a reduced cross-sectional area of the lumen of the greater arteries [13, 37, 63]. Due to poor compliance, the large arteries fail to expand and subsequently recoil effectively in systole and diastole of the cardiac cycle, respectively. There is a resultant increase in aortic PP and PWV. Consequently, the reflected wave which would normally return during diastole, returns during late systole and augments systolic pressure; SBP increases while the DBP decreases [43, 63]. In line with this, we observed higher values of average SBPC in the ISH groups than in the normotensive group, and these were comparable to that of hypertensive participants. This was coupled with relatively low DBPC for all ISH sub-types when compared to the hypertensive group. By definition, PP is the difference between SBP and DBP, thus its normal value is approximately 40 mm Hg [64]. Pulse Pressure values exceeding 60 mm Hg are associated with target organ damage which may or may not be asymptomatic [3]. In the present study, PP was markedly increased in participants with ISHC, with an average of 69.7 mm Hg. Wallace et al. [65] also observed similar elevated SBP and PP (67 mm Hg) in their ISHC group. This finding was as expected based on the definition and underlying physiology of the condition [16, 18, 61] since PP is the difference between systolic and diastolic BPs; and an increase in the former and/or decrease in the latter would raise PP.

#### *5.1.3 Obesity*

In general, all the ISH groups in this study were obese. Average BMI values ranging from 30.9 to 31.4 were recorded for these groups, all of which exceed the obesity threshold of 30 for BMI [66]. The role of obesity as a risk factor for ISH is well documented [25, 35, 57, 63, 67]. Erhun et al. [68] observed the highest prevalence of ISH among the extremely obese group in their study. The ISH subgroup in the research by Grebla et al. [24] was overweight, and these authors suggested that obesity may be an important determinant of ISH in young adults [25]. A study by Nemes et al. [69] showed that obesity is associated with increased arterial stiffness and that this is true even for young obese adults, whose arterial stiffness they found comparable to that of elderly non-obese individuals. Although all of these studies investigated obesity in ISH by conventional BP measurement, their findings may extend to all the ambulatory subtypes of the condition as well. Our results show that in all participants with any forms of ISH, arterial stiffness as measured by PWV was increased in comparison to normotensives.

Several mechanisms have been described that may explain the role of obesity in ISH. Hyperinsulinaemia and insulin resistance, which are both strongly associated with obesity [70], may mediate aortic stiffness through glycation of vascular wall proteins and subsequent increased cross-linking [69]. Insulin has also been associated with smooth muscle hypertrophy and increased endothelial dysfunction of large arteries likely resulting from oxidant stress, causing increased susceptibility to atherosclerosis [69, 71]. One other significant mechanism that has been implicated in the relationship between obesity and ISH is the activity of leptin [69]. Hyperleptinaemia is associated with endothelial dysfunction in obese individuals [72], which is an underlying cause of arterial stiffness. Schutte et al. [73] reported a strong negative correlation between leptin and arterial compliance coupled with a strong positive relationship between leptin and SBP as well as leptin and PP in obese/overweight hypertensive African women. The high-leptin state of overweight/obese women in our study population, which was predominantly African, has been previously described [74] and may play an important role in ISH.

#### **5.2 Isolated systolic hypertension target and target organ changes**

### *5.2.1 Arterial stiffness*

We measured PWV by applanation tonometry, a minimally invasive method which is widely recognised as the 'gold standard' in the determination of arterial stiffness [65, 75]. As far as we know there are no studies which have investigated PWV in ambulatory subtypes of ISH, however, the general association of ISHC with arterial and aortic stiffness has been reported [65, 76, 77]. Antza et al. [77] in their study of arterial stiffness in ISHC observed an increase in arterial stiffness in patients with the condition, and suggested that ISHC may have a role to play in large artery arteriosclerosis.

This observation can be explained in terms of the haemodynamic changes associated with ISH. Since ISH is characterised by elevated systolic and pulse pressures, these parameters exert increased mechanical stress on the arteries over time, leading to elastin fragmentation and subsequent calcification, collagen deposition and smooth muscle cell hypertrophy [34, 37, 76]. In addition to this, endothelial dysfunction associated with the shear stress also triggers the inhibition of NO production and the release of pro-inflammatory cytokines and growth factors such as TGF-β [31, 34, 65]. These augment arterial damage by promoting smooth muscle cell hypertrophy and the increased production of extracellular matrix proteins;

**89**

this clinical entity.

*5.2.2 Left ventricular hypertrophy*

*Ambulatory Isolated Systolic Hypertension and Cardiovascular Target Organ Damage in People…*

moreover, TGF-β inhibits the activity of those metalloproteases which would otherwise assist by breaking down the collagen build-up, such as MMP-9 [38]. All these factors culminate in arterial stiffening of mainly the central arteries. In essence, ISH speeds up the rate of arterial ageing and increases arterial stiffness, thereby leading to its own exacerbation in a vicious cycle [65]. Several scholars agree that the causal

With this in mind, it is not surprising that we observed significantly elevated PWV in all subtypes of ISH when compared to normotensives. Of interest, is that all ISH groups had an increase in PWV that is comparable to that of the sustained hypertensive group. This suggests that the arterial damage caused by the ISH groups may equal arterial stiffness arising from sustained hypertension in this population. This is contrary to our expectation. We expected the PWV of the ISH24 to be higher than that of the other groups due to the cumulative effects of a high systolic BP that is sustained over a 24-hout period. The explanation for this apparent discrepancy is that 24-hour BP is a combination of both daytime and night-time BP. Since BP decreases at night, that decline in nocturnal BP may have a damping effect on the

When we used ROC curve analysis to determine how well the different subgroups of ISH would predict an increased PWV in this population, our results indicate that all ISH subtypes predict PWV. Conventional ISH was the strongest predictor of arterial stiffness with an AUC of 0.88 followed by ISHD at 0.83. In this respect, daytime BP is emerging as the best predictor of ISH in this population as both conventional and daytime ambulatory BP are measured during the day. This is due to the 24-hour pattern of BP in which BP increases during the day and decreases at night. Our results indicate that the increase in daytime systolic BP in people with ISH is exaggerated, resulting in a high PP of 70 mmHg, which is 30 mm Hg the normal value of 40 mm Hg. This is PP value is higher than that of people with sustained hypertension. The same pattern was observed in people with ISHD. As discussed earlier, PP is an independent risk factor for vascular disease. This explains why ISHC and ISHD which have the highest PP, are the strongest predictors of arterial stiffness. Even though ISHN predicts arterial to a lesser extent than ISHC and ISHD, it is still a strong predictor of arterial stiffness with an AUC of 0.78. This highlights the importance of this study which is the first to discover the existence of

Left ventricular mass index has been used as an indication of LVH, a major independent predictor of cardiovascular mortality and morbidity [78–80]. We used echocardiography, a well-accepted, efficient and non-invasive tool for the estimation of LVMI [79, 80]. In this study, there were no clear differences in LVMI values obtained for the ambulatory ISH sub-types (ISHD, ISHN and ISH24), suggesting that there are no major differences in the development of LVH among these three subtypes; although the extent of cardiac damage they caused is similar to that associated with hypertension. This implies that even if diastolic BP can be normal, the impact of systolic BP alone is significant has a significant impact on cardiac morphology. The premature return of the reflected wave in ISH is probably the most significant cause of LVM increase [81] in this condition. The augmentation of SBP by the reflected wave results in an increased afterload to the left ventricle. As the left ventricle adapts to the increased workload, concentric hypertrophy of surrounding tissue occurs, resulting in thickening and increase in mass of the left ventricle wall [37]. Poor coronary perfusion owing to low DBP may also exacerbate the effects of increased LVM in ISH as increased oxygen demand of the myocardium

relationship between arterial stiffness and ISH is bidirectional [31, 34, 38].

*DOI: http://dx.doi.org/10.5772/intechopen.96521*

\*overall effect of ISH24 on arterial stiffness.

#### *Ambulatory Isolated Systolic Hypertension and Cardiovascular Target Organ Damage in People… DOI: http://dx.doi.org/10.5772/intechopen.96521*

moreover, TGF-β inhibits the activity of those metalloproteases which would otherwise assist by breaking down the collagen build-up, such as MMP-9 [38]. All these factors culminate in arterial stiffening of mainly the central arteries. In essence, ISH speeds up the rate of arterial ageing and increases arterial stiffness, thereby leading to its own exacerbation in a vicious cycle [65]. Several scholars agree that the causal relationship between arterial stiffness and ISH is bidirectional [31, 34, 38].

With this in mind, it is not surprising that we observed significantly elevated PWV in all subtypes of ISH when compared to normotensives. Of interest, is that all ISH groups had an increase in PWV that is comparable to that of the sustained hypertensive group. This suggests that the arterial damage caused by the ISH groups may equal arterial stiffness arising from sustained hypertension in this population. This is contrary to our expectation. We expected the PWV of the ISH24 to be higher than that of the other groups due to the cumulative effects of a high systolic BP that is sustained over a 24-hout period. The explanation for this apparent discrepancy is that 24-hour BP is a combination of both daytime and night-time BP. Since BP decreases at night, that decline in nocturnal BP may have a damping effect on the \*overall effect of ISH24 on arterial stiffness.

When we used ROC curve analysis to determine how well the different subgroups of ISH would predict an increased PWV in this population, our results indicate that all ISH subtypes predict PWV. Conventional ISH was the strongest predictor of arterial stiffness with an AUC of 0.88 followed by ISHD at 0.83. In this respect, daytime BP is emerging as the best predictor of ISH in this population as both conventional and daytime ambulatory BP are measured during the day. This is due to the 24-hour pattern of BP in which BP increases during the day and decreases at night. Our results indicate that the increase in daytime systolic BP in people with ISH is exaggerated, resulting in a high PP of 70 mmHg, which is 30 mm Hg the normal value of 40 mm Hg. This is PP value is higher than that of people with sustained hypertension. The same pattern was observed in people with ISHD. As discussed earlier, PP is an independent risk factor for vascular disease. This explains why ISHC and ISHD which have the highest PP, are the strongest predictors of arterial stiffness. Even though ISHN predicts arterial to a lesser extent than ISHC and ISHD, it is still a strong predictor of arterial stiffness with an AUC of 0.78. This highlights the importance of this study which is the first to discover the existence of this clinical entity.

#### *5.2.2 Left ventricular hypertrophy*

Left ventricular mass index has been used as an indication of LVH, a major independent predictor of cardiovascular mortality and morbidity [78–80]. We used echocardiography, a well-accepted, efficient and non-invasive tool for the estimation of LVMI [79, 80]. In this study, there were no clear differences in LVMI values obtained for the ambulatory ISH sub-types (ISHD, ISHN and ISH24), suggesting that there are no major differences in the development of LVH among these three subtypes; although the extent of cardiac damage they caused is similar to that associated with hypertension. This implies that even if diastolic BP can be normal, the impact of systolic BP alone is significant has a significant impact on cardiac morphology. The premature return of the reflected wave in ISH is probably the most significant cause of LVM increase [81] in this condition. The augmentation of SBP by the reflected wave results in an increased afterload to the left ventricle. As the left ventricle adapts to the increased workload, concentric hypertrophy of surrounding tissue occurs, resulting in thickening and increase in mass of the left ventricle wall [37]. Poor coronary perfusion owing to low DBP may also exacerbate the effects of increased LVM in ISH as increased oxygen demand of the myocardium

becomes difficult to meet [82]. Our results bear some similarity to those obtained by Pearson et al. [83], who reported that ISHC patients exhibited increased LVMI arising from thickened septal and posterior walls of the left ventricle. Lip et al. [84] had related outcomes, they found that LVMI and other echographic parameters were similar between ISHC and full hypertension (SDH) groups. Our study adds significantly to this body of knowledge by showing that ISH has a number of subtypes which are as detrimental to cardiac pathology as both ISHC and sustained hypertension. Some research has shown that increased LVMI even within the "normal" range is clinically relevant i.e. it is associated with significant cardiovascular risk [85]. Since ISH increases the risk of LVH at least twofold, even the preclinical increases in LVM observed in this study may progress to cardiac pathology over time as the elevated SBP persists.

Most ISH studies in the past have been carried out on elderly participants, however, our results show that even after correcting for age the associations and predictions remain unchanged, suggesting that ISH is just as detrimental to the elderly as it is to younger age groups with respect to left ventricle structure and consequently, cardiovascular function. Levy et al. [79] also found that the relationship between increased LVMI and cardiovascular morbidity and mortality was applicable to the middle-aged study group as much as the elderly study group, although their focus was not particularly on ISH. Obesity, which was identified in this ISH population, is thought to increase the risk of LVM and LVH by its tendency to attract other risk factors such as metabolic syndrome and diabetes mellitus [85]. Genetics also plays an important and complex role in the increase of LVM and development of LVH. So, the population under study - being predominantly black, may be at higher risk of LVH. Skelton et al. [86] reported a very high prevalence of increased LVM in an African-American population. This highlights the need for more studies to investigate the impact of ISH subtypes to be investigated.

Similar to PWV, again ISHC and ISHD were the strongest predictors of increased LVMI according to ROC analysis (AUC = 0.86 and 0.80 respectively), followed by ISH24 (AUC = 0.76) and ISHN (AUC = 0.71). This confirms the impact of the increases in daytime systolic BP on cardiovascular organs. There is no comparable research on ISH subtypes predictive power on increased LVMI, however our results provide strong evidence that ISH subtypes, which were not known previous to this study, predict preclinical cardiac pathology similar to hypertension, indicating that these subtypes are clinical entities that require intervention.
