Cardiovascular hazards of components of blood pressure

Hypertension is an established highly prevalent, powerful, independent and modifiable promoter of cardiovascular disease. It damages and compromises the vascular supply to the heart, brain, kidneys and limbs. It also directly alters the structure and function of the myocardium by promoting left ventricular hypertrophy (LVH). Despite the acknowledged importance of hypertension as a promoter of cardiovascular disease, there is uncertainty about the relative importance of its various components. Since the beginning of the twentieth century, medical research was preoccupied with diastolic blood pressure as the chief hazard of hypertension [1–4]. Lately, the focus has shifted to the systolic and, most recently, the pulse pressure. In a review of the subject, Rutan et al. pointed out that after the Framingham Study, a large number of diverse prospective population-based investigations found that systolic blood pressure exerted a stronger influence than diastolic pressure [5]. Consideration of vascular haemodynamics suggests that pulse pressure plays a role in the contribution of hypertension to the development of cardiovascular disease. Diastolic blood pressure rises with peripheral arterial resistance and falls with increased central artery stiffness so the relative contributions of these opposing forces determine the diastolic and, ultimately, the pulse pressure. Usually, pulse pressure and systolic blood pressure are highly correlated because both components rise with increases in vascular resistance and large artery stiffness. However, when assessed individually in the Framingham Study, increments in pulse pressure at particular systolic pressures were associated with a greater risk of coronary heart disease (CHD) than were increments in systolic blood pressure at fixed pulse pressure [6]. It appears that despite the high correlation of pulse pressure with systolic pressure, pulse pressure predominates in predicting CHD because of the contribution of the strong pulsatile stress in subjects with discordantly low diastolic blood pressure. Whether this also applies to myocardial hypertrophy is more conjectural, but LVH is an important phenomenon in the evolution of hypertension on the path to myocardial infarction and heart failure. Increased pulsatile load plays a dominant role in clinical disease, large artery atherosclerosis, vascular remodelling of small resistance arteries, LVH and eventually heart failure. Prediction of cardiac hypertrophy from high pulse pressure and low diastolic pressure has been reported [7,8]. Left ventricular hypertrophy is no longer accepted as an incidental compensatory feature of long-standing or severe hypertension. It is now recognized as an ominous harbinger of cardiovascular disease. A recent population-based investigation of a representative sample of individuals with essential hypertension has again confirmed that left ventricular mass is a powerful independent predictor of cardiovascular morbidity. For each 39 g increase in left ventricular mass per m2, there is a 40% increase in cardiovascular events [9]. It is therefore important to examine the relationship of components of blood pressure to LVH and systolic dysfunction, as performed by Celentano et al. [10]. This can provide valuable insights into the pathogenesis of this ominous sequel of hypertension and the optimal therapy required to prevent or correct it. A major impediment to meaningful examination of the net impact of the various components of blood pressure on the structure and function of the heart is their high correlation with each other. The investigation reported by Celentano et al. confirms that the correlation between systolic blood pressure and pulse pressure is 0.90, making dissociation of the effects extremely problematic whatever statistical methodology is employed [10]. Another problem is the fact that there appears to be an interaction with age, such that with age there is a trend of declining importance of diastolic pressure and a corresponding increase in systolic pressure as predictors of CHD. A recent Framingham Study investigation found that, with increasing age, there is a shift from diastolic, to systolic and then to pulse pressure as predictors of CHD [11]. From the age of 60 years onward, diastolic pressure is negatively related to CHD so that pulse pressure becomes superior to systolic pressure. The sample investigated by Celentano and coworkers had an average age of only 47 years with only 3% being aged over 65 years. This may explain why this study and others fail to agree on the relative importance of systolic and pulse pressure [12]. However, there is disagreement about the relative importance of systolic and pulse pressure even in the elderly. The Cardiovascular Health Study, in contrast to the Framingham Study, found systolic pressure to be a better predictor of cardiovascular events than pulse pressure in persons aged 65 years and older [13]. This may be attributable to the difficulty of sorting out the net effect of these highly correlated blood pressure variables. However, all this information relates to the impact of components of blood pressure on development of clinical cardiovascular events and not to preclinical pathology, such as LVH and systolic dysfunction, where prospective data are sparse. Another possible problem is the fact that the data reported by Celentano et al. are derived from cross-sectional rather than prospective population-based data and thus are subject to selection bias. They require confirmation in a longitudinal prospective population-based investigation. As expected, arterial compliance, determined by the ratio of stroke volume to pulse pressure in the reported investigation, was strongly correlated with pulse pressure. In the past, some have argued that underlying stiff diseased artery is responsible for the increased risk of cardiovascular disease associated with isolated systolic hypertension or increased pulse pressure. However, the investigation by the Framingham Study indicates an effect of systolic and pulse pressure taking arterial compliance into account [14], and trials indicate that antihypertensive treatment of isolated systolic hypertension reduces the risk of cardiovascular disease fairly promptly [15,16]. The risk of adverse events such as heart failure, myocardial infarction and stroke increases when hypertension induces LVH. Left ventricular hypertrophy is a prominent feature of evolving heart failure. Approximately 20% of heart failure cases have antecedent ECG-LVH and 60–70% exhibit it on the more sensitive echocardiogram. Adjusted for age and other risk factors, it increases the heart failure risk imposed by hypertension by two- to three-fold [17]. In the investigation by Celentano et al., it is puzzling to note that pulse pressure, and presumably systolic pressure, appear to be unrelated to left ventricular systolic function. This should not be taken to mean that cardiac function is unaffected by the pulse pressure. Altered diastolic filling is observed in patients with isolated systolic hypertension (and hence increased pulse pressure) and they have been found to have heightened systolic performance suggesting an enhanced contractile state [18]. Morphological studies indicate detrimental structural remodelling of the hypertensive heart. These include a disproportionate accumulation of fibrillar collagen in arteriolar adventitia and interstitial space, and microscopic myocardial scars replacing necrotic myocytes [19]. There is also some evidence suggesting that LVH may be associated with the development of hypertension indicating that there may be a common factor that is promoting both [20]. Alterations in the renin–angiotensin system and catecholamines have been implicated in both the aetiology of hypertension and the development of LVH [21,22]. Angiotensin converting enzyme (ACE) inhibitor therapy not only lowers blood pressure, but also improves arterial compliance. Long-term ACE-inhibitor therapy that improves aortic compliance is often associated with simultaneous regression of LVH [23]. This infers that reduction in the pulse pressure reduces left ventricular mass. The HOPE study results suggest that the major action of ACE-inhibition in reducing cardiovascular events is a consequence of the direct protective effect on the vasculature and myocardium, because only 47% of the participants had hypertension and the overall blood pressure reduction was only 3/1 mmHg [24]. Some, but not all, of the protection of the ACE-inhibition in the HOPE trial resulted from long-term regression of LVH and improved vascular compliance. There are no trials specifically designed to test the benefit of treating a wide pulse pressure but there are trials demonstrating the efficacy of treating isolated systolic hypertension that is, by definition, wide pulse pressure hypertension. Two major intervention trials have shown a significant benefit of reducing systolic blood pressure and, along with it, the pulse pressure [15,16]. It is not clear from these trials whether treatment with a diuretic or calcium antagonist prevents or corrects the LVH that often accompanies isolated systolic hypertension. The optimal recommended treatment for isolated systolic hypertension is to maximize systolic blood pressure reduction and minimize diastolic blood pressure reduction, thereby reducing pulse pressure. All antihypertensive agents can reduce pulse pressure by lowering peripheral resistance, but nitrates, ACE inhibitors and vasopeptidase inhibitors affect the renin–angiotensin system and have actions that improve large artery stiffness [25]. Evidence is mounting to support the contention that cardiovascular hazards of hypertension involve large artery stiffness and early wave reflection as well as peripheral resistance. The current concept of hypertensive cardiovascular pathogenesis tends to over emphasize vascular resistance and underestimate arterial stiffness. Despite demonstration of the efficacy of treating systolic hypertension, poor blood pressure control is overwhelmingly due to lack of systolic pressure control, even among treated individuals [26]. Guidelines for clinicians need to place greater emphasis on achieving systolic blood pressure goals in all hypertensive patients and especially in those with target organ damage such as LVH. Future investigations need to focus on the specific benefits of improving arterial compliance and lowering pulse pressure to improve systolic and diastolic cardiac function, LVH and vascular function. The benefit of correcting isolated systolic hypertension, and by inference pulse pressure, to avoid clinical cardiovascular events is established. It may not be possible to establish whether the benefit derives more from a reduction in systolic blood pressure or a narrowing of pulse pressure because it is difficult to modify one without affecting the other.