Autonomic and Hemodynamic Origins of Pre-Hypertension

Abstract

Objective To better understand the origins and progression of prehypertension. Background Prehypertension is a risk factor for progression to hypertension, cardiovascular disease and increased mortality. We used a cross-sectional twin study design to probe the role of heredity in likely pathophysiological events (autonomic or hemodynamic) in prehypertension. Methods 812 individuals (337 normotensive, 340 prehypertensive, 135 hypertensive) were evaluated in a sample of twin pairs, their siblings and other family members. They underwent non-invasive hemodynamic, autonomic and biochemical testing, as well as estimates of trait heritability (h2: % of trait variance accounted for by heredity) and pleiotropy (rG: genetic covariance or shared genetic determination of traits) by variance components. Results In the hemodynamic realm, an elevation of cardiac contractility (LV dP/dT max) prompted increased stroke volume, in turn increasing CO, which elevated blood pressure into the prehypertension range. Autonomic monitoring detected an elevation of norepinephrine secretion plus a decline in cardiac parasympathetic tone. Twin pair variance components documented substantial heritability as well as joint genetic determination for blood pressure and the contributory autonomic and hemodynamic traits. Genetic variation at a pathway locus also indicated pleiotropic effects on contractility and blood pressure. Conclusions Elevated blood pressure in prehypertension results from increased CO, driven by contractility as well as heart rate, which may reflect both diminished parasympathetic and increased sympathetic tone. In the face of increased CO, SVR fails to decline homeostatically. Such traits display substantial heritability and shared genetic determination, though by loci not yet elucidated. These findings clarify the role of heredity in the origin of prehypertension and its autonomic and hemodynamic pathogenesis. The results also establish pathways that suggest new therapeutic targets for prehypertension, or approaches to its prevention.

Prehypertension is a comorbid state with autonomic and metabolic dysfunction

“…A previous study showed that elevated sympathetic tone was associated with high normal BP states, and intriguingly, it was also coupled with metabolic alterations similar to those observed in our study . Other studies have also demonstrated that decreased parasympathetic tone, along with increased sympathetic activity, underlies the pathogenesis of prehypertension . Further, our observation reinforced the notion that prehypertension is associated with subclinical target organ damage, in aspects of “vascular” and “cardiac” structure and function.…”

Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes

“…Heterogeneity in statin responsiveness has attracted considerable attention. However, additional microarray-derived associations exist with nonlipid risk factors, such as gene expression in adipose, hepatic, and β cell tissues in obesity and diabetes107 or those relating to the origins of hypertension 108…”

Resistive and Pulsatile Arterial Hemodynamics and Cardiovascular Events: The Multiethnic Study of Atherosclerosis

“…Although elevated SVR and arterial pressure are clearly relevant for cardiovascular outcomes, a derangement in pulsatile arterial hemodynamics may predict cardiovascular risk earlier, more accurately, or be associated with a different spectrum of morbidities. 2–5 Most previous studies have assessed pulse pressure compared with mean arterial pressure as a predictor of cardiovascular outcomes. 6–8 However, the determinants of pulse pressure and mean arterial pressure extend beyond large arterial properties and microvascular resistance, and depend also on the flow generated by the heart (stroke volume and cardiac output).…”