Exaggerated Blood Pressure Variability Superimposed on Hypertension Aggravates Cardiac Remodeling in Rats via Angiotensin II System-Mediated Chronic Inflammation

Abstract

Abstract-Hypertensive patients with large blood pressure variability (BPV) have aggravated end-organ damage.However, the pathogenesis remains unknown. We investigated whether exaggerated BPV aggravates hypertensive cardiac remodeling and function by activating inflammation and angiotensin II-mediated mechanisms. A model of exaggerated BPV superimposed on chronic hypertension was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). SAD increased BPV to a similar extent in Wistar Kyoto rats and SHRs without significant changes in mean blood pressure. SAD aggravated left ventricular and myocyte hypertrophy and myocardial fibrosis to a greater extent and impaired left ventricular systolic function in SHRs. SAD induced monocyte chemoattractant protein-1, transforming growth factor-␤, and angiotensinogen mRNA upregulations and macrophage infiltration of the heart in SHRs. The effects of SAD on cardiac remodeling and inflammation were much smaller in Wistar Kyoto rats compared with SHRs. Circulating levels of norepinephrine, the active form of renin, and inflammatory cytokines were not affected by SAD in Wistar Kyoto rats and SHRs. A subdepressor dose of candesartan abolished the SAD-induced left ventricular/myocyte hypertrophy, myocardial fibrosis, macrophage infiltration, and inductions of monocyte chemoattractant protein-1, transforming growth factor-␤, and angiotensinogen and subsequently prevented systolic dysfunction in SHRs with SAD. These findings suggest that exaggerated BPV induces chronic myocardial inflammation and thereby aggravates cardiac remodeling and systolic function in hypertensive hearts. The cardiac angiotensin II system may play a role in the pathogenesis of cardiac remodeling and dysfunction induced by a combination of hypertension and exaggerated BPV. Key Words: blood pressure variability Ⅲ hypertension Ⅲ inflammation Ⅲ angiotensin II Ⅲ cardiac hypertrophy T he goal of hypertension treatment is not only to reduce blood pressure (BP) levels but also to prevent cardiovascular events. Among hypertensive patients, patients with large BP variability (BPV) have more advanced end-organ damage, such as left ventricular (LV) hypertrophy and carotid atherosclerosis. [1][2][3][4][5][6][7] Recent studies have shown that exaggerated BPV is a risk factor for cardiovascular events in hypertensive patients, 8 -10 independent of diurnal BP changes. 11 An exaggerated BPV is a characteristic feature of hypertension, especially in the elderly and in patients with carotid atherosclerosis. 12-14 However, little is known about the mechanism underlying the aggravation of end-organ damage induced by a combination of hypertension and large BPV aggravates.Our recent studies have shown that perivascular inflammation plays a pivotal role in hypertensive cardiac remodeling, especially in myocardial fibrosis (for review see References 15 and 16): in Wistar Kyoto rats (WKYs) with suprarenal aortic constriction, BP elevation induces perivascular inflammation characterized by ...

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“…LV fractional shortening and the early to late filling velocity ratio (E/A) were measured at Day 28 using an echocardiograph equipped with a 10-MHz transducer (Aloka, Tokyo, Japan). 11,22,23 Hemodynamic measurement. At Day 28, rats (n¼7 per group) were intraperitoneally anesthetized with 15 mg kg À1 pentobarbital.…”

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“…20,21 Bilateral SAD At 12 weeks old, the SHRs underwent bilateral SAD as previously described. 13,22 Briefly, the rats were anesthetized intraperitoneally with a mixture of ketamine (50 mg kg À1 ), medetomidine (0.5 mg kg À1 ) and atropine sulfate (0.5 mg kg À1 ). The aortic depressor nerve and the superior laryngeal nerve were cut bilaterally.…”

“…13 Thereafter, the rats were housed individually in a hemodynamic monitoring cage. At 7 days after telemeter implantation (19-weeks-old), 24-h BP and heart rate were monitored under the unrestricted, conscious condition.…”

“…Recently, we have created a rat model exhibiting a combination of hypertension and large BP variability by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). 13 This model can also be considered to represent the characteristic features of hypertension in the elderly or those having carotid atherosclerosis. 14 We have shown that SAD induces cardiac inflammation, which leads to aggravation of hypertensive remodeling (myocyte hypertrophy and myocardial fibrosis) in SHRs.…”

“…14 We have shown that SAD induces cardiac inflammation, which leads to aggravation of hypertensive remodeling (myocyte hypertrophy and myocardial fibrosis) in SHRs. 13 It is thought that cardiac remodeling in this model would reflect the synergistic effects of the response to sustained pressure overload and the response to increased BP variability.…”