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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 ...

Diastolic dysfunction is more prevalent in individuals with hypertension, particularly postmenopausal women; however, the pathogenesis of diastolic dysfunction remains unknown. Pressure overload activates cardiac inflammation, which induces myocardial fibrosis and diastolic dysfunction in rats with a suprarenal aortic constriction (AC). Therefore, we examined the effects of bilateral ovariectomy (OVX) on left ventricle (LV) remodeling, diastolic dysfunction and cardiac inflammation in hypertensive female rats. Rats were randomized to OVX+AC, OVX and AC groups as well as a Control group receiving sham operations for both the procedures. Rats underwent OVX at 6 weeks and AC at 10 weeks (Day 0). At Day 28, OVX did not appear to affect arterial pressure, cardiac hypertrophy or LV fractional shortening in AC rats. However, OVX increased myocardial fibrosis, elevated LV end-diastolic pressure and reduced the transmitral Doppler spectra early to late filling velocity ratio in AC rats. AC-induced transient myocardial monocyte chemoattractant protein-1 expression and macrophage infiltration, both of which peaked at Day 3 and were augmented and prolonged by OVX. At Day 28, dihydroethidium staining revealed superoxide generation in the intramyocardial arterioles in the OVX+AC group but not in the AC group. NOX1, a functional subunit of nicotinamide adenine dinucleotide phosphate oxidase, was upregulated only in the OVX+AC group at Day 28. Chronic 17b-estradiol replacement prevented the increases in macrophage infiltration, NOX1 upregulation, myocardial fibrosis and diastolic dysfunction in OVX+AC rats. In conclusion, we suggest that estrogen deficiency augments cardiac inflammation and oxidative stress and thereby aggravates myocardial fibrosis and diastolic dysfunction in hypertensive female rats. The findings provide insight into the mechanism underlying diastolic dysfunction in hypertensive postmenopausal women. Hypertension Research (2011) 34, 496-502; doi:10.1038/hr.2010; published online 20 January 2011Keywords: estradiol; gender medicine; macrophage; myocardial fibrosis; oxidative stress INTRODUCTIONThe ejection fraction of the left ventricle (LV) is normal in approximately half of all patients with congestive heart failure, which indicates that impaired diastolic function in these patients is the major cause of heart failure. [1][2][3] Hypertension is the most common coexisting disease in patients with diastolic heart failure. Diastolic heart failure is more prevalent in women than in men, especially in postmenopausal hypertensive women, which may be due to decreased estrogen levels. 2,3 Determinants of diastolic function include active myocardial relaxation and passive properties of the LV wall. 2 Sequestration of calcium and cross-bridge uncoupling after systole are involved in the active process of relaxation. Previous studies have shown that estrogen

iurnal blood pressure (BP) change, such as nocturnal BP fall, is an established risk for target organ damage and cardiovascular events. [1][2][3][4] Along with diurnal BP change, an increase in short-term BP variability is a characteristic feature of hypertension, especially in the elderly and in patients with carotid atherosclerosis. [5][6][7][8] Among hypertensive patients with similar BP levels, the degree of hypertensive target organ damage is more advanced in patients with larger BP variability. 9-11 However, little is known about the mechanism whereby a combination of hypertension and large BP variability aggravates target organ damage. In this article, we review the clinical relevance of BP variability in hypertensive patients, and introduce our recent studies showing that chronic cardiac inflammation plays a role in aggravating hypertensive cardiac remodeling in a novel rat model of hypertension and large BP variability. Short-Term BP Variability and Hypertensive Target Organ DamageTwenty-four-hour BP varies not only because of a reduction during night sleep (diurnal BP change), but also because of sudden, fast and short-lasting changes (short-term BP variability) that may occur both during the day and, to a lesser extent, during the night. 12 It has been shown that short-term BP variability increases in hypertensive patients as their BP levels increase, when quantified as the standard deviations (SDs) of the BP values recorded intra-arterially in 30-min intervals. 5 Parati et al investigated the incidence and the severity of target organ damage in 108 hypertensive patients. 9 The patients were divided into 5 groups according to the increasing value of their 24-h average mean BP, and the subjects in each group were further subdivided into 2 classes according to whether their intra-half-hour SD of mean BP, ie, short-term BP variability, was below or above the average of SDs of all the study patients. Within each group, although the 2 classes had a similar 24-h mean BP, the incidence and the severity of target organ damage were greater in the class in which short-term BP variability was higher (Figure 1). 9 Palatini et al studied 67 normotensive patients and 171 borderline, 309 mild, 140 moderate and 41 severe hypertensive patients with noninvasive ambulatory BP monitoring. 10 Each patient was assigned a target organ damage score of 0 to 5 on the basis of funduscopic changes and degree of left ventricular (LV) hypertrophy calculated from ECG and chest roentgenogram. An increased daytime BP variability was associated with a higher degree of hypertensive cardiovascular complications. 10 Moreover, a longitudinal study revealed that the degree of target organ damage and echocardiographic LV hypertrophy at a followup examination (4-13 years later, mean 7.4 years) depended on the extent of 24-h BP variability at the time of the initial evaluation, independently of the 24-h mean BP, in 73 Large Blood Pressure Variability andHypertensive Cardiac Remodeling Role of Cardiac InflammationHisashi Kai, MD; Hiroshi Kudo...

A safer, less invasive method for repeated transgene administration is desirable for clinical application of gene therapy targeting chronic diseases, including pulmonary hypertension (PH). Thus, effects of prostaglandin I2 (prostacyclin) synthase (PGIS) gene transfer by the naked DNA method into skeletal muscle were investigated in monocrotaline (MCT)-induced PH rats. A single injection of rat PGIS cDNA-encoding plasmid into thigh muscle 3 days after bupivacaine pretreatment transiently increased muscle PGIS protein expression and muscle and serum levels of a stable prostacyclin metabolite (6-keto-prostaglandin F1). The muscle 6-keto-prostaglandin F1 level peaked on day 2 but was still elevated on day 7; prostacyclin selectively increased lung cyclic AMP levels as compared with liver and kidney. MCT induced a marked rise in right ventricular (RV) systolic pressure, pulmonary arterial wall thickening, and RV hypertrophy. Repeated PGIS gene transfer every week lowered RV systolic pressure and ameliorated RV and pulmonary artery remodeling in MCT-induced PH rats. Furthermore, repeated PGIS gene transfer significantly improved the survival rate of MCT-induced PH rats. In conclusion, repeated PGIS gene transfer into skeletal muscle not only attenuated the development of PH and cardiovascular remodeling but also improved the prognosis for MCT-induced PH rats. This study may provide insight into a new treatment strategy for PH.

Pronounced variability in blood pressure (BP) is an aggravating factor of hypertensive end-organ damage. However, its pathogenesis remains unknown. Statins have various protective effects on the cardiovascular system. Thus, we determined whether simvastatin would attenuate the aggravation of hypertensive cardiac remodeling in a rat model of hypertension with large BP variability, and also investigated the signaling mechanism involved in its effect. A model of hypertension with large BP variability was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). A SAD or sham operation was performed in 12-week-old rats. Thereafter, simvastatin (0.2 mg kg À1 per day) or vehicle was intraperitoneally administered every day. After 6 weeks , telemetric recordings revealed that SAD enhanced BP variability without changing the mean BP. SAD increased myocyte hypertrophy, myocardial fibrosis and macrophage infiltration associated with the upregulation of brain natriuretic peptide (BNP), type I procollagen, transforming growth factor (TGF)-b and monocyte chemoattractant protein (MCP)-1, and activation of RhoA, Ras and ERK1/2. Simvastatin did not change the mean BP or BP variability in SAD-operated SHRs. In SAD-operated SHRs, simvastatin attenuated myocyte hypertrophy and BNP expression, as well as RhoA, Ras and ERK1/2 activities. In contrast, simvastatin did not change myocardial fibrosis, macrophage infiltration, or the expression of procollagen and TGF-b or MCP-1 in SAD-operated SHRs. Simvastatin did not affect serum lipid levels. In conclusion, simvastatin attenuated the large BP variability-induced aggravation of cardiac hypertrophy, but not myocardial fibrosis, in SHRs. The activation of RhoA/Ras-ERK pathways may contribute to the aggravation of cardiac hypertrophy by a combination of hypertension and large BP variability.

Abstract-It is still controversial whether intrinsic interferon (IFN)-␥ promotes or attenuates vascular remodeling in hyperproliferative vascular disorders, such as neointima formation after balloon injury. Thus, we investigated whether inhibition of intrinsic IFN-␥ function prevents neointima formation. For this purpose, naked DNA plasmid encoding a soluble mutant of IFN-␥ receptor ␣-subunit (sIFN␥R; an IFN-␥ inhibitory protein) or mock plasmid was injected into the thigh muscle of male Wistar rats 2 days before balloon injury (day Ϫ2). sIFN␥R gene transfer significantly elevated serum levels of sIFN␥R protein for 2 weeks. In mock-treated rats, balloon injury induced smooth muscle cell proliferation in the neointima with a peak at day 7 and produced thick neointima at day 14. sIFN␥R treatment reduced the number of proliferating intimal smooth muscle cells by 50% at day 7 and attenuated neointima formation with a 45% reduction of the intima/media area ratio at day 14. In mock-treated rats, at day 7, balloon injury induced phosphorylation of signal transducer and activator of transcription-1 and upregulations of IFN regulatory factor-1 (a transcription factor mediating IFN-␥ signal). Balloon injury also upregulated the key molecules of neointima formation, such as intercellular adhesion molecule-1 and platelet-derived growth factor ␤-receptor. These changes were suppressed by sIFN␥R treatment. In conclusion, it is suggested that intrinsic IFN-␥ promotes neointima formation probably through IFN regulatory factor-1/intercellular adhesion molecule-1-mediated and platelet-derived growth factor-mediated mechanisms. Thus, inhibition of IFN-␥ signaling may be a new therapeutic target for prevention of neointima formation of hyperproliferative vascular disorders.

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