Myocardial fibrosis: functional significance and regulatory factors

Weber, Karl T.; Brilla, Christian G.; Janicki, Joseph S.

doi:10.1093/cvr/27.3.341

Cited by 436 publications

(277 citation statements)

References 69 publications

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“…11 These histological changes mimic myocardial remodeling observed in patients at early stages of hypertensive heart disease. 26 Using this model, we demonstrated that a series of inflammatory changes are induced by pressure overload around the intramyocardial arteries. Acute increases in pressure occur concurrently with transient inductions of MCP-1 and superoxide generation in the intramyocardial arteries associated with perivascular macrophage infiltration (Days 1-3).…”

Section: Discussionmentioning

confidence: 93%

Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women

et al. 2011

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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

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Section: Discussionmentioning

confidence: 93%

Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women

et al. 2011

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“…In this regard, it is interesting to note that myocyte hypertrophy and myocardial fibrosis are regulated independently in hypertensive hearts. 36,37 Mechanical stress itself has a role in initiating hypertrophic responses in myocytes by activating multiple signaling pathways. 38,39 In contrast, the circulating and autocrine/paracrine humoral factors, such as angiotensin II, TGF-b and MCP-1, have been implicated in hypertensive myocardial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

et al. 2010

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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.

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“…Patients with a prior history of AF appear to derive greater benefit from ACEI-based therapy in the prevention of AF. 66,71,72 Emerging data from the analysis of large prospective clinical studies also demonstrate the beneficial effects of blockade of RAAS in preventing AF in patients with hypertension. In the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study, ARB-based therapy (losartan) was associated with a 33% reduction in the incidence of AF and with a significant reduction in the incidence of subsequent stroke compared with b-blocker-based therapy (atenolol).…”

Section: Clinical Implicationmentioning

confidence: 99%

“…The regression of LVH by ARB in patients with hypertension is independent of its blood pressure-lowering effect. 66 Furthermore, regression of hypertensive LVH is seen independently of lowering blood pressure. 67 Experimental studies have shown that blockade of ARB or ACEI attenuates atrial structural remodelling with fibrosis and atrial electrical remodelling, both factors that predispose to AF.…”

Section: Clinical Implicationmentioning

confidence: 99%

Hypertension and cardiac arrhythmias: a review of the epidemiology, pathophysiology and clinical implications

Yiu

Tse

2008

J Hum Hypertens

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Hypertension is commonly associated with cardiac arrhythmias in patients with and without concomitant cardiovascular disease. Experimental and epidemiological studies have demonstrated potential links between hypertension and atrial and ventricular arrhythmias, although the underlying pathophysiological mechanism remains unclear. Nonetheless, the importance of hypertension as a cause of atrial and ventricular arrhythmias is not well recognized. In particular, the occurrence of left ventricular hypertrophy is a strong predictor for the development of AF, ventricular ectopy and sudden cardiac death. Recent prospective clinical trials reveal that antihypertensive therapy may delay or prevent the occurrence of cardiac arrhythmias and sudden cardiac death in patients with hypertension. Although antihypertensive agents that block the renin-angiotensin-aldosterone system appear to protect against cardiac arrhythmias, this needs to be confirmed by current ongoing clinical trials.

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Myocardial fibrosis: functional significance and regulatory factors

Cited by 436 publications

References 69 publications

Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women

Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

Hypertension and cardiac arrhythmias: a review of the epidemiology, pathophysiology and clinical implications

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