Collagen deposition and the reversal of coronary reserve in cardiac hypertrophy.

Isoyama, Shogen; Ito, Nobuhiko; Satoh, Kimio; Takishima, Tamotsu

doi:10.1161/01.hyp.20.4.491

Cited by 41 publications

(11 citation statements)

References 44 publications

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“…Considering the facts that in various animal experimental models other factors, such as perfusion pressure (7), heart rate (9), extravascular compression forces (8,28), vascular remodeling due to medial thickening (2) or perivascular fibrosis (11), and coronary capillary resistance (12), have been implicated in the alterations of maximal myocardial perfusion, their contribution to the difference in the level of maximal perfusion in our two groups of infarcted rats cannot be excluded. However, since our data indicate that perfusion pressure, heart rate, and the size of capillary bed were similar in MI ϩ IVA and MI rats, neither of these factors could affect the level of maximal myocardial perfusion.…”

Section: Discussionmentioning

confidence: 98%

Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen

Dedkov¹,

Zheng²,

Christensen³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Dedkov EI, Zheng W, Christensen LP, Weiss RM, MahlbergGaudin F, Tomanek RJ. Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen. Am J Physiol Heart Circ Physiol 293: H590-H598, 2007. First published March 23, 2007; doi:10.1152/ajpheart.00047.2007.-We tested the hypothesis that chronically reducing the heart rate in infarcted middle-aged rats using ivabradine (IVA) would induce arteriolar growth and attenuate perivascular collagen and, thereby, improve maximal perfusion and coronary reserve in the surviving myocardium. Myocardial infarction (MI) was induced in 12-mo-old male Sprague-Dawley rats, which were then treated with either IVA (10.5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ; MI ϩ IVA) or placebo (MI) via intraperitoneal osmotic pumps for 4 wk. Four weeks of IVA treatment limited the increase in left ventricular end-diastolic pressure and the decrease in ejection fraction but did not affect the size of the infarct, the magnitude of myocyte hypertrophy, or the degree of arteriolar and capillary growth. However, treatment reduced interstitial and periarteriolar collagen in the surviving myocardium of MI ϩ IVA rats. The reduced periarteriolar collagen content was associated with improvement in maximal myocardial perfusion and coronary reserve. Although the rates of proliferation of periarteriolar fibroblasts were similar in the MI and MI ϩ IVA groups, the expression levels of the AT 1 receptor and transforming growth factor (TGF)-␤1 in the myocardium, as well as the plasma level of the ANG II peptide, were lower in treated rats 14 days after MI. Therefore, our data reveal that improved maximal myocardial perfusion and coronary reserve in MI ϩ IVA rats are most likely the result of reduced periarteriolar collagen rather than enhanced arteriolar growth. myocardial infarction; coronary circulation; coronary vessels; reninangiotensin system A MYOCARDIAL INFARCTION (MI) initiates progressive structural remodeling within the surviving left ventricular (LV) myocardium. Features of such remodeling include cardiac myocyte hypertrophy, fibroblast proliferation, and interstitial/perivascular fibrosis (4, 26). These alterations compromise maximal coronary blood perfusion and coronary reserve in the remaining LV myocardium (5,6,15,16,18,20).Since adequate tissue perfusion is key for survival and effective function of hypertrophied myocytes in the remaining overloaded LV myocardium, the recovery of normal tissue perfusion in this region has become a major focus of several studies (14, 15), including those from our laboratory (5, 20). Because the major cause of limited myocardial perfusion and coronary reserve in post-MI hearts was long thought to be a failure to match the adaptive growth of the intramyocardial vasculature to the degree of myocyte hypertrophy, earlier studies, which were conducted on young and young-adult rats, were designed either to reduce myocyte hypertrophy (14,24) or to promote the growth of the coronary vasculature (20).MI i...

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Section: Discussionmentioning

confidence: 98%

Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen

Dedkov¹,

Zheng²,

Christensen³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…Moreover, perivascular fibrosis may have also impaired the vasodilatory ability. The importance of periarteriolar collagen for diminished coronary flow reserve was elucidated by Isoyama et al (16). Normalization of arterial pressure after debanding of the rat aorta induced regression of medial hypertrophy, but normalization of coronary flow reserve was achieved only after the additional reversal of colla- gen accumulation in the adventitia (16).…”

Section: Discussionmentioning

confidence: 99%

Myocardial fibrosis, impaired coronary hemodynamics, and biventricular dysfunction in salt-loaded SHR

Varagić¹,

Fröhlich²,

Díez³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Arterial pressure in most experimental and clinical hypertensions is exacerbated by salt. The effects of salt excess on right and left ventricular (RV and LV, respectively) functions and their respective coronary vasodilatory responses have been less explored. We therefore examined the effects of 8 wk of NaCl excess (8% in food) on arterial pressure, RV and LV functions (maximal rate of increase and decrease of ventricular pressure; dP/dtmax and dP/dtmin), coronary hemodynamics (microspheres), and collagen content (hydroxyproline assay and collagen volume fraction) in young adult normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), aged 16 wk by the end of the study. Prolonged salt excess in WKY and SHR elevated pressure only modestly, but it markedly increased LV mass, especially in SHR. Moreover, salt excess significantly impaired RV and LV diastolic function in SHR but only LV diastolic function in WKY rats. However, salt loading affected neither RV nor LV contractile function in both strains. Interstitial and perivascular collagen deposition was increased, whereas coronary vasodilatory responses to dipyridamole diminished in both ventricles in the saltloaded SHR but not in WKY rats. Therefore, accumulation of ventricular collagen as well as altered myocardial perfusion importantly contributed to the development of salt-related RV and LV dysfunctions in this model of naturally occurring hypertension. The unique effects of salt loading on both ventricles in SHR, but not WKY rats, strongly suggest that nonhemodynamic mechanisms in hypertensive disease participate pathophysiologically with salt-loading hypertension. These findings point to the conclusion that the concept of "salt sensitivity" in hypertension is far more complex than simply its effects on arterial pressure or the LV. sodium excess; left and right ventricular function; spontaneously hypertensive rats; Wistar-Kyoto rats MANY FORMS of experimental and clinical hypertension are exacerbated by salt loading (9,12,20). Not only is arterial pressure increased, but there is also an increase in left ventricular (LV) mass (6 -8, 12, 20, 37) that is complicated further by excessive LV collagen deposition (1, 37). We recently extended these findings by demonstrating that the sensitivity to salt loading in spontaneously hypertensive rats (SHR), an excellent model for naturally occurring essential hypertension, was also manifested by significant LV functional impairment that was associated with marked ventricular fibrosis (1). On the other hand, because very few studies have considered right ventricular (RV) involvement in hypertensive disease (2, 5, 24), the effects of salt excess on RV have been less explored as well. Indeed, reports concerning RV structural changes in response to salt loading are extremely rare and even contradictory (19, 37). Moreover, RV functional response to dietary salt loading is unknown.Therefore, we hypothesized that cardiac response to salt excess was not purely a LV response but that the RV was involved as wel...

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“…[23][24][25] Myocardial fibrosis accounts for the development of LV diastolic dysfunction 25 and for the impairment of coronary vasodilator reserve. 4,5,26 The development of reactive myocardial fibrosis in hypertension is related to a stimulated RAAS that was finally proved at the cellular level where angiotensin II stimulates fibroblast-mediated collagen synthesis in a dose-dependent manner and suppresses collagenase activity, synergistically leading to progressive collagen accumulation within the cardiac interstitium. 27,28 Perivascular fibrosis is seen in both the right and left ventricles and extends to the adjacent interstitial space to rise to interstitial fibrosis after angiotensin II treatment, 29 accompanied by a cellular response of myocytes and macrophages in the media.…”

Section: Coronary Blood Flow Measurementsmentioning

confidence: 99%

Repair of Coronary Arterioles After Treatment With Perindopril in Hypertensive Heart Disease

et al. 2000

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Abstract-In hypertensive heart disease, no data are available on the repair of coronary resistance vessels in patients after long-term ACE inhibitor treatment. Fourteen patients with essential hypertension were studied with coronary flow reserve and with transvenous endomyocardial biopsy before and after 12 months of antihypertensive treatment with perindopril (4 to 8 mg/d, mean 5.9Ϯ2.3 mg/d). Left ventricular muscle mass index decreased by 11% (from 145Ϯ41 to 128Ϯ36 g/m 2 , Pϭ0.04). Maximal coronary blood flow was increased by 54% (from 170Ϯ46 to 263Ϯ142 mL ⅐ min Ϫ1 ⅐ 100 g Ϫ1 , Pϭ0.001), and minimal coronary vascular resistance was diminished by 33% (from 0.67Ϯ0.21 to 0.45Ϯ0.19 mm Hg ⅐ min ⅐ 100 g ⅐ mL Ϫ1 , Pϭ0.001); consequently, coronary reserve increased by 67% from 2.1Ϯ0.6 to 3.5Ϯ1.9 (Pϭ0.001). Structural analysis revealed regression of periarteriolar collagen area by 54% (from 558Ϯ270 to 260Ϯ173 m 2 , Pϭ0.04) and of total interstitial collagen volume density by 22% (from 5.5Ϯ3.8 Vv% to 4.3Ϯ3.2 Vv%, Pϭ0.04), whereas arteriolar wall area was slightly but not significantly reduced. Long-term therapy with the ACE inhibitor perindopril induces structural repair of coronary arterioles that is mainly characterized by the regression of periarteriolar fibrosis and associated with a marked improvement in coronary reserve. These findings indicate the beneficial reparative effects of ACE inhibition on coronary microcirculation in hypertensive heart disease. (Hypertension. 2000;36:220-225.) Key Words: arterioles Ⅲ collagen Ⅲ hypertension, arterial Ⅲ angiotensin-converting enzyme inhibitors Ⅲ coronary reserve A rterial hypertension is the most common cause of pressure overload of the left ventricle, and left ventricular (LV) hypertrophy (LVH) is its common sequelae. Furthermore, LVH is a strong independent risk factor for cardiovascular morbidity and mortality. 1 Potential mechanisms that might account for this observation include increased vulnerability of the hypertrophied myocardium to ischemic damage and enhanced arrhythmogenesis. 2 Moreover, it is increasingly recognized that patients with arterial hypertension and LVH have symptoms and signs of myocardial ischemia despite angiographically normal coronary arteries, and this was found to be related to impaired coronary flow reserve. 3 Functional and structural abnormalities of the coronary microcirculation have been described in hypertensive heart disease. 4 -6 Thus, an adequate increase in myocardial blood flow may be prevented in response to increased metabolic demand and may precipitate myocardial ischemia in these patients. 7 Important structural components of impaired coronary reserve are thickening of the media wall with reduced lumen size and accumulation of collagen in the periarteriolar region. 4,5 The thickening and hardening of arterioles have been called arteriolosclerosis and are characteristic of pathological hypertensive hypertrophy. 8,9 Antihypertensive treatment has been shown to normalize blood pressure and to reverse LVH in hypertensive patients...

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Collagen deposition and the reversal of coronary reserve in cardiac hypertrophy.

Cited by 41 publications

References 44 publications

Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen

Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen

Myocardial fibrosis, impaired coronary hemodynamics, and biventricular dysfunction in salt-loaded SHR

Repair of Coronary Arterioles After Treatment With Perindopril in Hypertensive Heart Disease

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