Acute aortocaval fistula: role of low perfusion pressure and subendocardial remodeling on left ventricular function.

The experimental model of aortocaval fistula is a useful model of cardiac hypertrophy in response to volume overload. In the present study it has been used to investigate the pathologic subendocardial remodeling associated with the development of heart failure during the early phases (day 1, 3, and 7) following volume overload. Compared with sham treated rats, aortocaval fistula rats showed lower systemic blood pressure and higher left ventricular end-diastolic pressure This resulted in lower coronary driving pressure and left ventricular systolic and diastolic dysfunction. Signs of myocyte necrosis, leukocyte cell infiltration, fibroplasia and collagen deposition appeared sequentially in the subendocardium where remodeling was more prominent than in the non-subendocardium. Accordingly, increased levels of TNF-alpha, IL-1 beta, and IL-6, and enhanced MMP-2 activity were all found in the subendocardium of rats with coronary driving pressure ≤ 60 mmHg. The coronary driving pressure was inversely correlated with MMP-2 activity in subendocardium in all time-points studied, and blood flow in this region showed positive correlation with systolic and diastolic function at day 7. Thus the predominant subendocardial remodeling that occurs in response to low myocardial perfusion pressure during the acute phases of aortocaval fistula contributes to early left ventricular dysfunction.

Subendocardial fibrosis in remote myocardium results from reduction of coronary driving pressure during acute infarction in rats.

OBJECTIVE: To investigate the role of hemodynamic changes occurring during acute MI in subsequent fibrosis deposition within non-MI. METHODS: By using the rat model of MI, 3 groups of 7 rats each [sham, SMI (MI <30%), and LMI (MI >30%)] were compared. Systemic and left ventricular (LV) hemodynamics were recorded 10 minutes before and after coronary artery ligature. Collagen volume fraction (CVF) was calculated in picrosirius red-stained heart tissue sections 4 weeks later. RESULTS: Before surgery, all hemodynamic variables were comparable among groups. After surgery, LV end-diastolic pressure increased and coronary driving pressure decreased significantly in the LMI compared with the sham group. LV dP/dt max and dP/dt min of both the SMI and LMI groups were statistically different from those of the sham group. CVF within non-MI interventricular septum and right ventricle did not differ between each MI group and the sham group. Otherwise, subendocardial (SE) CVF was statistically greater in the LMI group. SE CVF correlated negatively with post-MI systemic blood pressure and coronary driving pressure, and positively with post-MI LV dP/dt min. Stepwise regression analysis identified post-MI coronary driving pressure as an independent predictor of SE CVF. CONCLUSION: LV remodeling in rats with MI is characterized by predominant SE collagen deposition in non-MI and results from a reduction in myocardial perfusion pressure occurring early on in the setting of MI.

Coronary reserve impairment prevents the improvement of left ventricular dysfunction and adversely affects the long-term outcome of patients with hypertensive dilated cardiomyopathy.

In hypertension, left ventricular (LV) hypertrophy develops as an adaptive mechanism to compensate for increased afterload and thus preserve systolic function. Associated structural changes such as microvascular disease might potentially interfere with this mechanism, producing pathological hypertrophy. A poorer outcome is expected to occur when LV function is put in jeopardy by impaired coronary reserve. The aim of this study was to evaluate the role of coronary reserve in the long-term outcome of patients with hypertensive dilated cardiomyopathy. Between 1996 and 2000, 45 patients, 30 of them male, with 52+/-11 years and LV fractional shortening <30% were enrolled and followed until 2006. Coronary flow velocity reserve was assessed by transesophageal Doppler of the left anterior descending coronary artery. Sixteen patients showed >/=10% improvement in LV fractional shortening after 17+/-6 months. Coronary reserve was the only variable independently related to this improvement. Total mortality was 38% in 10 years. The Cox model identified coronary reserve (hazard ratio=0.814; 95% CI=0.72-0.92), LV mass, low diastolic blood pressure, and male gender as independent predictors of mortality. In hypertensive dilated cardiomyopathy, coronary reserve impairment adversely affects survival, possibly by interfering with the improvement of LV dysfunction.

Low coronary driving pressure is associated with subendocardial remodelling and left ventricular dysfunction in aortocaval fistula.

1. The role of haemodynamic changes in left ventricular remodelling has been poorly investigated, especially in the context of volume overload cardiac hypertrophy. Low diastolic blood pressure and high left ventricular filling pressure are expected to affect coronary driving pressure negatively and thereby put in jeopardy subendocardial perfusion in particular. The consequences to global left ventricular remodelling remain undetermined. The aim of the present study was to investigate the role of coronary driving pressure in the development of subendocardial remodelling and the conceivable effects on cardiac function, using a rat model of aortocaval fistula. 2. Wistar rats, weighing 330-350 g, were submitted to aortocaval fistula (ACF group) or sham (control group) operations. Two haemodynamic measurements were determined following surgery, the initial measurement at week 1 and the final measurement at week 8. Cytokine expression, myeloperoxidase (MPO) activity, metalloproteinase expression and activity and fibrosis were assessed in two distinct left ventricular myocardial layers: the subendocardium (SE) and the non-subendocardium (non-SE). 3. The ACF group showed lower initial and final coronary driving pressure and lower final +dP/dt and -dP/dt compared with the control group. Multivariate analyses disclosed initial coronary driving pressure as the only haemodynamic parameter independently associated with SE fibrosis (R(2) = 0.76; P < 0.0001) and with +dP/dt (R(2) = 0.55; P = 0.0004) and -dP/dt (R(2) = 0.91; P < 0.0001). Matrix metalloproteinase (MMP)-2 expression and activity predominated in the SE of ACF animals, particularly in those with low coronary driving pressure. Increased levels of interleukin (IL)-6 and IL-1beta also predominated in the SE of the ACF group. Otherwise, MPO activity and levels of tumour necrosis factor-alpha and IL-10 were similar in both groups. Final coronary driving pressure correlated with both the expression and activity of MMP-2. 4. Low coronary driving pressure early in the course of ACF determines SE damage and, by this mechanism, interferes negatively in left ventricular function.

Bradykinin B2 receptor antagonism attenuates inflammation, mast cell infiltration and fibrosis in remote myocardium after infarction in rats.

Bradykinin may interfere with myocardial remodelling by promoting inflammation and mast cell activation or, alternatively, by counteracting angiotensin II-dependent collagen accumulation. The aim of the present study was to investigate the role of bradykinin B2 receptor antagonism in inflammatory and mast cell infiltration, fibroplasia and fibrosis accumulation following myocardial infarction (MI). Myocardial infarction was produced by the ligature of the left coronary artery in male Wistar rats that were 10 weeks of age. Immediately after MI, rats received the B2 receptor antagonist Hoe140 (0.5 microg/kg per min, s.c.) or saline over a period of 3 days, 1 week or 4 weeks, constituting three separate groups and their respective controls. Coronal myocardial tissue sections underwent haematoxylin and eosin, Giemsa and picrosirius red staining, as well as immunohistochemistry for alpha-smooth muscle actin (SMA). Morphometric studies were undertaken in three different myocardial regions: MI, remote non-infarcted subendocardium (non-MI SE) and remote non-infarcted interventricular septum (non-MI IVS). The MI size was comparable between Hoe140-treated groups and their respective controls (day 3: 42 +/- 4%, n = 8, vs 43 +/- 3%, n = 6; week 1: 37 +/- 5%, n = 5, vs 39 +/- 2%, n = 5; week 4: 35 +/- 3%, n = 9, vs 36 +/- 3%, n = 7). At day 3, Hoe140 treatment reduced inflammatory cell reaction within the MI (585 +/- 59 vs 995 +/- 170 cells/mm2; P = 0.02), non-MI SE (77 +/- 12 vs 214 +/- 57 cells/mm2; P = 0.02) and non-MI IVS (93 +/- 16 vs 135 +/- 14 cells/mm2; P = 0.03) regions. Mast cells were reduced within the non-MI IVS region (0.8 +/- 0.1 vs 2.5 +/- 0.4 cells/mm2; P = 0.006), but not within the MI region. In non-MI SE, mast cells were rarely found. At week 1, Hoe140 treatment reduced alpha-SMA-positive myofibroblast infiltration within the MI (2535 +/- 383 vs 5636 +/- 968 cells/mm2; P = 0.01) and non-MI SE (222 +/- 33 vs 597 +/- 162 cells/mm2; P = 0.03) regions. In the non-MI IVS region, alpha-SMA-positive myofibroblasts were rarely found. At week 4, Hoe140 treatment reduced collagen volume fraction within the MI (37 +/- 4 vs 53 +/- 4%; P = 0.03), non-MI SE (1.3 +/- 0.2 vs 2.6 +/- 0.3%; P = 0.001) and non-MI IVS (1.1 +/- 0.2 vs 1.8 +/- 0.2%; P = 0.01) regions. Bradykinin promotes inflammation, fibroplasia and fibrosis after MI. Mast cells may have a role in fibrosis deposition through a bradykinin-related mechanism.