Subendomyocardial exhaustion of blood flow reserve and increased fibrosis in conscious dogs with heart failure.

Abstract

The effects of near-maximal coronary vasodilation were examined in conscious dogs with left ventricular (LV) failure after pressure overload hypertrophy induced by either aortic banding alone or aortic banding plus a peripheral arteriovenous shunt. The findings were compared with results in littermates with compensated LV hypertrophy and with a third group of normal dogs. At rest, there was a marked difference in the intramyocardial distribution of coronary flow, measured with radiolabeled microspheres. The endocardial/epicardial (endo/epi) flow ratio in the LV failure dogs was 0.96 +/- 0.08 as compared with control dogs (1.28 +/- 0.06, p less than 0.05) or dogs with compensated LV hypertrophy (1.23 +/- 0.08, p less than 0.05). During near-maximal coronary vasodilation with adenosine, all groups showed similar increases in subepimyocardial (epi) flow. While significant increases in subendomyocardial (endo) flow during adenosine infusion were seen in the control group (0.88 +/- 0.10 to 3.53 +/- 0.24 ml/min/g) and in dogs with compensated LV hypertrophy (1.12 +/- 0.14 to 3.60 +/- 0.16 ml/min/g), there was no change in endo flow in the LV failure dogs (1.55 +/- 0.20 to 1.71 +/- 0.47 ml/min/g) and a further significant reduction in the endo/epi flow ratio was observed (0.30 +/- 0.06, p less than 0.01). These hemodynamic changes were associated with chronic multifocal interstitial or discrete areas of fibrosis observed preferentially in endo layers. Thus, endo flow reserve is nearly exhausted in dogs with decompensated pressure overload LV hypertrophy, which may induced periodic episodes of endo ischemia resulting in myocyte necrosis and fibrosis, which in turn results in exacerbation of LV failure.

Doppler Estimation of Reduced Coronary Flow Reserve in Mice with Pressure Overload Cardiac Hypertrophy

“…Coronary flow reserve (CFR), as estimated by the hyperemic/baseline coronary velocity ratio (H/B) as isoflurane is increased from 1.0% to 2.5%, is virtually absent 21 days after aortic banding. Similar reductions in CFR have been reported in dogs with cardiac hypertrophy induced by aortic banding (Parrish et al, 1985;Hittinger et al, 1989), and in humans with aortic stenosis (Marcus et al, 1982).…”

“…Similarly high systolic velocities with an average S/D of 0.7 can been seen in the Doppler waveforms and data presented by Hozumi, et al (1998) from the LAD coronary arteries of patients with aortic valve disease. Indeed, it has been found in patients and experimental animals that there is relative subendocardial underperfusion and ischemia with pressure overload cardiac hypertrophy (Marcus, 1983;Hittinger et al, 1989;Hittinger et al, 1995), and subendocardial ischemia has been proposed as one of the precipitating factors leading to decompensated heart failure (Parrish et al, 1985;Vatner and Hittinger, 1993).…”

“…Banded mice have significantly elevated HW/BW after 1-5 weeks, some show signs of heart failure, and many die within 3 to 5 weeks after banding (Barrick et al, 2007). In dogs with pressure overload cardiac hypertrophy it has been shown that CFR is reduced and that the subendocardium becomes more seriously underperfused and dysfunctional (Hittinger et al, 1989;Vatner and Hittinger, 1993;Duncker et al, 1998;Hittinger et al, 1995;Bache et al, 1987). We hypothesized that mice would have lower CFR as estimated by H/B after banding but before the development of symptomatic heart failure.…”

“…Because oxygen delivery and cardiac work are closely related, the magnitude of CFR is similar to that of cardiac reserve (the ratio of maximal/baseline cardiac output) in normal individuals, and both CFR and exercise capacity tend to be reduced by similar amounts in the presence of cardiovascular disease (Rushmer, 1976). It is thought that decompensated heart failure ensues only after cardiac and coronary reserves are exhausted (Rushmer, 1976;Fallen et al, 1967;Vatner and Hittinger, 1993;Hittinger et al, 1989). Now that mice are being used as cardiovascular disease models (Niebauer et al, 1999;Rockman et al, 1993;Brickson et al, 2006;Barrick et al, 2007;Tanaka et al, 1996;Maslov et al, 2007), it is important to determine if the changes in myocardial perfusion and reserve in the face of increased loading conditions are similar in mice, humans, and larger mammals.…”

Impaired Endocardial Radial Strain in Hypertensive Patients with Electrocardiographic Strain Pattern on Twodimensional Speckle-Tracking Echocardiography

“…Moreover, radial thickening is influenced by the complex 3-dimensional fiber rearrangement in the LV wall [27]. In dogs with severe LV hypertrophy, exhaustion of subendocardial blood flow reserve is associated with myocyte necrosis and fibrosis, demonstrating that structural alterations play an important role in the development of heart failure [28]. Poulsen et al [29] showed that reduced longitudinal strain is associated with increased collagen turnover and degree of myocardial fibrosis in hypertensive patients.…”