Left Ventricular Myocardial Collagen Research Articles

Cardiovascular Function of Modern Pigs Does not Comply with Allometric Scaling Laws

Growing concerns have been expressed regarding cardiovascular performance in modern farm pigs, which has been proposed as a critical factor contributing to the reduced adaptability of modern pigs to stress. Here we tested the hypothesis that cardiac dimensions and pump function in modern heavy farm pigs are disproportionally low for their body weight, and investigated potential underlying mechanisms. The results from the present study indeed demonstrate disproportionally low values for stroke volume and cardiac output in pigs with bodyweights over 150 kg. Importantly, these low values were not the result of impaired left ventricular (LV) systolic contractile function, but were due to a disproportionally small LV end-diastolic volume. The latter was associated with changes in determinants of LV passive stiffness, including (i) an increase in LV myocardial collagen, (ii) a shift from the compliant N2BA titin isoform towards the stiff N2B, and (iii) a marked elevation of aortic blood pressure. Taken together, these results demonstrate reduced pumping capacity of the hearts of heavy modern pigs, due to structural abnormalities in the LV myocardium.

Long-Term Low Intensity Physical Exercise Attenuates Heart Failure Development in Aging Spontaneously Hypertensive Rats

Background: Physical exercise is a strategy to control hypertension and attenuate pressure overload-induced cardiac remodeling. The influence of exercise on cardiac remodeling during uncontrolled hypertension is not established. We evaluated the effects of a long-term low intensity aerobic exercise protocol on heart failure (HF) development and cardiac remodeling in aging spontaneously hypertensive rats (SHR). Methods: Sixteen month old SHR (n=50) and normotensive Wistar-Kyoto (WKY, n=35) rats were divided into sedentary (SED) and exercised (EX) groups. Rats exercised in treadmill at 12 m/min, 30 min/day, 5 days/week, for four months. The frequency of HF features was evaluated at euthanasia. Statistical analyses: ANOVA and Tukey or Mann-Whitney, and Goodman test. Results: Despite slightly higher systolic blood pressure, SHR-EX had better functional capacity and lower HF frequency than SHR-SED. Echocardiography and tissue Doppler imaging showed no differences between SHR groups. In SHR-EX, however, left ventricular (LV) systolic diameter, larger in SHR-SED than WKY-SED, and endocardial fractional shortening, lower in SHR-SED than WKY-SED, had values between those in WKY-EX and SHR-SED not differing from either group. Myocardial function, assessed in LV papillary muscles, showed improvement in SHR-EX over SHR-SED and WKY-EX. LV myocardial collagen fraction and type I and III collagen gene expression were increased in SHR groups. Myocardial hydroxyproline concentration was lower in SHR-EX than SHR-SED. Lysyl oxidase gene expression was higher in SHR-SED than WKY-SED. Conclusion: Exercise improves functional capacity and reduces decompensated HF in aging SHR independent of elevated arterial pressure. Improvement in functional status is combined with attenuation of LV and myocardial dysfunction and fibrosis.

Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy.

Historically, the tissue inhibitors of matrix metalloproteinases (TIMPs) were considered monochromatic in function. However, differential TIMP profiles more recently observed with left ventricular (LV) dysfunction and matrix remodeling suggest more diverse biological roles for individual TIMPs. This study tested the hypothesis that cardiac-specific overexpression (TIMP-4OE) or deletion (knockout; TIMP-4KO) would differentially affect LV function and structure following pressure overload (LVPO). LVPO (transverse aortic constriction) was induced in mice (3.5 ± 0.1 mo of age, equal sex distribution) with TIMP-4OE (n = 38), TIMP-4KO (n = 24), as well as age/strain-matched wild type (WT, n = 25), whereby indexes of LV remodeling and function such as LV mass and ejection fraction (LVEF) were determined at 28 days following LVPO. Following LVPO, both early (7 days) and late (28 days) survival was ~25% lower in the TIMP-4KO group (P < 0.05). While LVPO increased LV mass in all groups, the relative hypertrophic response was attenuated with TIMP-4OE. With LVPO, LVEF was similar between WT and TIMP-4KO (48 ± 2% and 45 ± 3%, respectively) but was higher with TIMP-4OE (57 ± 2%, P < 0.05). With LVPO, LV myocardial collagen expression (type I, III) increased by threefold in all groups (P < 0.05), but surprisingly this response was most robust in the TIMP-4KO group. These unique findings suggest that increased myocardial TIMP-4 in the context of a LVPO stimulus may actually provide protective effects with respect to survival, LV function, and extracellular matrix (ECM) remodeling. These findings challenge the canonical belief that increased levels of specific myocardial TIMPs, such as TIMP-4 in and of themselves, contribute to adverse ECM accumulation following a pathological stimulus, such as LVPO.

Angiotension AT1Receptor Inhibition in Pacing Induced Heart Failure: Effects on Left Ventricular Myocardial Collagen Content and Composition

The progression of left ventricular (LV) dilation with congestive heart failure (CHF) is associated with an increased incidence of morbidity and mortality. The LV myocardial extracellular matrix has been implicated to play an important role in maintaining chamber shape and myocyte alignment. While angiotensin II AT1receptor (Ang AT1) receptor activation has been demonstrated to contribute to increased vascular resistance with the CHF, whether activation of the myocardial Ang AT1receptor system contributes to LV dilation and myocardial collagen remodelling with CHF remains unclear. The goal of this study was to examine the effects of Ang AT1receptor inhibition on LV geometry and myocardial collagen content and structure with the development of pacing CHF. Pigs (25 kg) were instrumented in order to measure LV function in the conscious state and were assigned to one of three groups: (1) Pacing CHF: rapid atrial pacing (240 bpm) for 3 weeks (n=7); (2) Pacing CHF and Ang AT1Block: concomitant Ang AT1receptor blockade (valsartan, Novartis, Basel 60 mg/day) and rapid pacing (n=7); (3) sham controls (n=7). The Ang AT1receptor antagonist was delivered by osmotic minipump and this dose has been demonstrated previously to significantly blunt the Ang-II pressor response. LV pump function and geometry was assessed by echocardiography and LV myocardial collagen content by computer assisted histomorphometry and biochemistry. In the pacing CHF group, LV fractional shortening was reduced (17±2v45±1%) and LV end-diastolic dimension increased (5.91±0.09v3.75±0.07 cm) compared to controls (P<0.05). In the pacing CHF and Ang AT1blockade group, LV pump function and dimensions were similar to untreated pacing CHF values. The relative content of LV myocardial fibrillar collagen was reduced with pacing CHF (7.6±0.4v11.3±0.6%) compared to controls (P<0.05), and was similarly reduced in the pacing CHF and Ang AT1receptor blockade group (8.3±0.4%,P<0.05). LV myocardial hydroxyproline was reduced with pacing CHF compared to controls (2.35±0.21v2.89±0.42 mg/gdwt,P<0.05). While reduced with pacing CHF and Ang AT1receptor blockade (2.54±0.25 mg/gdwt), this was not significantly different from controls (P=0.23). Ang AT1receptor inhibition in this model of CHF did not appear to favorably affect the degree of LV dilation and myocardial collagen structure. These results suggest that activation of the myocardial Ang AT1receptor may not significantly contribute to LV remodelling with pacing CHF.

Myocardial matrix metalloproteinase activity and abundance with congestive heart failure.

The left ventricular (LV) myocardial collagen matrix has been proposed to participate in the maintenance of LV geometry. Thus alterations in the composition of the LV myocardial collagen matrix may influence LV function. The matrix metalloproteinases (MMPs) are a family of enzymes that contribute to extracellular remodeling in several disease states. However, the types of MMPs expressed in the normal and congestive heart failure (CHF) state and the relation to MMP activity remained unclear. Accordingly, after 3 wk of pacing (240 beats/min), changes in LV function, substrate-specific MMP activity, and MMP subclass abundance were measured in comparison with control pigs (n = 6). Changes in LV function and geometry were measured by echocardiography; LV end-diastolic dimension increased (3.6 +/- 0.1 vs. 6.0 +/- 0.1 cm, P < 0.05) and LV fractional shortening decreased (47 +/- 1 vs. 15 +/- 1%, P < 0.05) compared with controls. Degradation of fibrillar collagen is achieved through the combined action of interstitial collagenase (MMP-1), gelatinase A (MMP-2), and stromelysin (MMP-3) (He, C., S. Wilheilm, A. Pentland, B. Marmer, G. Grant, A. Eisen, and G. Goldberg. Proc. Natl. Acad. Sci. USA 86:2632-2636, 1989; Woessner, J. FASEB J. 5: 2145-2154, 1991). Accordingly, the relative abundance of specific MMPs (MMP-1, MMP-2, and MMP-3) was examined by immunoblotting. With pacing CHF, the relative abundance for MMP-1 increased to 319 +/- 94%, MMP-2 increased to 194 +/- 31%, and MMP-3 increased to 493 +/- 159% (all P < 0.05). With pacing CHF, LV myocardial zymographic activity for the substrate gelatin increased by 119% (P < 0.05) and for the substrate collagen III by 153% (P < 0.05) over controls. Caseinolytic activity also increased with pacing CHF by 139% (P < 0.05) over controls. In conclusion, LV myocardial MMP activity and abundance increased with pacing-induced CHF. These findings demonstrate that pacing-induced CHF leads to changes in myocardial MMP activity and expression that may be responsible for LV remodeling in CHF.

Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: relation to ventricular and myocyte function.

The development of congestive heart failure (CHF) is associated with left ventricular (LV) dilation and myocardial remodeling. However, fundamental mechanisms that contribute to this remodeling process with the progression of CHF remain unclear. The matrix metalloproteinases (MMPs) have been demonstrated to play a significant role in tissue remodeling in a number of pathological processes. The present project tested the hypothesis that the LV dilation and remodeling during the progression of CHF is associated with early changes in MMP expression and zymographic activity. LV and myocyte function, collagen content, and MMP expression and zymographic activity were serially measured during the progression of CHF caused by pacing-induced supraventricular tachycardia (SVT) in pigs. After 7 days of SVT, LV end-diastolic dimension and myocyte length both increased by 15% from control values, and LV fractional shortening fell by 20%. At the level of the myocyte, percent shortening fell by 16% after 7 days of SVT, with no change in the steady-state velocity of shortening. Longer durations of SVT caused progressive LV dilation, LV pump failure, and myocyte contractile dysfunction. Specifically, 21 days of SVT resulted in a >50% increase in LV dimension, a 56% fall in LV fractional shortening, and a 33% decline in myocyte velocity of shortening. The decline in LV and myocyte function with 21 days of SVT was accompanied by signs and symptoms of CHF. Thus, SVT causes time-dependent changes in LV geometry and function and the subsequent development of CHF. LV myocardial collagen content and confluence fell by >25% after 7 days of SVT and were accompanied by an 80% increase in LV myocardial MMP zymographic activity against the substrate gelatin. After 14 days of SVT, total LV myocardial collagen content was reduced by 24%, and LV myocardial MMP zymographic activity increased by >100% from control values. Interstitial collagenase (MMP-1), stromelysin (MMP-3), and 72-kD gelatinase (MMP-2) were increased by approximately 2-fold after 7 days of SVT. LV MMP zymographic activity and abundance remained elevated with longer durations of SVT. The results of the present study demonstrated that in this model of CHF, early changes in LV myocardial MMP zymographic activity and protein levels occurred with the initiation and progression of LV dilation and dysfunction. These findings suggest that an early contributory mechanism for the initiation of LV remodeling that occurred in this model of developing CHF is enhanced expression and potentially increased activity of LV myocardial MMPs.