Differential effects of pressure or volume overload on myocardial MMP levels and inhibitory control

2000 ◽  
Vol 278 (1) ◽  
pp. H151-H161 ◽  
Author(s):  
Yoshitatsu Nagatomo ◽  
Blase A. Carabello ◽  
Mytsi L. Coker ◽  
Paul J. McDermott ◽  
Shintaro Nemoto ◽  
...  
Keyword(s):  
Mitral Regurgitation ◽  
Inhibitory Control ◽  
Species Abundance ◽  
Volume Overload ◽  
Abundance Ratio ◽  
Left Ventricular ◽  
Myocardial Remodeling ◽  
Disease States ◽  
Mmp Inhibitor ◽  
The Matrix

Left ventricular (LV) pressure (PO) or volume (VO) overload is accompanied by myocardial remodeling, but mechanisms that contribute to this progressive remodeling process remain unclear. The matrix metalloproteinases (MMPs) contribute to tissue remodeling in a number of disease states. This study tested the hypothesis that increased MMP expression and activity occur after the induction of an LV overload, which is accompanied by a loss of endogenous MMP inhibitory control. LV MMP zymographic activity and species abundance were measured in dogs under the following conditions: acute PO induced by ascending aortic balloon inflation (6 h, n = 9), prolonged PO by aortic banding (10 days, n = 5), acute VO through mitral regurgitation secondary to chordal rupture (6 h, n = 6), prolonged VO due to mitral regurgitation (14 days, n = 7), and sham controls ( n = 11). MMP zymographic activity in the 92-kDa region, indicative of MMP-9 activity, increased over threefold in acute PO and VO and fell to control levels in prolonged PO and VO. The MMP-9 activity-to-abundance ratio increased by over fourfold with acute VO and twofold in acute PO, suggesting a loss of inhibitory control. Endogenous MMP inhibitor content was unchanged with either PO or VO. Interstitial collagenase (MMP-1) content decreased by 50% with acute VO but not with acute PO. Stromelysin (MMP-3) levels increased by 40% with acute VO and increased by 80% with prolonged PO. Although changes in LV myocardial MMP activity and inhibitory control occurred in both acute and prolonged PO and VO states, these changes were not identical. These results suggest that the type of overload stimulus may selectively influence myocardial MMP activity and expression, which in turn would affect the overall LV myocardial remodeling process in LV overload.

scholarly journals Mechanisms of cardiac hypertrophy in canine volume overload

1998 ◽  
Vol 275 (1) ◽  
pp. H65-H74 ◽  
Author(s):  
Takeshi Matsuo ◽  
Blase A. Carabello ◽  
Yoshitatsu Nagatomo ◽  
Masaaki Koide ◽  
Masayoshi Hamawaki ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mitral Regurgitation ◽  
Protein Degradation ◽  
Volume Overload ◽  
Left Ventricular ◽  
Translational Efficiency ◽  
Protein Accumulation ◽  
Severe Mitral Regurgitation ◽  
Fractional Rate ◽  
Lv Mass

This study tested whether the modest hypertrophy that develops in dogs in response to mitral regurgitation is due to a relatively small change in the rate of protein synthesis or, alternatively, is due to a decreased rate of protein degradation. After 3 mo of severe experimental mitral regurgitation, the left ventricular (LV) mass-to-body weight ratio increased by 23% compared with baseline values. This increase in LV mass occurred with a small, but not statistically significant, increase in the fractional rate of myosin heavy chain (MHC) synthesis (Ks), as measured using continuous infusion with [3H]leucine in dogs at 2 wk, 4 wk, and 3 mo after creation of severe mitral regurgitation. Translational efficiency was unaffected by mitral regurgitation as measured by the distribution of MHC mRNA in polysome gradients. Furthermore, there was no detectable increase in translational capacity as measured by either total RNA content or the rate of ribosome formation. These data indicate that translational mechanisms that accelerate the rate of cardiac protein synthesis are not responsive to the stimulus of mitral regurgitation. Most of the growth after mitral regurgitation was accounted for by a decrease in the fractional rate of protein degradation, calculated by subtracting fractional rates of protein accumulation at each time point from the corresponding Ks values. We conclude that 1) volume overload produced by severe mitral regurgitation does not trigger substantial increases in the rate of protein synthesis and 2) the modest increase in LV mass results primarily from a decrease in the rate of protein degradation.

scholarly journals Dissociation between cardiomyocyte function and remodeling with β-adrenergic receptor blockade in isolated canine mitral regurgitation

2008 ◽  
Vol 295 (6) ◽  
pp. H2321-H2327 ◽  
Author(s):  
Betty Pat ◽  
Cheryl Killingsworth ◽  
Thomas Denney ◽  
Junying Zheng ◽  
Pamela Powell ◽  
...  
Keyword(s):  
Mitral Regurgitation ◽  
Adrenergic Receptor ◽  
Volume Overload ◽  
Left Ventricular ◽  
Ultrastructural Changes ◽  
Receptor Blockade ◽  
Lv Mass ◽  
Lv Remodeling ◽  
Fractional Shortening ◽  
Adrenergic Receptor Blockade

The low-pressure volume overload of isolated mitral regurgitation (MR) is associated with increased adrenergic drive, left ventricular (LV) dilatation, and loss of interstitial collagen. We tested the hypothesis that β1-adrenergic receptor blockade (β1-RB) would attenuate LV remodeling after 4 mo of MR in the dog. β1-RB did not attenuate collagen loss or the increase in LV mass in MR dogs. Using MRI and three-dimensional (3-D) analysis, there was a 70% increase in the LV end-diastolic (LVED) volume-to-LV mass ratio, a 23% decrease in LVED midwall circumferential curvature, and a >50% increase in LVED 3-D radius/wall thickness in MR dogs that was not attenuated by β1-RB. However, β1-RB caused a significant increase in LVED length from the base to apex compared with untreated MR dogs. This was associated with an increase in isolated cardiomyocyte length (171 ± 5 μm, P < 0.05) compared with normal (156 ± 3 μm) and MR (165 ± 4 μm) dogs. Isolated cardiomyocyte fractional shortening was significantly depressed in MR dogs compared with normal dogs (3.73 ± 0.31 vs. 5.02 ± 0.26%, P < 0.05) and normalized with β1-RB (4.73 ± 0.48%). In addition, stimulation with the β-adrenergic receptor agonist isoproterenol (25 nM) increased cardiomyocyte fractional shortening by 215% ( P < 0.05) in β1-RB dogs compared with normal (56%) and MR (50%) dogs. In summary, β1-RB improved LV cardiomyocyte function and β-adrenergic receptor responsiveness despite further cell elongation. The failure to attenuate LV remodeling associated with MR could be due to a failure to improve ultrastructural changes in extracellular matrix organization.

P4379Pathophysiology of left atrial filling in mitral regurgitation. A new volumetric flow rate index describing disturbed left atrial filling behavior in mitral regurgitation by 3D TTE

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D Frumkin ◽  
K Stangl ◽  
A Muegge ◽  
T Buck ◽  
B Plicht
Keyword(s):  
Mitral Regurgitation ◽  
Left Atrium ◽  
Flow Rate ◽  
Left Atrial ◽  
Volume Overload ◽  
Volumetric Flow Rate ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Mean Flow ◽  
Flow Rates

Abstract Background In chronic mitral regurgitation (MR) the left atrium (LA) is one of the first cardiac structures involved in remodeling by progressive volume overload. Real-time three-dimensional echocardiography is able to monitor volumetric changes of the left atrium during the heart cycle. Purpose We hypothesized that chronic volume overload due to MR leads to detectable changes in the LA filling behavior described by mean and maximum filling flow rates and their relation called volumetric flow rate index. Methods We prospectively analyzed data of 36 patients in different stages of chronic MR and 13 patients without MR. Transthoracic echocardiography was conducted using the Epiq 7G Ultrasound System. Standard 2D- and 3D apical 4-chamber views were recorded and stored for offline analysis. We generated volume-time-curves by 3D volume analysis to derive mean and maximum volumetric flow rates during LA reservoir, conduit and pump phase. Volumetric flow rate index was calculated as the quotient of mean flow rate/maximum flow rate. Results Average MR severity, calculated with the MR Scoring system introduced from Buck et al. and implicated in the ESC Guidelines, was 6.2 points (±2.5) according to Grade I-II. We included 13 patients without MR, 18 with mild MR, 12 patients with moderate MR, 6 patients with severe MR. Left ventricular ejection fraction was similar in the different groups (51,2±12,3%). Maximum and mean flow rate showed no significant correlation with MR severity. Correlation of MR severity with LA dilation (ml/m2 BSA) was r=0.41; p<0.001. Flow rate index showed strong significant correlation with MR severity in left atrial reservoir phase (r=−0.75; p<0.001). There was no statistically relevant difference of volumetric flow rate parameters in left atrial pump and conduit phase. Line chart Conclusions We observed a significant correlation of the volumetric flow rate index to MR severity in the left atrial reservoir phase with stronger correlation than MR severity to left atrial dilation. The results of this work encourage further investigations to establish the presented volumetric flow rate index as a progression marker of MR and to evaluate its prognostic value.

scholarly journals Surgical treatment of secondary mitral regurgitation in heart failure: a present-day view

2021 ◽  
Vol 13 (1) ◽  
pp. 40-48
Author(s):  
E. G. Agafonov ◽  
M. A. Popov ◽  
D. I. Zybin ◽  
D. V. Shumakov
Keyword(s):  
Heart Failure ◽  
Mitral Valve ◽  
Left Ventricle ◽  
Mitral Regurgitation ◽  
Volume Overload ◽  
Left Ventricular ◽  
Functional Class ◽  
Functional Mitral Regurgitation ◽  
Admission Rates ◽  
Replacement Surgery

Rationale. Secondary, or functional, mitral regurgitation is the most common complication of heart failure. Dysfunction of one or more mitral valve structures occurs in 39–74% of patients thus complicating the course of the disease and significantly worsening the prognosis in patients with left ventricle dilatation. An unfavorable prognosis in patients with the development of mitral regurgitation is conditioned by the progressive changes that form a vicious circle: the continuing volume overload and dilatation of the left ventricle cause its remodeling, leading to further dilatation of the mitral valve annulus. Dysfunctions of the papillary muscles lead to the increased tension of the left ventricle wall and increased mitral regurgitation. Clinically, this process is manifested by the congestive heart failure progression and worsened prognosis of the further course, which in the future may lead to considering the inclusion of this patient group on the waiting list for heart transplantation.Purpose. The purpose of this article is to review the role of surgical management in patients with heart failure complicated by mitral regurgitation.Conclusions. The main principles of the treatment for functional mitral regurgitation include the reverse left ventricular remodeling and mitral valve repair or replacement surgery which lead to an improved quality of life, the transition of patients to a lower functional class, reduced hospital admission rates, and also to a regression or slower progression of the heart failure and to an improved survival.

Left ventricular function in experimental volume overload hypertrophy

1989 ◽  
Vol 256 (4) ◽  
pp. H974-H981 ◽  
Author(s):  
B. A. Carabello ◽  
K. Nakano ◽  
W. Corin ◽  
R. Biederman ◽  
J. F. Spann
Keyword(s):  
Mitral Regurgitation ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Left Ventricular Dysfunction ◽  
Ventricular Dysfunction ◽  
Contractile Function ◽  
Weight Ratio ◽  
Volume Overload ◽  
Left Ventricular ◽  
Mean Velocity

Left ventricular function in volume overload hypertrophy is controversial. In humans, chronic severe volume overload eventually results in left ventricular dysfunction; paradoxically, experimental volume overload hypertrophy has nearly always been associated with normal left ventricular function. However, in most cases, experimental volume overload hypertrophy has either been mild or only present for a short duration. To help resolve the issue of contractile function in volume overload hypertrophy, we examined ventricular function in a recently described model of severe chronic experimental mitral regurgitation. Left ventricular function was measured before and 3 mo after the creation of severe mitral regurgitation (averaged regurgitant fraction 0.64 +/- 0.04). At 3 mo end-diastolic volume had increased from 78 +/- 5 to 114 +/- 7 ml (P less than 0.01). Significant left ventricular hypertrophy had occurred with an increase in the left ventricular weight-to-body weight ratio from 3.84 +/- 0.2 to 5.22 +/- 0.2 (P less than 0.01). All indicators of left ventricular function (ejection fraction, the end ejection stress-volume relationship, this relationship corrected for eccentric hypertrophy, and mean velocity of circumferential fiber shortening at a common stress) were reduced at 3 mo. Our study produced 64% volume overload which was maintained for 3 mo at which time there was a 36% increase in left ventricular mass. This amount of volume overload of this duration produced significant left ventricular dysfunction.

scholarly journals Cardiac-restricted overexpression of extracellular matrix metalloproteinase inducer causes myocardial remodeling and dysfunction in aging mice

2008 ◽  
Vol 295 (4) ◽  
pp. H1394-H1402 ◽  
Author(s):  
Juozas A. Zavadzkas ◽  
Rebecca A. Plyler ◽  
Shenikqua Bouges ◽  
Christine N. Koval ◽  
William T. Rivers ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Left Ventricular ◽  
Myocardial Remodeling ◽  
End Diastolic Volume ◽  
Lv Remodeling ◽  
The Matrix ◽  
Adverse Remodeling ◽  
Membrane Type

The matrix metalloproteinases (MMPs) play a pivotal role in adverse left ventricular (LV) myocardial remodeling. The transmembrane protein extracellular MMP inducer (EMMPRIN) causes increased MMP expression in vitro, and elevated levels occur in patients with LV failure. However, the direct consequences of a prolonged increase in the myocardial expression of EMMPRIN in vivo remained unexplored. Cardiac-restricted EMMPRIN expression (EMMPRINexp) was constructed in mice using the full-length human EMMPRIN gene ligated to the myosin heavy chain promoter, which yielded approximately a twofold increase in EMMPRIN compared with that of the age/strain-matched wild-type (WT) mice; EMMPRINexp ( n = 27) and WT ( n = 33) mice were examined at 3.2 ± 0.1 or at 13.3 ± 0.5 mo of age ( n = 43 and 26, respectively). LV end-diastolic volume (EDV) was similar in young EMMPRINexp and WT mice (54 ± 2 vs. 57 ± 3 μl), but LV ejection fraction (EF) was reduced (51 ± 1 vs. 57 ± 1%; P < 0.05). In old EMMPRINexp mice, LV EDV was increased compared with WT mice values (76 ± 3 vs. 58 ± 3 μl; P < 0.05) and LV EF was significantly reduced (45 ± 1 vs. 57 ± 2%; P < 0.05). In EMMPRINexp old mice, myocardial MMP-2 and membrane type-1 MMP levels were increased by >50% from WT values ( P < 0.05) and were accompanied by a twofold higher collagen content ( P < 0.05). Persistent myocardial EMMPRINexp in aging mice caused increased levels of both soluble and membrane type MMPs, fibrosis, and was associated with adverse LV remodeling. These findings suggest that EMMPRIN is an upstream signaling pathway that can play a mechanistic role in adverse remodeling within the myocardium.

Intrinsic cardiac elastography in patients with primary mitral regurgitation: predictive role after mitral valve repair

2020 ◽  
Author(s):  
Tais De Jesus ◽  
Mahmoud M Alashry ◽  
Ratnasari Padang ◽  
Sorin V Pislaru ◽  
Vuyisile T Nkomo ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Mitral Regurgitation ◽  
Mitral Valve Repair ◽  
Volume Overload ◽  
Normal Subjects ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Valve Repair ◽  
Short Term ◽  
Myocardial Stiffness

Abstract Aims  Chronic volume-overload can impair systolic and diastolic myocardial properties. We tested the hypothesis that Intrinsic Cardiac Elastography may detect alterations in passive myocardial elasticity in patients with chronic severe mitral regurgitation (MR) and predict worsening left ventricular (LV) function after mitral valve repair (MVr). Methods and results  Comprehensive transthoracic echocardiography and cardiac elastography were performed in 80 patients with primary MR (prolapse and/or flail leaflets) of varying severity and compared with 40 normal subjects. In patients who underwent MVr (n = 51), elastography measurements were related to changes in left ventricular ejection fraction (LVEF) at short-term (3–4 days post-op) and mid-term (1 year) follow-up. Most patients were asymptomatic or mildly symptomatic and had preserved LVEF (&gt;60%). Intrinsic velocity propagation (iVP) of myocardial stretch, a direct measure of myocardial stiffness, was higher in patients with severe MR {median 2.0 [interquartile range (IQR) 1.5–2.2] m/s, range 1.1–3.4 m/s; n = 56} compared to normal subjects [median 1.7 (IQR 1.5–1.8) m/s; n = 40; P = 0.0005], but not in those with mild or moderate MR [median 1.7 (IQR 1.4–1.9) m/s; n = 24]. A higher iVP was associated with more severe LV volume-overload and LV and left atrial enlargement (P &lt; 0.05 for all). In patients undergoing MVr, a higher iVP independently predicted a larger drop in LVEF post-intervention (short-term, P = 0.001; 1 year, P = 0.007), incrementally to pre-operative LVEF (P &lt; 0.05). Conclusion  Non-invasive measurements of myocardial stiffness were able to predict functional deterioration after MVr for chronic primary MR. Further studies should investigate the mechanisms and practical utility of this novel measurement.

Myocardial matrix metalloproteinase activity and abundance with congestive heart failure

1998 ◽  
Vol 274 (5) ◽  
pp. H1516-H1523 ◽  
Author(s):  
Mytsi L. Coker ◽  
Chadwick V. Thomas ◽  
Mark J. Clair ◽  
Jennifer W. Hendrick ◽  
R. Stephen Krombach ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Relative Abundance ◽  
Collagen Matrix ◽  
Left Ventricular ◽  
Lv Function ◽  
Disease States ◽  
Collagen Iii ◽  
The Matrix ◽  
Myocardial Collagen

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.

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