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      Changes in Metalloproteinase and Tissue Inhibitor of Metalloproteinase during Tachycardia-Induced Cardiomyopathy by Rapid Atrial Pacing in Dogs


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          Background: It was the aim of this study to investigate the variation in metalloproteinase and tissue inhibitor of metalloproteinase (TIMP) connexin levels during tachycardia-induced cardiomyopathy (TIC). Methods: Canine models of TIC were established by rapid right atrial pacing at 350–400 beats per min for 8 weeks in 11 dogs, with another 6 dogs acting as sham operation group. Echocardiography, left ventricular pressure and its first derivation with time (positive and negative maximum, dp/dt<sub>max</sub> and –dp/dt<sub>max</sub>), as well as intracardiac electrograms were recorded before and after rapid pacing at 1, 4 and 8 weeks. Data were acquired in sinus rhythm. Ultrastructural changes in left ventricular tissue were observed by transmission electron microscope. The relative abundance of matrix metalloproteinase (MMP)-9 and TIMP-1 was studied by immunoblotting. Results: The following hemodynamic changes were detected after 8 weeks of rapid pacing: the TIC group had decreased dp/dt<sub>max</sub> (p < 0.05), the left ventricular relaxation time constant (τ) was prolonged (p < 0.05), both left ventricular end-diastolic volume and left ventricular end-systolic volume were decreased (p <0.05), left ventricular end-diastolic pressure was significantly increased (p <0.05), and –dp/dt<sub>max</sub> was significantly decreased (p <0.001) compared with the control group; no statistical differences in the left ventricular ejection fraction between weeks 1, 4 or 8 (p >0.05) were observed, but left ventricular ejection fraction was significantly decreased after 1 week of pacing (p < 0.05). The left ventricular end-diastolic volume was increased after 1 week of pacing compared with the control group (24.15 ± 8.15 vs.11.19 ± 4.41 ml; p <0.05), as shown by echocardiography. Compared with the control group, MMP-9 was significantly higher (0.217 ± 2.16 E-02 vs. 0.314 ± 5.263 E-02; p < 0.001), while TIMP-1 was decreased (0.230 ± 8.944 E-02 vs. 0.120 ± 9.258 E-03; p < 0.001). Conclusions: Ventricular dilatation and systolic dysfunction occurred after 1 week of rapid right atrial pacing. Enlarged and disarrayed fibers and mitochondria with disintegrated crystal and an anarchic pattern were observed. Additionally, moderate dilation of the rough endoplasmic reticulum and intercalated disk discontinuity were seen after 8 weeks of pacing, and MMP-9 was increased and TIMP-1 was decreased after the same time period.

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          Most cited references 21

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          Hemodynamic determinants of the time-course of fall in canine left ventricular pressure.

          The hemodynamic determinants of the time-course of fall in isovolumic left ventricular pressure were assessed in isolated canine left ventricular preparations. Pressure fall was studied in isovolumic beats or during prolonged isovolumic diastole after ejection. Pressure fall was studied in isovolumic relaxation for isovolumic and ejecting beats (r less than or equal to 0.98) and was therefore characterized by a time constant, T. Higher heart rates shortened T slightly from 52.6 +/- 4.5 ms at 110/min to 48.2 +/- 6.0 ms at 160/min (P less than 0.01, n = 8). Higher ventricular volumes under isovolumic conditions resulted in higher peak left ventricular pressure but no significant change in T. T did shorten from 67.1 +/- 5.0 ms in isovolumic beats to 45.8 +/- 2.9 ms in the ejecting beats (P less than 0.001, n = 14). In the ejecting beats, peak systolic pressure was lower, and end-systolic volume smaller. To differentiate the effects of systolic shortening during ejection from those of lower systolic pressure and smaller end-systolic volume, beats with large end-diastolic volumes were compared to beats with smaller end-diastolic volumes. The beats with smaller end-diastolic volumes exhibited less shortening but similar end-systolic volumes and peak systolic pressure. T again shortened to a greater extent in the beats with greater systolic shortening. Calcium chloride and acetylstrophanthidin resulted in no significant change in T, but norepinephrine, which accelerates active relaxation, resulted in a significant shortening of T (65.6 +/- 13.4 vs. 46.3 +/- 7.0 ms, P less than 0.02). During recovery from ischemia, T increased significantly from 59.3 +/- 9.6 to 76.8 +/- 13.1 ms when compared with the preischemic control beat (P less than 0.05). Thus, the present studies show that the time-course of isovolumic pressure fall subsequent to maximum negative dP/dt is exponential, independent of systolic stress and end-systolic fiber length, and minimally dependent on heart rate. T may be an index of the activity of the active cardiac relaxing system and appears dependent on systolic fiber shortening.
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            Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy.

            Ten patients aged 22 to 80 years (median 57) with severe left ventricular (LV) dysfunction and atrial fibrillation (AF) with rapid ventricular response were evaluated after therapy. Because most patients were unaware of their arrhythmia, duration was usually unknown. All patients had heart failure symptoms; 9 presented with New York Heart Association class III or IV disability, and 1 with class II disability. Initial LV ejection fraction ranged from 12 to 30% (median 25). No patient had symptomatic coronary artery disease (4 underwent angiography). Myocarditis and infiltrative processes were excluded by biopsy in 5 patients. All patients were considered initially to have idiopathic dilated cardiomyopathy with secondary AF. Ventricular rate was controlled in all patients, with sinus rhythm restored in 5. At follow-up (median 30 months, range 3 to 56), all patients were asymptomatic. LV ejection fraction after treatment ranged from 40 to 64% (median 52). It is concluded that in some patients initially considered to have idiopathic dilated cardiomyopathy, AF with rapid ventricular response may be the primary cause rather than the consequence of severe LV dysfunction. LV dysfunction may be completely reversible with ventricular rate control.
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              Time course of hemodynamic changes and improvement of exercise tolerance after cardioversion of chronic atrial fibrillation unassociated with cardiac valve disease.

              This study prospectively assessed the time course, magnitude and mechanism of the hemodynamic changes after restoration of sinus rhythm in patients with chronic atrial fibrillation (AF) unassociated with valvular disease. Severe cardiac dysfunction may occur after chronic supraventricular tachycardia in patients with and without underlying cardiac disease. Improvement may follow abolishment of the arrhythmia or adequate slowing of the ventricular rate. Eight patients were studied with a mean previous duration of AF of 10 +/- 9 months. Ejection fraction, exercise capacity and the atrial contribution to the left ventricular filling (only during sinus rhythm) were studied before cardioversion, after cardioversion and 1 week, 1 month and 6 months thereafter. A significant improvement in ejection fraction from 36 +/- 13 to 53 +/- 8% (p < 0.05) occurred at 1 month after cardioversion. Concomitantly, peak oxygen consumption had increased at 1 month, from 20.1 +/- 7 to 25.2 +/- 6 ml/min/kg (p < 0.05). Thereafter, no further improvement in hemodynamic parameters occurred. The atrial systole improved already at 1 week (from 3 +/- 5 to 16 +/- 11%, p < 0.05) and remained unchanged thereafter. Thus, restoration of sinus rhythm was associated with a delayed improvement in ejection fraction and maximal exercise capacity, preceded by an early restoration of atrial contractility and an acute slowing of the heart rate. The discrepancy in time course of restoration of atrial and ventricular function parameters suggests that an intrinsic left ventricular cardiomyopathy is present in patients with AF.

                Author and article information

                S. Karger AG
                June 2006
                03 July 2006
                : 106
                : 1
                : 22-28
                Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, and Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
                92519 Cardiology 2006;106:22–28
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 2, References: 35, Pages: 7
                Original Research


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