Left Ventricular Eccentric Remodeling and Matrix Loss Are Mediated by Bradykinin and Precede Cardiomyocyte Elongation in Rats With Volume Overload
Thomas D. Ryan, MD, PhD*,3,
Emily C. Rothstein, PhD*,2,3,
Inmaculada Aban, PhD ,
Jose A. Tallaj, MD , ,
Ahsan Husain, PhD*,,
Pamela A. Lucchesi, PhD*,1 and
Louis J. Dell’Italia, MD*,,,*
* Departments of Physiology and Biophysics, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama
Department of Biostatistics, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama
Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama
Birmingham Veteran Affairs Medical Center, Birmingham, Alabama.
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Figure 1 LV Remodeling in Age-Matched Sham and ACF Rats
Left ventricular (LV) remodeling in aortocaval fistula (ACF) (open circles) at 12 h; 2 and 5 days; and 4, 8, and 15 weeks compared with age-matched shams (closed circles). Left ventricular end-diastolic dimension (LVEDD) (A), LVEDD/wall thickness (B), isolated cardiomyocyte length (C), left ventricular end-diastolic (LVED) wall thickness (D), and LV wet weight (E). Alternating black and white boxes each represent one 24-h period. Data are presented as mean ± SEM, n values given in Tables 1 and 2 except: 4-week sham LVEDD, LVEDD/wall thickness, LVED wall thickness (n = 9); 4-week ACF echocardiographic parameters and LV wet weight (n = 9); 8-week sham echocardiographic parameters and LV wet weight (n = 8); 15-week sham LV wet weight (n = 12); and 15-week ACF LV wet weight (n = 9). *p < 0.008 (= 0.05/6) for sham versus ACF at each time of the 6 time points except for isolated cardiomyocyte length, where p < 0.01 (= 0.05/5) for each of the 5 time points. Analyses were based on ranks of all the variables in this figure.
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Figure 2 Representative Examples of LV Interstitial Collagen in Control and ACF Rats
Representative examples of LV interstitial collagen in control (CTL) (n = 8) (A) and ACF at 12 h (n = 5) (B), 2 days (n = 8) (C), and 5 days (n = 4) (D). Mean collagen volume percent in 2-day CTL vs. ACF at 12 h, 2 days, and 5 days, where *p < 0.0167 (= 0.05/3) using variance component analysis (E). Mean collagen fiber width at 5 days of ACF versus CTL (F) where *p < 0.05 using t test. Data are presented as mean ± SEM. Abbreviations as in Figure 1.
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Figure 3 Indexes of LV Systolic Function in Age-Matched Sham and ACF Rats
Left ventricular (LV) function in ACF (open circles) at 12 h; 2 and 5 days; and 4, 8, and 15 weeks compared with age-matched shams (closed circles). Left ventricular end-systolic (LVES) pressure (A), left ventricular end-systolic dimension (LVESD) (B), LV fractional shortening (FS) (C), LVES wall stress ( ) (D), and LV velocity of circumferential shortening (VCFr) (E). Alternating black and white boxes each represent one 24-h period. Data are presented as mean ± SEM, n values given in Table 1 except: 4-week sham LVESD, LV fractional shortening, and LV VCFr (n = 9); 8-week sham LVESD, LV fractional shortening, and LV VCFr (n = 8). *p < 0.008 (= 0.05/6) sham versus ACF at each of the 6 time points. Analyses for left ventricular end-systolic pressure (LVESP), LVESD, and LVVCFr were based on their ranks, whereas analyses for LV fractional shortening and LVES were based on their natural logarithms.
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Figure 4 Indexes of Diastolic LV Remodeling in Age-Matched Sham and ACF Rats
Indexes of diastolic LV remodeling in ACF (open circles) at 12 h; 2 and 5 days; and 4, 8, and 15 weeks compared with age-matched shams (closed circles). LVED pressure (A), LVED wall stress () (B), lung wet weight (C), and right ventricular (RV) wet weight (D). Alternating black and white boxes each represent one 24-h period. Data are presented as mean ± SEM, n values given in Table 1 except: 4-week sham LVED pressure and LVED (n = 5); 4-week sham lung wet weight and RV wet weight (n = 8); 4-week ACF lung wet weight and RV wet weight (n = 9); 8-week sham lung wet weight and RV wet weight (n = 8); 15-week sham lung wet weight and RV wet weight (n = 12); and 15-week ACF lung wet weight and RV wet weight (n = 9). *p < 0.008 (= 0.05/6) sham versus ACF at each of the 6 time points. Analyses were based on ranks of all the variables in this figure. Abbreviations as in Figure 1.
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Figure 5 Indexes of Collagen Homeostasis in Hoe 140-Treated Sham and ACF Rats
Collagen volume percent (A), matrix metalloproteinase (MMP)-13 (B), tissue inhibitor of matrix metalloproteinase (TIMP)-1 (C), and TIMP-4 (D) levels at 2 days in sham (SHM) and ACF rats with and without Hoe 140 treatment. Data are presented as mean ± SEM, n values given in Table 3. *p < 0.008 (= 0.05/6) versus SHM; p < 0.008 versus ACF. Collagen volume and MMP-13 were analyzed via variance component, whereas TIMP-1 and -4 were analyzed using a Kruskal-Wallis test. Abbreviations as in Figure 1.
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Figure 6 Volume Percent of Collagen in Ramipril-Treated Sham and ACF Rats
Collagen volume percent in 4-week sham (SHM) and aortocaval fistula (ACF), 4-week sham + ramipril, and 4-week ACF + ramipril. Data are presented as mean ± SEM, n values given in Table 5. *p < 0.008 (= 0.05/6) versus sham, p < 0.008 versus ACF, p < 0.008 versus sham + ramipril. Variance components analysis was used.
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