Myocardial interaction of apixaban after experimental acute volume overload.

OBJECTIVE: Acute volume overload (AVO) induces early ischemia-like changes in intramyocardial arteries. We investigated whether the Factor Xa (FXa) inhibitor apixaban interacts with the myocardium early after AVO. METHODS: Fifty-five syngeneic Fisher rats underwent surgical abdominal aortocaval fistula to induce AVO. Among them, 17 rats were treated with apixaban (10 mg/kg/day). The myocardial outcome was studied using histological analysis and by measuring atrial natriuretic peptide (ANP) and matrix metalloprotease 9 (MMP9) gene expression. RESULTS: After 3 days, the total number of intramyocardial arteries was significantly increased in the AVO+apixaban (AVO+A) group compared with that in the AVO group (12.0 ± 1.2 and 10.2 ± 1.5, point score units, respectively). In the AVO+A group, there were significantly more edematous nuclei in myocardial arteries in the right and left ventricle compared with that in the AVO group. ANP and MMP9 expression levels continued to increase significantly in the AVO+A group compared with those in the AVO group. CONCLUSION: Apixaban interacts with intramyocardial arteries in the left and right ventricles after AVO and ANP and MMP9 expression levels increased. Thus, the myocardial effect of Factor Xa inhibition needs to be monitored after AVO.

Early reversibility of histological changes after experimental acute cardiac volume-overload.

Unloading the heart may aid recovery after acute cardiac volume-overload (AVO). We experimentally investigated whether unloading the heart after AVO by heterotopic transplantation histologically impacts myocardial outcome. Thirty-two syngeneic Fisher 344 rats underwent surgery for abdominal arterial-venous fistula to induce AVO. Seven hearts were heterotopically transplanted one day after AVO to simulate a non-working state of the left ventricle (AVO+Tx). In addition, six rats without AVO or surgery (Normal) and five rats with sham surgery (Sham) served as controls. Myocardial outcome was studied using histology and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis for hypoxia inducible factor 1alpha (HIF1α), inducible nitric oxide synthase (iNOS), E-selectin, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), vascular endothelial growth factor alpha (VEGFα), matrix metalloprotease 9 (MMP9), chitinase-3-like protein (YKL-40) and transforming growth factor beta (TGFß). Relative ischemia of the right ventricle and septal intramyocardial arteries was decreased in AVO+Tx as compared with AVO (0.04±0.01 vs. 0.09±0.02, PSU, P=0.040 and 0.04±0.01 vs. 0.16±0.02, PSU, P=0.008, respectively). Quantitative RT-PCR showed an increase in the expression of iNOS, YKL-40 and VEGFα, and decrease in ANP in AVO+Tx as compared with AVO (5.78±1.23 vs. 2.46±0.81, P=0.039, 22.39±5.22 vs. 10.79±1.70, P=0.039 and 1.15±0.22 vs. 0.60±0.08, P=0.030, and 1.32±0.16 vs. 2.85±0.70, P=0.039, respectively). Unloading the heart by heterotopic transplantation induces early ischemic recovery of intramyocardial arteries after AVO. A non-working state reverses acute ischemic myocardial injury after AVO.

Monoamine oxidase A inhibition protects the myocardium after experimental acute volume overload.

OBJECTIVE: The molecular pathway leading to myocardial cellular destruction after acute volume overload (AVO) may include monoamine oxidases. The aim of the present study was to investigate whether moclobemide (Mo), a monoamine oxidase inhibitor, protects the myocardium after AVO. METHODS: Sixty syngeneic Fischer rats underwent surgical abdominal aortocaval fistula to induce AVO. Eighteen rats were treated with Mo 10 mg/kg/day and were compared with 42 untreated rats with AVO without treatment. Myocardial recovery was analyzed using quantitative reverse transcription polymerase chain reaction for hypoxia-inducible factor 1-alpha, inducible nitric oxide synthase, interleukin 6, E-selectin, atrial natriuretic peptide (ANP), brain natriuretic peptide, vascular endothelial growth factor-alpha, matrix metalloproteinase 9, chitinase 3-like protein (YKL-40), and transforming growth factor-beta. RESULTS: After 3 days, the relative number of ischemic intramyocardial arteries in the left ventricle was lower in AVO treated with Mo than in without [0.04 (0.02-0.07) vs. 0.09 (0.07-0.14), point score unit]. After 1 day, ANP was lower in AVO treated with Mo than in without [0.95 (0.37-1.84) vs. 2.40 (1.33-3.09), fold changes from the baseline (FC), p=0.044], whereas after 1 and 3 days, YKL-40 was higher in AVO treated with Mo than in without [22.66 (14.05-28.83) vs. 10.06 (6.23-15.02), FC, p=0.006 and 6.03 (4.72-7.18) vs. 3.70 (2.62-5.35), FC, p=0.025]. CONCLUSION: Mo decreases intramyocardial arterial ischemia of the left ventricle after AVO while increases YKL-40, reflecting cellular protection during early cardiac remodeling. In the future, adding Mo may be a simple means for myocardial protection after AVO.

Surgical Acute Volume-Overload Impacts Early on Myocardium - An Experimental Study.

BACKGROUND: Acute volume-overload (AVO) predisposes to cardiac failure. Global cardiac injury may ensue after acute right-sided distension of the heart due to AVO. We experimentally investigated whether surgical AVO impacts early on the myocardium and some markers of injury. METHODS: Thirty-four syngeneic Fisher rats underwent surgical abdominal aortocaval fistula to induce AVO. The hearts were procured for regional and quantitative histology after one and three days. Gene expressions for atrial natriuretic peptide (ANP), matrix metalloprotease 9 (MMP9), transforming growth factor ß (TGFß) and YKL40 were investigated for myocardial injury. RESULTS: The relative number of ischemic intramyocardial arteries were abundant in the septum of the hearts with AVO compared with controls at day 1 and 3 [0.16 ± 0.02 vs. 0.02 ± 0.01, point score unit (PSU), p = 0.002 and 0.14 ± 0.02 vs. 0.02 ± 0.01, PSU, p = 0.009, respectively] followed by similar changes in the left ventricle at day 3 (0.11 ± 0.02 vs. 0.04 ± 0.01, PSU, p = 0.007). Indicating early myocardial injury, ANP (p = 0.019) was increased in AVO hearts as compared with controls at day 1, as expected. More interestingly, MMP9 (p = 0.003 and p = 0.006), TGFß (p = 0.002 and p = 0.004) and YKL40 (p = 0.001 and p = 0.003) expressions were significantly increased at day 1 and 3, along with macrophage infiltration into the myocardium supporting the role of factors produced by alternatively activated macrophages in the pathogenesis of AVO-induced pathophysiology in the heart. CONCLUSIONS: Surgical AVO induces an early ischemic myocardial response observed in the intramyocardial arteries. Early expression of key parameters of cardiac remodeling suggest for the onset of early cardiac failure after AVO.