Effects of timed administration of doxycycline or methylprednisolone on post-myocardial infarction inflammation and left ventricular remodeling in the rat heart

Abstract

The development of strategies to ameliorate post-myocardial infarction (MI) remodeling and improve function continues to be an area of clinical importance. Use of steroids for this purpose is controversial since the effects of timed treatment on relevant inflammatory, biochemical and structure/function endpoints are unclear. In a previous report, we demonstrated that use of doxycycline pre-treatment improves post-MI remodeling and passive left ventricular (LV) function. However, the effects of timed doxycycline post-MI treatment are unknown. To examine these issues, we performed a study using a rat MI model. Animals were administered one of the following: doxycycline (DOX), the corticosteroid methylprednisolone (MP), or aqueous vehicle. Treatment was given early, short-term (at time of MI to 24 h post-MI) or late, long term (2-7 days post-MI). Animals were sacrificed at 3, 7 or 42 days post-surgery. We assessed LV hemodynamics, pressure-volume, and pressure-scar strains, histomorphometry, inflammation via measurements of myeloperoxidase activity, and matrix metalloproteinase (MMP) activity. Late MP treatment yielded a robust right-shifted pressure-volume curve, which was accompanied by increased scar strains. Late DOX treatment yielded reduced average heart weight and size and preserved scar thickness. DOX treatment did not suppress inflammation, which contrasts with the suppressive effects of MP. Use of early or late MP yielded increased MMP activity in infarcted and non-infarcted regions. Early and late treatment with DOX yielded infarct-associated MMP activity levels comparable to those of vehicle-treated animals. In conclusion, results indicate that late use of MP yields adverse post-MI structure/function outcomes that correlate with suppression of inflammation and increased MMP activity. These observations contrast with those of DOX, in particular, late treatment where improved outcomes were observed in LV structure and were accompanied by the lack of suppression of inflammation.

Effects of a timely therapy with doxycycline on the left ventricular remodeling according to the pre-procedural TIMI flow grade in patients with ST-elevation acute myocardial infarction

“…Although we cannot exclude the possibility that doxycycline may have other protective effects because of its reported pleiotropic actions including inhibition of proinflammatory cytokines and ROS, it is plausible that, to the plasma concentration achievable with the dose of doxycycline used in our study [13], MMP inhibition, as opposed to ROS scavenging, may be the main mechanism of its protective action [25]. Results of preclinical studies show that the use of doxycycline in the first 7 days post-MI may exert a cardioprotective effect reducing LV remodeling [14,15] and infarct size [26][27][28]. Recently, the TIPTOP trial confirmed the benefit of Table 4 A and B Hierarchical multiple regression analysis of LVEDVi change from baseline to 6 months in the patients with baseline TIMI flow grade B1 correcting first for age, diabetes, hypertension, R STe pre-PCI and post-PCI, Troponin I peak (A) or CK-MB peak (B), pro-BNP peak, before entering ACE inhibitor/ARB and beta adrenergic blocker at step 2, and then doxycycline at step 3 LVEDVi change from baseline to 6 months in the patients with baseline TIMI flow grade B1…”

“…was administered at 100 mg oral dose immediately after primary PCI and then every 12 h for 7 days. The antimicrobial dose we used ensures plasma levels of doxycycline similar to those obtained with higher doses used in the experimental model where the doxycycline has been proved effective in inhibiting MMPs [13], and preventing abdominal aortic aneurysm [13] and post-infarction LV remodeling [14,15]. The R ST-segment elevation immediately before primary PCI was considered as a surrogate of the area of myocardium at risk [16].…”

Dynamic Changes in Myocardial Matrix and Relevance to Disease

“…One issue relates to the timing of treatment after MI. 64 It is generally accepted that drugs whose effects attenuate collagen production should be avoided early after MI because they may impair the formation of a mature scar. In this category are anti-inflammatory agents such as indomethacin or prednisone.…”

Early changes of left ventricular filling pattern after reperfused ST-elevation myocardial infarction and doxycycline therapy: Insights from the TIPTOP trial

“…was administered at 100 mg oral dose immediately after primary PCI and then every 12 h for 7 days. The antimicrobial dose we used ensures plasma levels of doxycycline similar to those obtained with higher doses used in the experimental model where the doxycycline has been proved effective in inhibiting MMPs and preventing abdominal aortic aneurysm [17] and postinfarction LV remodeling [10,11]. The pre-defined primary endpoint of the TIPTOP trial was the percent change from baseline to 6 months in echocardiographic LV enddiastolic volume index (LVEDVi).…”

“…doxycycline [8] mainly related to its ability to act as a matrix metalloproteinases (MMPs) inhibitor at the level of extracellular collagen matrix (ECM) [9] could explain this favorable anti-remodeling effect observed in the experimental [10,11] and clinical [12] setting. Metalloproteinases activation can also occur intracellularly in heart subjected to ischemia/reperfusion (I/R), and it is responsible for the degradation of sarcomeric proteins including titin [13][14][15], thus contributing to cardiomyocytes injury under oxidative stress.…”