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

Abstract

Aim: Metalloproteinases inhibition by doxycycline reduces cardiac protein degradation at extracellular and intracellular level in the experimental model ischemia/reperfusion injury. Since both extracellular cardiac matrix and titin filaments inside the cardiomyocyte are responsible for the myocardial stiffness, we hypothesized that doxycycline could favorably act on left ventricular (LV) filling pressures in patients after reperfused acute ST-elevation myocardial infarction (STEMI). Methods and results: Seventy-three of 110 patients of the TIPTOP trial underwent a 2D-Echo-Doppler on admission, and at pre-discharge and at 6-month after a primary PCI for STEMI and LV dysfunction. From admission to pre-discharge, LV filling changed from a high filling pressure (HFP) to a normal filling pressure (NFP) pattern in 91% of the doxycycline-group, and in 67% of the control-group. Conversely, 1% of the doxycycline-group, and 37% of the control-group changed the LV filling from NFP to HFP pattern. Overall, a pre-discharge HFP pattern was present in 4 patients (11%) of the doxycycline-group and in 13 patients (36%) of the control-group (p = 0.025). The evaluation of metalloproteinases and their tissue inhibitors plasma concentrations provide possible favorable action of doxycycline. On the multivariate analyses, troponine I peak (p = 0.026), doxycycline (p = 0.033), and on admission to pre-discharge LVEF changes (p = 0.044) were found to be associated with predischarge HFP pattern. Independently of their baseline LV filling behavior, the 6-month remodeling was less in patients with pre-discharge NFP pattern than in patients with HFP pattern. Conclusions: In patients with STEMI and LV dysfunction doxycycline can favorably modulate the LV filling pattern early after primary PCI.© 2017 Elsevier B.V. All rights reserved. . Thus, a major unresolved question is how to optimally manage AMI patients having advanced LV diastolic dysfunction [6].For the first time in the clinical setting, the TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodeling) trial [7] demonstrated that a timely, short-term therapy with doxycycline is safe and able to induce a significant decrease in LV dilation in patients successfully treated with primary percutaneous coronary intervention (pPCI) for a first ST-elevation AMI (STEMI) and LV dysfunction. Several pleiotropic properties of International Journal of Cardiology xxx (2017) xxx-xxx Abbreviations: STEMI, ST-elevation myocardial infarction; MMPs, mealloproteinases; NFP, normal filling pressure; HFP, high filling pressure; E-wave, transmitral early peak velocity; A-wave, transmitral late peak velocity; DT, deceleration time of transmitral early peak velocity; E', early peak velocity on the septal side of the mitral annulus; Vp, left ventricular flow propagation velocity during early filling; LVEDVi, left ventricular end diastolic volume index; LVESVi, left ventricular end systolic vo...

Delivery of a matrix metalloproteinase-responsive hydrogel releasing TIMP-3 after myocardial infarction: effects on left ventricular remodeling

“…All animals were treated and cared for in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (8th ed., Washington, DC: The National Academies Press, 2011), and all protocols were approved by the University of South Carolina's Institutional Animal Care and Use Committee. Serial experiments were carried out until 28 days post-MI because this time period encompasses a rapid change in LV geometry and function in both animals and patients (3,6,7,33). After the final set of LV function measurements, LV regions were subjected to mRNA analysis for myofibroblast phenotype expression (14,32,35,41).…”

“…The reasons for the failure of this initial post-MI clinical trial were likely multifactorial and included problematic issues, from dosing and reaching therapeutic levels to that of small cohorts of patients enrolled from national and international sites with surprisingly modest degrees of LV remodeling post-MI. In a more recent study using doxycycline that putatively influenced MMP activity, LV functional outcomes were improved in patients with a significant MI (6,7). Moreover, this clinical trial identified shifts in plasma profiles of the endogenous tissue inhibitors of metalloproteinase (TIMPs), which were associated with indexes of LV remodeling post-MI (38).…”

“…Elevated MMP plasma levels occur in patients and animals after MI and appear to serve as a predictor for the subsequent development of heart failure (9,11,17,19,22,24,28,31,33,(37)(38)(39). Although initial clinical trials using systemic inhibitors of MMPs in the post-MI setting were disappointing, results from recent clinical trials suggest that targeting the MMP system remains an important therapeutic target (6,7,16). The results from the present study provide a critical proof-ofconcept study that localized delivery of a bioresponsive hydrogel into the MI region, which releases a recombinant TIMP in response to local MMP activity, can significantly attenuate adverse LV remodeling and key hemodynamic indexes of heart failure progression.…”

Therapeutic Acellular Scaffolds for Limiting Left Ventricular Remodelling-Current Status and Future Directions

“…Clinical studies pointed out a significant increase in plasma levels of MMPs in the early MI phase, which was also linked to adverse LV remodelling [ 157 , 158 ]. Though a few clinical studies have already targeted MMPs in MI patients, therapeutic outcomes were not completely clear due to issues related to limited sample size, a modest degree of LV remodelling, difficult targeted delivery and problematic dose up to significant therapeutic levels [ 159 ]. Indeed, targeting the MMP system to circumvent adverse LV remodelling post-MI holds therapeutic relevance.…”

Dynamics of Extracellular Matrix Degradation Markers in Patients with STEMI in Different Strategies of Treatment

“…Зниження фракції викиду лівого шлуночка може бути наслідком зниженої скорочувальної функції серця через обширне пошкодження міокарда або наслідком дилатації лівого шлуночка, викликаної поширенням зони інфаркту і розтягуванням рубцевої області міокарда. Функція лівого шлуночка є важливим предиктором результату ГІМ [5,6].…”