87Effects of the chymase inhibitor fulacimstat on adverse cardiac remodelling after acute myocardial infarction - Results of the CHIARA MIA 2 trial

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
H D Duengen ◽  
R J Kim ◽  
D Zahger ◽  
K Orvin ◽  
D Admon ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Mri ◽  
Left Ventricular ◽  
Cardiac Remodelling ◽  
Left Ventricular Ejection ◽  
Controlled Study ◽  
P Value ◽  
Tissue Remodelling ◽  
Ventricular Ejection Fraction ◽  
Chymase Inhibitor

Abstract Introduction Adverse cardiac remodelling represents the most important risk factor for the development of heart failure (HF) after myocardial infarction (MI). Chymase is a protease that generates locally pro-fibrotic factors such as angiotensin II, TGFβ, and matrixmetallproteases that contribute to tissue remodelling. Purpose This phase IIa study examined the effects of the chymase inhibitor fulacimstat on functional parameters of adverse cardiac remodelling after acute MI. Methods A double-blind, multinational, randomized, placebo-controlled study was performed in patients after first STEMI who were treated with primary percutaneous coronary intervention within 24h of symptom onset. To enrich for patients at risk of adverse remodelling, main inclusion criteria were a left-ventricular ejection fraction (LVEF)≤45% and an infarct size>10% on day 5 to 9 post MI as measured by cardiac MRI. On day 6 to 12 post MI, patients were randomized to treatment with either 25 mg fulacimstat (n=54) or placebo (n=53) twice daily on top of standard of care. The changes in LVEF, LVEDVI, and LVESVI from baseline to 6 months of treatment were analyzed by a central blinded cardiac MRI core laboratory. Results Fulacimstat was safe and well tolerated, 64.8% of patients treated with fulacimstat and 75.5% of patients treated with placebo reported treatment emergent adverse events. Fulacimstat achieved exposures that were approximately 10-fold higher than those predicted to be required for minimal therapeutic activity. After six months of treatment, there were no effects of fulacimstat compared to placebo on the changes in LVEF, LVEDVI, and LVESVI (see Table). Analysis of primary efficacy parameters Parameter Placebo Fulacimstat p-value LVEF (%) baseline 37.2±6.1 39.1±5.5 0.15 6 months 41.2±8.4 42.6±8.4 0.45 delta 4.0±5.0 3.5±5.4 0.69 LVEDVI (mL/m2) baseline 80.0±17.1 77.4±18.2 0.51 6 months 85.1±19.1 84.7±23.4 0.94 delta 5.1±18.9 7.3±13.3 0.54 LVESVI (mL/m2) baseline 50.5±13.0 47.3±12.3 0.26 6 months 51.1±16.9 49.6±18.1 0.71 delta 0.6±14.8 2.3±11.2 0.56 Data are given as mean ± standard deviation. Conclusion Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on adverse cardiac remodelling in the experimental setting of this study. Acknowledgement/Funding The study was funded by its sponsor BAYER AG

scholarly journals Prevention of left ventricular remodeling after myocardial infarction: efficacy of physical training

2016 ◽  
Vol 70 (2) ◽  
Author(s):  
Camillo Taglieri ◽  
Enrico Lombardo ◽  
Mauro Feola
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Physical Training ◽  
Angiotensin Receptor Blockers ◽  
Left Ventricular ◽  
Post Myocardial Infarction ◽  
Cardiac Remodelling ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Positive Effect

Post-myocardial infarction left ventricular remodelling should be considered an important therapeutic target in patients after an acute myocardial infarction, considering the heavy prognostic implication. The therapies used in these patients should reduce the progression of the left ventricular dysfunction to refractory heart failure. In order to prevent post-myocardial infarction cardiac remodelling, different therapies have been tested, and for ACE-inhibitors and betablockers a clear demonstration of efficacy has been obtained. Losartan and valsartan, two widely used angiotensin receptor blockers, demonstrated to be safe and equally useful compared to ACEI. The addition of spironolactone to the standard therapy for heart failure has a clear beneficial effect but the clinical use has been refrained by the risk of iperkaliemia. Aerobic physical training improves the left ventricular ejection fraction in patients with systolic dysfunction, reducing the progressive enlargement after myocardial infarction. The positive effect of aerobic training on cardiac remodelling might be related to the positive effect on neurhormonal assessment, to he improvement of microcirculatory myocardial perfusion and of endothelial function.

scholarly journals Effect of Ischemic Preconditioning and Postconditioning on Exosome-Rich Fraction microRNA Levels, in Relation with Electrophysiological Parameters and Ventricular Arrhythmia in Experimental Closed-Chest Reperfused Myocardial Infarction

2019 ◽  
Vol 20 (9) ◽  
pp. 2140 ◽  
Author(s):  
Andreas Spannbauer ◽  
Denise Traxler ◽  
Dominika Lukovic ◽  
Katrin Zlabinger ◽  
Johannes Winkler ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Ischemic Preconditioning ◽  
Cardiac Mri ◽  
Left Ventricular ◽  
Cardiac Conduction ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
St Elevation ◽  
Antiarrhythmic Effects

We investigated the antiarrhythmic effects of ischemic preconditioning (IPC) and postconditioning (PostC) by intracardiac electrocardiogram (ECG) and measured circulating microRNAs (miRs) that are related to cardiac conduction. Domestic pigs underwent 90-min. percutaneous occlusion of the mid left anterior coronary artery, followed by reperfusion. The animals were divided into three groups: acute myocardial infarction (AMI, n = 7), ischemic preconditioning-acute myocardial infarction (IPC-AMI) (n = 9), or AMI-PostC (n = 5). IPC was induced by three 5-min. episodes of repetitive ischemia/reperfusion cycles (rI/R) before AMI. PostC was induced by six 30-s rI/R immediately after induction of reperfusion 90 min after occlusion. Before the angiographic procedure, a NOGA endocardial mapping catheter was placed again the distal anterior ventricular endocardium to record the intracardiac electrogram (R-amplitude, ST-Elevation, ST-area under the curve (AUC), QRS width, and corrected QT time (QTc)) during the entire procedure. An arrhythmia score was calculated. Cardiac MRI was performed after one-month. IPC led to significantly lower ST-elevation, heart rate, and arrhythmia score during ischemia. PostC induced a rapid recovery of R-amplitude, decrease in QTc, and lower arrhythmia score during reperfusion. Slightly higher levels of miR-26 and miR-133 were observed in AMI compared to groups IPC-AMI and AMI-PostC. Significantly lower levels of miR-1, miR-208, and miR-328 were measured in the AMI-PostC group as compared to animals in group AMI and IPC-AMI. The arrhythmia score was not significantly associated with miRNA plasma levels. Cardiac MRI showed significantly smaller infarct size in the IPC-AMI group when compared to the AMI and AMI-PostC groups. Thus, IPC led to better left ventricular ejection fraction at one-month and it exerted antiarrhythmic effects during ischemia, whereas PostC exhibited antiarrhythmic properties after reperfusion, with significant downregulaton of ischemia-related miRNAs.

Colchicine for Left Ventricular Infarct Size Reduction in Acute Myocardial Infarction: A Phase II, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Study Protocol – The COVERT-MI Study

Cardiology ◽  
2021 ◽  
pp. 1-10
Author(s):  
Didier Bresson ◽  
François Roubille ◽  
Cyril Prieur ◽  
Loic Biere ◽  
Fabrice Ivanes ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Phase Ii ◽  
Myocardial Injury ◽  
Ventricular Remodeling ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Controlled Study ◽  
Ventricular Ejection Fraction

Inflammatory processes have been identified as key mediators of ischemia-reperfusion injury in ST-segment elevation myocardial infarction (STEMI). They add damage to the myocardium and are associated with clinical adverse events (heart failure and cardiovascular death) and poor myocardial recovery. Colchicine is a well-known alkaloid with potent anti-inflammatory properties. In a proof-of-concept phase II trial, colchicine has been associated with a significant 50% reduction of infarct size (assessed by creatine kinase levels) in comparison to placebo in acute STEMI patients referred for primary percutaneous coronary intervention (PPCI). The Colchicine in STEMI Patients Study (COVERT-MI) is an ongoing confirmative prospective, multicenter, randomized, double-blind trial testing whether a short course oral treatment with colchicine versus placebo decreases myocardial injury in patients presenting with STEMI referred for PPCI. Adult patients, with a first STEMI episode and an initial TIMI flow ≤1, referred for PPCI, will be randomized (<i>n</i> = 194) in a 1:1 ratio to receive an oral bolus of colchicine of 2 mg followed by 0.5 mg b.i.d. treatment during 5 days or matching placebo. The primary endpoint will be the reduction in infarct size as assessed by cardiac magnetic resonance at 5 ± 2 days between both groups. The main secondary endpoints will be tested between groups in hierarchical order with left ventricular ejection fraction at 5 days, microvascular obstruction presence at 5 days, and absolute adverse left ventricular remodeling between 5 days and 3 months. This academic study is being financed by a grant from the French Ministry of Health (PHRCN-16-0357). Results from this study will contribute to a better understanding of the complex pathophysiology underlying myocardial injury after STEMI. The present study describes the rationale, design, and methods of the trial.

A translational model of chronic heart failure in rats

2018 ◽  
pp. 136-148
Author(s):  
С.А. Крыжановский ◽  
И.Б. Цорин ◽  
Е.О. Ионова ◽  
В.Н. Столярук ◽  
М.Б. Вититнова ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Chronic Heart Failure ◽  
Left Ventricular ◽  
Compensatory Hypertrophy ◽  
Experimental Myocardial Infarction ◽  
Left Ventricular Ejection ◽  
Translational Model ◽  
Innovative Drug ◽  
Ventricular Ejection Fraction

Цель исследования - разработка трансляционной модели хронической сердечной недостаточности (ХСН) у крыс, позволяющей, с одной стороны, изучить тонкие механизмы, лежащие в основе данной патологии, а с другой стороны, выявить новые биомишени для поиска и изучения механизма действия инновационных лекарственных средств. Методика. Использован комплекс эхокардиографических, морфологических, биохимических и молекулярно-биологических исследований, позволяющий оценивать и дифференцировать этапы формирования ХСН. Результаты. Динамические эхокардиографические исследования показали, что ХСН формируется через 90 дней после воспроизведения переднего трансмурального инфаркта миокарда. К этому времени у животных основной группы отмечается статистически значимое по сравнению со 2-ми сут. после воспроизведения экспериментального инфаркта миокарда снижение ФВ левого желудочка сердца (соответственно 55,9 ± 1,4 и 63,9 ± 1,6%, р = 0,0008). Снижение насосной функции сердца (на 13% по сравнению со 2-ми сут. после операции и на ~40% по сравнению с интактными животными) сопровождается увеличением КСР и КДР (соответственно с 2,49 ± 0,08 до 3,91 ± 0,17 мм, р = 0,0002, и с 3,56 ± 0,11 до 5,20 ± 0,19 мм, р = 0,0001), то есть к этому сроку развивается сердечная недостаточность. Результаты эхокардиографических исследований подтверждены данными морфометрии миокарда, продемонстрировавшими дилатацию правого и левого желудочков сердца. Параллельно проведенные гистологические исследования свидетельствуют о наличии патогномоничных для данной патологии изменений миокарда (постинфарктный кардиосклероз, компенсаторная гипертрофия кардиомиоцитов, очаги исчезновения поперечной исчерченности мышечных волокон и т.д.) и признаков венозного застоя в легких и печени. Биохимические исследования выявили значимое увеличение концентрации в плазме крови биохимического маркера ХСН - мозгового натрийуретического пептида. Данные молекулярно-биологических исследований позволяют говорить о наличии гиперактивности ренин-ангиотензин-альдостероновой и симпатоадреналовой систем, играющих ключевую роль в патогенезе ХСН. Заключение. Разработана трансляционная модель ХСН у крыс, воспроизводящая основные клинико-диагностические критерии этого заболевания. Показано наличие корреляции между морфометрическими, гистологическими, биохимическими и молекулярными маркерами прогрессирующей ХСН и эхокардиографическими диагностическими признаками, что позволяет использовать неинвазивный метод эхокардиографии, характеризующий состояние внутрисердечной гемодинамики, в качестве основного критерия оценки наличия/отсутствия данной патологии. Aim. Development of a translational model for chronic heart failure (CHF) in rats to identify new biotargets for finding and studying mechanisms of innovative drug effect in this disease. Methods. A set of echocardiographic, morphological, biochemical, and molecular methods was used to evaluate and differentiate stages of CHF development. Results. Dynamic echocardiographic studies showed that CHF developed in 90 days after anterior transmural myocardial infarction. By that time, left ventricular ejection fraction was significantly decreased in animals of the main group compared with rats studied on day 2 after experimental myocardial infarction (55.9 ± 1.4% vs . 63.9 ± 1.6%, respectively, p<0.0008). The decrease in heart’s pumping function (by 13% compared with day 2 after infarction and by approximately 40% compared to intact animals) was associated with increased ESD and EDD (from 2.49 ± 0.08 to 3.91 ± 0.17 mm, p = 0.0002, and from 3.56 ± 0.11 to 5.20 ± 0.19 mm, respectively, p = 0.0001); therefore, heart failure developed by that time. The results of echocardiographic studies were confirmed by myocardial morphometry, which demonstrated dilatation of both right and left ventricles. Paralleled histological studies indicated presence of the changes pathognomonic for this myocardial pathology (postinfarction cardiosclerosis, compensatory hypertrophy of cardiomyocytes, foci of disappeared transverse striation of muscle fibers, etc.) and signs of venous congestion in lungs and liver. Biochemical studies demonstrated a significant increase in plasma concentration of brain natriuretic peptide, a biochemical marker of CHF. Results of molecular studies suggested hyperactivity of the renin-angiotensin-aldosterone and sympathoadrenal systems, which play a key role in the pathogenesis of CHF. Conclusions. A translational model of CHF in rats was developed, which reproduced major clinical and diagnostic criteria for this disease. Morphometric, histological, biochemical, and molecular markers for progressive CHF were correlated with echocardiographic diagnostic signs, which allows using this echocardiographic, noninvasive method characterizing the intracardiac hemodynamics as a major criterion for the presence / absence of this pathology.

Randomized, double blind, placebo-controlled, safety and efficacy study of dutogliptin in combination with filgrastim in early recovery post-MI: rationale, design and first interim analysis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D Von Lewinski ◽  
B Merkely ◽  
I Buysschaert ◽  
R.A Schatz ◽  
G.G Nagy ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Stem Cells ◽  
Adverse Events ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
Early Recovery ◽  
Ventricular Ejection Fraction ◽  
Combined Application

Abstract Background Regenerative therapies offer new approaches to improve cardiac function after acute ST-elevation myocardial infarction (STEMI). Mobilization of stem cells and homing within the infarcted area have been identified as the key mechanisms for successful treatment. Application of granulocyte-colony stimulating factor (G-CSF) is the least invasive way to mobilize stem cells while DDP4-inhibitor facilitates homing via stromal cell-derived factor 1 alpha (SDF-1α). Dutogliptin, a novel DPP4 inhibitor, combined with stem cell mobilization using G-CSF significantly improved survival and reduced infarct size in a murine model. Purpose We initiated a phase II, multicenter, randomized, placebo-controlled efficacy and safety study (N=140) analyzing the effect of combined application of G-CSF and dutogliptin, a small molecule DPP-IV-inhibitor for subcutaneous use after acute myocardial infarction. Methods The primary objective of the study is to evaluate the safety and tolerability of dutogliptin (14 days) in combination with filgrastim (5 days) in patients with STEMI (EF &lt;45%) following percutaneous coronary intervention (PCI). Preliminary efficacy will be analyzed using cardiac magnetic resonance imaging (cMRI) to detect &gt;3.8% improvement in left ventricular ejection fraction (LV-EF). 140 subjects will be randomized to filgrastim plus dutogliptin or matching placebos. Results Baseline characteristics of the first 26 patients randomized (24 treated) in this trial reveal a majority of male patients (70.8%) and a medium age of 58.4 years (37 to 84). During the 2-week active treatment period, 35 adverse events occurred in 13 patients, with 4 rated as serious (hospitalization due to pneumonia N=3, hospitalization due to acute myocardial infarction N=1), and 1 adverse event was rated as severe (fatal pneumonia), 9 moderate, and 25 as mild. 6 adverse events were considered possibly related to the study medication, including cases of increased hepatic enzymes (N=3), nausea (N=1), subcutaneous node/suffusion (N=1) and syncope (N=1). Conclusions Our data demonstrate that the combined application of dutogliptin and G-CSF appears to be safe on the short term and feasible after acute myocardial infarction and may represent a new therapeutic option in future. Funding Acknowledgement Type of funding source: Other. Main funding source(s): This research is funded by the sponsor RECARDIO, Inc., 1 Market Street San Francisco, CA 94150, USA. RECARDIO Inc. is funding the complete study. The Scientific Board of RECARDIO designed the study. Data Collection is at the participating sites. Interpretation of the data by the Scientific Board and Manuscript written by the authors and approved by the Sponsor

scholarly journals The Use of Artificial Hypoxia in Endurance Training in Patients after Myocardial Infarction

2021 ◽  
Vol 18 (4) ◽  
pp. 1633 ◽  
Author(s):  
Agata Nowak-Lis ◽  
Tomasz Gabryś ◽  
Zbigniew Nowak ◽  
Paweł Jastrzębski ◽  
Urszula Szmatlan-Gabryś ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricle ◽  
Endurance Training ◽  
Exercise Tolerance ◽  
Collateral Circulation ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Test Duration ◽  
Hemodynamic Parameters ◽  
Ventricular Ejection Fraction

The presence of a well-developed collateral circulation in the area of the artery responsible for the infarction improves the prognosis of patients and leads to a smaller area of infarction. One of the factors influencing the formation of collateral circulation is hypoxia, which induces angiogenesis and arteriogenesis, which in turn cause the formation of new vessels. The aim of this study was to assess the effect of endurance training conducted under normobaric hypoxia in patients after myocardial infarction at the level of exercise tolerance and hemodynamic parameters of the left ventricle. Thirty-five patients aged 43–74 (60.48 ± 4.36) years who underwent angioplasty with stent implantation were examined. The program included 21 training units lasting about 90 min. A statistically significant improvement in exercise tolerance assessed with the cardiopulmonary exercise test (CPET) was observed: test duration (p < 0.001), distance covered (p < 0.001), HRmax (p = 0.039), maximal systolic blood pressure (SBPmax) (p = 0.044), peak minute ventilation (VE) (p = 0.004) and breathing frequency (BF) (p = 0.044). Favorable changes in left ventricular hemodynamic parameters were found for left ventricular end-diastolic dimension LVEDD (p = 0.002), left ventricular end-systolic dimension LVESD (p = 0.015), left ventricular ejection fraction (LVEF) (p = 0.021), lateral e’ (p < 0.001), septal e’ (p = 0.001), and E/A (p = 0.047). Endurance training conducted in hypoxic conditions has a positive effect on exercise tolerance and the hemodynamic indicators of the left ventricle.

scholarly journals The outcome of patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) and impaired kidney function: a 3-year observational study

2021 ◽  
Author(s):  
Malgorzata Zalewska-Adamiec ◽  
Jolanta Malyszko ◽  
Ewelina Grodzka ◽  
Lukasz Kuzma ◽  
Slawomir Dobrzycki ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Incidence Rate ◽  
Kidney Function ◽  
Coronary Arteries ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Risk Of Death ◽  
Group 2 ◽  
Group 1

Abstract Background Myocardial infarction with nonobstructive coronary arteries (MINOCA) constitutes about 10% of the cases of acute coronary syndromes (ACS). It is a working diagnosis and requires further diagnostics to determine the cause of ACS. Methods In this study, 178 patients were initially diagnosed with MINOCA over a period of 3 years at the Department of Invasive Cardiology of the University Clinical Hospital in Białystok. The value of estimated glomerular filtration rate (eGFR) was calculated for all patients. The patients were divided into 2 groups depending on the value of eGFR: group 1—53 patients with impaired kidney function (eGFR < 60 mL/min/1.73 m2; 29.8%) and group 2—125 patients with normal kidney function (eGFR ≥ 60 mL/min/1.73 m2; 70.2%). Results In group 1, the mean age of patients was significantly higher than that of group 2 patients (77.40 vs 59.27; p < 0.0001). Group had more women than group 2 (73.58% vs 49.60%; p = 0.003). Group 1 patients had higher incidence rate of arterial hypertension (92.45% vs 60.80%; p < 0.0001) and diabetes (32.08% vs 9.60%; p = 0.0002) and smoked cigarettes (22.64% vs 40.80%; p = 0.020). Group 1 patients had higher incidence rate of pulmonary edema, cardiogenic shock, sudden cardiac arrest (13.21% vs 4.00%; p = 0.025), and pneumonia (22.64% vs 6.40%; p = 0.001). After the 37-month observation, the mortality rate of the patients with MINOCA was 16.85%. Among group two patients, more of them became deceased during hospitalization (7.55% vs 0.80%; p = 0.012), followed by after 1 year (26.42% vs 7.20%; p = 0.0004) and after 3 years (33.96% vs 9.6%; p < 0.0001). Multivariate analysis revealed that the factors increasing the risk of death in MINOCA are as follows: older age, low eGFR, higher creatinine concentration, low left ventricular ejection fraction, and ST elevation in ECG. Conclusion Impaired kidney function is diagnosed in every third patient with MINOCA. Early and late prognosis of patents with MINOCA and renal dysfunction is poor, and their 3-year mortality is comparable to patients with myocardial infarction with significant stenosis of the coronary arteries and impaired kidney function.

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