Project title: „Investigating Pathological Processes in Ischemic Human Myocardium; Basic Science Tools for Major Health Problem“ 

Project duration: 1.10.2014 – 30.9.2017.

Funding agency: Croatian Science Foundation

Dr. Darija Baković Kramarić, Cardiology, Project leader
Dr. Jasna Marinović, Physiology
Dr. Marko Ljubković, Physiology
Dr. Cristijan Bulat, Cardiac Surgery
Dr. Tonći Batinić, Radiology
Dr. Damir Fabijanić, Cardiology
Dr. Mihajlo Lojpur, Anesthesiology
Dr. Mladen Carev, Anesthesiology
Dr. Marija Ćavar, PhD student

International partners:
Dr. Ana Barać, Washington Hospital Center, Cardiology
Dr. Christophe Lemaire, University of Paris Sud, Faculty of Pharmacy
Dr. Mino Zanchi, OSPEDALE S. CROCE, Fano, Italy, Cardiology

Project summary:
Coronary artery disease (CAD), with its clinical representations (angina, acute myocardial infarction and chronic heart failure), is the most common cause of morbidity and mortality in developed world. The pathological remodelling occurring in ischemic myocardium gradually leads to chronic contractile dysfunction and affects many intracellular mechanisms participating in energy production, calcium homeostasis and apoptosis. In the current project, we propose to investigate these pathological processes in patients suffering from the CAD. Patients who are candidates for coronary artery bypass graft surgery will be included and will undergo a detailed cardiac evaluation, which, in addition to standard diagnostic tools, will be enriched by the advanced diagnostic techniques still non-existing in Croatia (stress cardiac magnetic resonance imaging). This will provide accurate identification and quantification of regional myocardial ischemia. Following clinical evaluation and during revascularization surgery, left ventricular biopsies will be taken from characterized ischemic regions, as well as from non-ischemic regions, and a detailed analysis of intracellular energy metabolism, calcium- contractility and endoplasmic reticulum stress will be performed. The Specific Aims of the project are:
Aim #1 is to assess regional myocardial perfusion and function in patients with CAD who are considered for revascularization therapy.
Aim #2 will investigate pathological processes affecting mitochondria, calcium homeostasis and endoplasmic reticulum stress that take place in the ischemic parts of myocardium.
Aim #3 is to evaluate the effects of the heart rate-lowering pharmacological therapy on ischemic myocardium.
Thus, the overreaching aim of this proposal is to investigate intracellular mechanisms underlying myocardial adaptation and remodelling in chronic ischemia and to identify predictors of outcomes in patients with coronary artery disease undergoing revascularization therapy.

Activities and results:
Stress perfusion testing adds important information about the amount and location of ischemia and aids in prognosis of patients with coronary artery disease. Utilization of novel imaging diagnostic tools enabled us accurate identification and quantification of regional myocardial ischemia in candidate patients.
Two complementary stress-imaging techniques, stress echocardiography and pharmacological perfusion stress testing with cardiac magnetic resonance (CMR) have been used in this study.
Stress echocardiography is a well-validated tool for detection and assessment of CAD. Its prognostic value has been well documented in multiple large studies, which have demonstrated its role for preoperative risk stratification before noncardiac surgery, recovery of function of viable myocardium, and identification of patients at increased risk of cardiac events and death. The test is less expensive than other stress imaging modalities, providing accuracy for detection of CAD and prognostic information equivalent to single-photon emission computed tomography (SPECT) perfusion imaging.
Perfusion CMR is a novel cardiac imaging technology that offers excellent spatial resolution in localizing ischemia and has recently demonstrated high diagnostic accuracy in coronary artery disease and superiority over SPECT testing.
This project allowed us to achieve expertise in accurate myocardial ischemia assessment and therefore advance our current diagnostic methods and clinical decision making. Non-invasive stress imaging techniques have not been performed in Croatia until now, despite their substantial clinical relevance. We made a successful introduction of the novel stress-imaging diagnostic tools in Split University Hospital and implanted them in routine clinical practice, thereby improving the therapeutic decision-making.

Figure 1. Split-screen display of apical four-chamber views from a dipyridamole-stress echocardiogram. The images were recorded at end-systole at rest (top left), low-dose (top right), peak (bottom left) and recovery (bottom right).

Figure 2. MRI perfusion studies use the “first pass” of an intravenously injected Gadolinium contrast agent during administration of a vasodilator (adenosine) to depict hemodynamically significant coronary artery stenosis.

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