Cardiovascular diseases represent one of the most important public health problems of nowadays in Croatia (1). These are commonly chronic diseases, with significant prevalence in the general population. The aforementioned group is accountable for about a half of the total annual mortality. Epidemiological data shows variability, which can be interpreted by aging of the population, by a decline in the number of the total population, the long-term negative socioeconomic trends, the level and continuity of prevention activities and the activities of the health sector. Significant progress in organizational terms was in line with the development of the activities relating to primary prevention, predominantly institutional development in the community health centers and a network of acute care in hospitals. The most significant organizational success was probably the establishment of the first network of early management of acute myocardial infarction, that is, the network of primary percutaneous coronary interventions (PCI-network) (2). In the last few years the activity of cardiac surgery centers has developed in Croatia, being active in the 5 university hospitals and one specialty hospital in total. We must specifically stress the activity of the Croatian Cardiac Society and affiliated associations that have also undertaken a number of public health measures and comprehensive principles of activities in the treatment and management of chronic cardiovascular diseases. Concordantly with the development of cardiology in the Republic of Croatia, there are two in-patient centers and one out-patient center for the rehabilitation of cardiovascular patients that have been established. In recent times, despite suboptimal resources of the health system, additional success was achieved owing to the availability and increased use of modern methods of non-invasive diagnostics, in the form of using cardiac and blood vessel multi-slice computed tomography (MSCT coronary angiography) and magnetic resonance imaging of the heart. Furthermore, a greater diversity of available diagnostic tests has also resulted in our getting closer to the standard of improved individualization of a diagnostic approach and subsequent therapeutic management of chest pain syndrome compared to the expected probability of the underlying coronary artery disease (CAD) (3).

A significant challenge in the management of cardiovascular disease is a chronic ischemic heart disease that in the general population has an expected prevalence of 1-4%, and it is several times greater than the acute coronary syndrome (4). Stable CAD is characterized by transient angina problems as a result of reversible inequality of myocardial oxygenated blood supply as per needs at the moments of physical exertion, emotional or other stress, but it can also occur at rest (5).

The basic tests in the first line diagnostic evaluation of stable CAD include: electrocardiogram (ECG) at rest, standard laboratory values, telemetric monitoring ECG or Holter ECG if necessary, echocardiography, and depending on the indication, chest X-ray. In case technical difficulties occur due to suboptimal transthoracic echocardiographic analysis of cardiac structures, function or segmental contractility disorders by applying a standard transhoracic echocardiographic examination and by using the contrast due to suboptimal technical availability, imaging diagnostics can be done by using magnetic imaging resonance (cardiac MRI) (6).

Based on clinical judgment, it is necessary to do a Bayesian analysis (statistical probability) of a relationship of pretest probability (PTP) of presence of CAD, which is entirely dependent on the progress of the future diagnostic and therapeutic interventions. The main factors to be taken into consideration are: age, gender, symptom characteristics, along with the standard treatment of pronounced cardiovascular risk factors. In case of treatment of persons with lower or moderate ratio of PTP of CAD, the diagnostics by using MSCT coronary angiography seems to be particularly beneficial, due to an excellent negative predictive value (more optimal for excluding the disease), whereas the treatment of young people with an expected lower proportion of calcium in the coronary arteries makes it more beneficial in the given circumstances.

Table 1 shows basic diagnostic tests for the evaluation of coronary artery disease.

Additional treatment of persons with lower PTP of CAD (<15%) include the diagnostics of non-coronary causes of chest pain syndromes. In the case of recurring problems along with the occurrence of angina pain at rest, it is worth considering the possibility of vasospastic angina (5). In patients with intermediate PTP of CAD (15-85%) additional treatment by using the available non-invasive diagnostics is required. In case that a high degree of PTP of CAD (>85%) along with clinical symptoms that clearly resembles angina chest pain, additional tests by noninvasive diagnostics are not necessarily taken, and a patient may well be referred for invasive coronary angiography (5). In the latter case, the application of additional noninvasive diagnostics does not, as expected, lead to a more precise answer about the presence of CAD, but if it is clinically justified, the application of additional tests helps in additional differentiation of risks for occurrence of major adverse cardiovascular events.

Regarding the subjects with intermediate degree of PTV of CAD, the use of MSCT to evaluate coronary artery calcification based on Agaston score, when the amounts of calcium >400 leads to a significant increase in the proportion of positive results (falsely and truly positive ones). The evaluation based on MSCT-calcium scoring can then partly be considered to be a reliable equivalent to conventional stress tests, but the decision on further treatment or invasive coronary angiography in terms of the urgency of the treatment is to be made on the basis of other characteristics of the clinical evaluation (7).

Stress tests by using the physical stress represent the first choice method in the diagnostic evaluation, simply because of the greater representativeness of pathophysiological changes in the controlled environment that are as close to the everyday life stress. Furthermore, the use of physical stress brings us valuable clinical data such as objective evaluation of a degree of endurance of physical stress, dynamics of blood pressure and pulse, accompanied by the monitoring of changes in the ECG. The application of pharmacological stress types is particularly suited for additional evaluation of already known segmental myocardial contractility disorders, or in patients who are unable to successfully perform the test with physical load.

Dobutamine stress test is established as particularly useful for inducing of mismatch of myocardial oxygen supply and myocardial oxygen demands. There are particularly great possibilities of identifying segmental deficits in the contractility after the administration of dobutamine, in terms of detection of viability/numbness of myocardium to MRI (8). It is important to note that the safety profile of the application of dobutamine stress is equal in MRI and echocardiography (9). The vasodilatator tests such as adenosine, or the so-called “MRI-perfusion” are significantly more commonly used in clinical practice, with a satisfactory safety profile and a sufficient degree of diagnostic accuracy, equaling to SPECT and PET tests (10). If qualitative methods of flow analysis are applied for the evaluation of perfusion deficit, the diagnostic accuracy of MRI approximately corresponds to invasive coronary angiography accompanied by using fractional flow reserve (FFR) analysis (11).

The evaluation of myocardial viability by using MRI provides high-resolution morphological details, including functional evaluation of the left ventricle in only 30 minutes of imaging. The principle of gadolinium-based imaging is based on a delayed wash out of gadolinium from normal myocardium compared to the one replaced by fibrosis a scar. A delayed imaging from 5 to 20 minutes after the injection of a contrast agent will clearly show fibrosis or a scar. In clinical trials on human subjects, cardiac MRI accompanied by the use of gadolinium as a contrast agent is introduced as an accurate method of identifying myocardial viability where the recovery of the myocardial function after coronary artery bypass surgery is presented as a reference standard. In 52 patients who underwent coronary revascularization, we observed a better regional function in 82% of segments in whom preoperative imbibition by the contrast agent was not established, in 64% of segments where myocardium was affected from 1% to 25%, and only 37% in segments where myocardium was affected from 26% to 50%. (12)

In a meta-analysis of of MSCT coronary angiography in the diagnostics of CAD shows a high rate of sensitivity (98-99%) and negative predictive value (99-100%), but with slightly lower specificity (82-89%) and positive predictive value (91- 93%) (13). A larger multi-centric study on patients with a history of CAD, previous percutaneous coronary interventions and previous myocardial infarction shows that the diagnostic accuracy is slightly lower (sensitivity 85%, specificity 90%) (14). Tachycardia, arrhythmia and an increased frequency of calcification of the coronary arteries due to mineral artifacts make the performance of the analysis of MSCT coronary angiography more difficult and reduce diagnostic accuracy (15).

The evaluation of the long-term clinical risk of stable CAD involves an analysis of a large number of factors in the field of clinical examination and processing of risk factors, relevant previous history data and findings of the current diagnostic workup assuming the application of the clinical management in accordance with applicable clinical practice guidelines or evidence-based medicine. The latest guidelines of the European Society of Cardiology (ESC) of 2013 suggest a high clinical risk, or the justification for additional invasive workup, accompanied by providing an adequate form of revascularization treatment (where possible) for patients with an expected rate of annual complications and major adverse events of ≥3% (5).

Diagnostic and therapeutic clinical question or evaluation of risk rate involves clinical re-evaluation, risk assessment based on the left ventricular ejection fraction, the response to stress test and morphological findings of coronary arteries. Table 2 shows the risk level, based on the diagnostic workup, according to the applicable ESC guidelines.

Primary microvascular disease clinically presents as a typical recurring angina symptoms. The above said disease commonly occurs with diabetes, hypertrophic cardiomyopathy or aortic stenosis, and is understood to be secondary microvascular disease, unlike the stable CAD. Long-term hypertension can sometimes lead to chest pain with normal morphology of epicardial coronary arteries, but the previous studies suggest the well-known case of determined reduced fractional flow reserve (FFR), even without significant left ventricular hypertrophy. Unlike this, hypertensive left ventricular hypertrophy is accompanied by hypertrophy of cardiomyocytes, proliferation of connective tissues, as well as perivascular changes in the intramural flow of coronary circulation with diastolic function disorders (16).

Additional evaluation is required when the imaging or ECG stress test methods suggest CAD, but the result of coronary angiography has excluded fixed or dynamic coronary stenosis in the flow of epicardial coronary arteries (17).

Diagnostics, treatment and prognostic factors of vasospastic angina, which also essentially is not considered as stable CAD are presented in the relevant ESC guidelines.

We have to note that the overall management of ischemic heart disease includes the activities involving early diagnostics and prevention as well as continuous comprehensive measures which must provide a favorable base in the form of chronic risk factor management. In our country, a relatively high prevalence of smoking, suboptimal control of hypertension, dyslipidemia and obesity and adverse socioeconomic profile that are essential challenge in public health terms are still present (18).

The treatment of stable CAD within the scope of evidencebased medicine basically involves the optimization of medical therapy combined with measures of intervention treatment by percutaneous coronary interventions and/or surgical interventions.

The goals of medical therapy of stable CAD include:

Regarding the antiatherosclerotic therapy, the treatment goals include stabilization and regression of known plaques, reduction of systemic inflammatory response of mild intensity and prevention of atherothrombotic complications. Optimal medical therapy of stable coronary artery disease includes several groups of drugs such as: antiplatelet, 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins), beta adrenergic receptor antagonists, nitrates, angiotensin- converting enzyme inhibitors, calcium antagonists, and a group of new anti-ischemic drugs such as ranolazine, trimetazidine and ivabradine (19).

Regarding general therapeutic notes, it is important to stress that within the scope of good medical practice, the treatment of stabile CAD involves the administration of at least two groups of drugs (anti-ischemic and preventive treatment of adverse cardiovascular events). Besides, the patients should be continually studied as to the state of the disease, associated risks, and the evaluation of therapy compliance and the therapeutic efficacy (resistance) should be made at the time of every follow-up.

In addition to statin, the mandatory therapy for prevention of cardiovascular adverse events includes acetylsalicylic acid or clopidogrel in case of intolerance of acetylsalicylates. Although the more recent P2Y antagonists prasugrel and ticagrelor proved in the previous studies to be more therapeutically effective than clopidogrel, the relevant studies primarily in terms of stable CAD are not yet available. The use of dual antiplatelet therapy for stable coronary or atherosclerotic diseases with increased cardiovascular risk (CHARISMA study) did not result in better prevention of major adverse cardiovascular events, but it exposed patients to additional risks of complications, i.e. bleeding (20). On contrary, in case of atherothrombotic complications and acute coronary syndrome the use of dual antiplatelet therapy is beneficial and useful, and is described in the relevant guidelines.

Revascularization treatment, as mentioned earlier, should be taken into consideration in patients with stable CAD and the expected estimated risk rate for cardiovascular events ≥3% per year. Additional clinical re-evaluation is recommended in the intermediate risk classes (≤1 to 3%/year) (5). The decision on the timing and extent of the optimal form of revascularization treatment is to be analyzed by multiprofessional teamwork involving intervention cardiologists, cardiac surgeons and other subspecialties with regard to the clinical issue. Additional risk stratifications have been described in the ESC relevant guidelines considering acute and postacute care settings.