Small Interfering Ribonucleic Acid as Lipid-Lowering Therapy: Inclisiran in Focus.

The PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) enzyme interferes with the metabolism of low-density lipoprotein (LDL) cholesterol. Inhibition of PCSK9 results in lower LDL cholesterol levels, which can be achieved by different molecular pathways. Monoclonal antibodies targeting circulating PCSK9 have shown strong and persistent effects on lowering the LDL cholesterol level, while reducing the risk of future cardiovascular events. However, this therapy requires once- or twice-monthly administration in the form of subcutaneous injection. This dosing regimen might impact the therapy adherence in cardiovascular patients who often require multiple drugs with different dosing intervals. Small interfering ribonucleic acid (siRNA) represents a promising therapy approach for patients with elevated LDL cholesterol level despite optimized background statin therapy. Inclisiran is a synthesized siRNA which inhibits PCSK9 synthesis in the liver and provides sustained and durable lowering of LDL cholesterol with twice-yearly application and a good tolerability profile. Herein, we present an overview of the current available data and critical review of the major clinical trials which assessed safety and efficacy of inclisiran in different groups of patients with elevated LDL cholesterol level.

Blood pressure cut-offs to diagnose impending hypertensive emergency depend on previous hypertension-mediated organ damage and comorbid conditions.

Background Hypertensive emergencies (HTN-E) are important due to a high risk of mortality. However, a sudden increase in blood pressure (BP) can damage target organs before the BP reaches cut-offs to diagnose HTN-E. We (i) analyse HTN guidelines for recommendations of treatment individualization, such as adjusting BP cut-offs for hypertensive urgency or impending HTN-E according to patient's susceptibility to complications (because of previous hypertension-mediated organ damage [HMOD], cardiovascular events and comorbid conditions), and (ii) provide a rationale for the inclusion of patient's susceptibility in protocols for treatment of acute HTN-E. Methods We searched PubMed, SCOPUS, Science Direct, Springer, Oxford Press, Wiley, SAGE and Google Scholar for the following terms: arterial hypertension, impending, emergency, target organ damage, hypertension-mediated organ damage, and comorbidity. Results The available guidelines do not recommend that when we estimate the probability of HTN-E in a patient with very high BP, we take into account not only the 'aggressive factor' (i.e. history of HTN, absolute BP values and rate of its increase), but also the 'vulnerability of the patient' due to previous major adverse cardio-vascular events, HMOD and comorbid conditions. Conclusion The risk does not depend only on the aggressiveness of the health threat but also on the strength of the host's defence. It is, therefore, surprising that one side of the natural interaction (i.e. susceptibility of a patient) is overlooked in almost all available guidelines on HTN.

A Discrepancy: Calcium Channel Blockers Are Effective for the Treatment of Hypertensive Left Ventricular Hypertrophy but Not as Effective for Prevention of Heart Failure.

Arterial hypertension (HTN) is important due to its high prevalence, morbidity, and mortality rates. Calcium channel blockers (CCBs) are the first-line antihypertensive drugs. HTN can lead to heart failure (HF) by causing hypertensive left ventricular hypertrophy (HTN LVH). CCBs are recommended for the treatment of HTN LVH. The aim of this study was to analyze the status of CCBs regarding (1) HTN LVH treatment and (2) capability to prevent HTN-induced HF in the guidelines. For this narrative review, the following databases were searched: Medline, Scopus, Science Direct, Springer, SAGE, Wiley, Oxford Journals, Cambridge, and Google Scholar. CCBs are effective antihypertensive drugs and a very good therapeutic option for HTN LVH as they can cause reverse LVH remodeling. Consequently, we may expect that CCBs would prevent HF. However, evidence suggests that CCBs confer less protection from HF than other first-line antihypertensive drugs. A negative inotropic action of nondihydropyridine CCBs may contribute to suboptimal protection against HF. This discrepancy is clinically relevant because CCBs are in one of the two recommended (single pill) combinations for the initial treatment of HTN. LVH is a strong risk factor for HF in HTN patients. When LVH arises, the risk of HF increases dramatically. CCBs are inferior to renin-angiotensin-aldosterone system blockers but still very effective in bringing about regression of HTN LVH; consequently, CCBs are expected to protect from HF. On the contrary, CCBs protect from HF less effectively than other first-line antihypertensive drugs. This discrepancy needs to be investigated further to improve clinical practice.

Long-term follow-up of patients with chronic total coronary artery occlusion previously randomized to treatment with optimal drug therapy or percutaneous revascularization of chronic total occlusion (COMET-CTO).

Background: The COMET-CTO trial was a randomized prospective study that assessed long-term follow-up in patients with chronic total occlusion (CTO) in coronary arteries treated with percutaneous coronary intervention (PCI) or with optimal medical therapy (OMT). During the 9-month follow-up, the incidence of major adverse cardiac events (MACE) did not differ between the two groups; no death or myocardial infarction (MI) was observed. There was a significant difference in quality of life (QoL), assessed by the Seattle Angina Questionnaire (SAQ), in favor of the PCI group. Here we report long-term follow-up results (56 ± 12 months). Methods: Between October 2015 and May 2017, a total of 100 patients with CTO were randomized into two groups of 50 patients: PCI CTO or OMT group. The primary endpoint of the current study was the incidence of MACE defined as cardiac death, MI, and revascularization [PCI or coronary artery bypass graft (CABG)]. As the secondary exploratory outcome, we analyzed all the cause-mortality rate. Results: Out of 100 randomized patients, 92 were available for long-term follow-up (44 in the PCI group and 48 in the OMT group). The incidence of MACE did not differ significantly between the two groups (p = 0.363). Individual components of MACE were distributed, respectively: cardiac death (OMT vs. PCI group, 6 vs. 3, p = 0.489), MI (OMT vs. PCI group, 1 vs. 0, p = 1), and revascularization (PCI: OMT vs. PCI group, 2 vs. 2, p = 1; CABG: OMT vs. PCI group, 1 vs. 1, p = 1). There was no significant difference between the two groups regarding the individual component of MACE. Six patients died from non-cardiac causes [five deaths were reported in the OMT group and one death in the PCI group (p = 0.206)]. Kaplan-Meier survival curves for MACE did not differ significantly between the study groups (log-rank 0.804, p = 0.370). Regarding the secondary exploratory outcome, a total of 15 patients died at 56 ± 12 months (11 in the OMT and 4 in the PCI group) (p = 0.093). The Kaplan-Meier survival curves for all-cause mortality rates did not differ significantly between the two groups (log rank 3.404, p = 0.065). There were no statistically significant differences between OMT and PCI groups in all five SAQ domains. There was a significant improvement in three SAQ domains in the PCI group: PL (p < 0.001), AF (p = 0.007), and QoL (p = 0.001). Conclusion: After 56 ± 12 months of follow-up, the incidence of MACE, as well as QoL measured by SAQ, did not differ significantly between the PCI and OMT groups.

Prognostic Value of Transthoracic Doppler Echocardiography Coronary Flow Velocity Reserve in Patients With Asymmetric Hypertrophic Cardiomyopathy.

Background Microvascular dysfunction might be a major determinant of clinical deterioration and outcome in patients with hypertrophic cardiomyopathy (HCM). However, long-term prognostic value of transthoracic Doppler echocardiography (TDE) coronary flow velocity reserve (CFVR) on clinical outcome is uncertain in HCM patients. Therefore, the aim of our study was to assess long-term prognostic value of CFVR on clinical outcome in HCM population. Methods and Results We prospectively included 150 HCM patients (82 women; mean age 48±15 years). Patients' clinical characteristics, echocardiographic and CFVR findings (both for left anterior descending [LAD] and posterior descending artery [PD]), were assessed in all patients. The primary outcome was a composite of: HCM related death, heart failure requiring hospitalization, sustained ventricular tachycardia and ischemic stroke. Patients were stratified into 2 subgroups depending on CFVR LAD value: Group 1 (CFVR LAD>2, [n=87]) and Group 2 (CFVR LAD≤2, [n=63]). During a median follow-up of 88 months, 41/150 (27.3%) patients had adverse cardiac events. In Group 1, there were 8/87 (9.2%), whereas in Group 2 there were 33/63 (52.4%, P<0.001 vs. Group 1) adverse cardiac events. By Kaplan-Meier analysis, patients with preserved CFVR LAD had significantly higher cumulative event-free survival rate compared to patients with impaired CFVR LAD (96.4% and 90.9% versus 66.9% and 40.0%, at 5 and 8 years, respectively: log-rank 37.2, P<0.001). Multivariable analysis identified only CFVR LAD≤2 as an independent predictor for adverse cardiac outcome (HR 6.54; 95% CI 2.83-16.30, P<0.001), while CFVR PD was not significantly associated with outcome. Conclusions In patients with HCM, impaired CFVR LAD (≤2) is a strong, independent predictor of adverse cardiac outcome. When the aim of testing is HCM risk stratification and CFVR LAD data are available, the evaluation of CFVR PD is redundant.

Functional Assessment of Myocardial Bridging With Conventional and Diastolic Fractional Flow Reserve: Vasodilator Versus Inotropic Provocation.

Background Functional assessment of myocardial bridging (MB) remains clinically challenging because of the dynamic nature of the extravascular coronary compression with a certain degree of intraluminal coronary reduction. The aim of our study was to assess performance and diagnostic value of diastolic-fractional flow reserve (d-FFR) during dobutamine provocation versus conventional-FFR during adenosine provocation with exercise-induced myocardial ischemia as reference. Methods and Results This prospective study includes 60 symptomatic patients (45 men, mean age 57±9 years) with MB on the left anterior descending artery and systolic compression ≥50% diameter stenosis. Patients were evaluated by exercise stress-echocardiography test, and both conventional-FFR and d-FFR in the distal segment of left anterior descending artery during intravenous infusion of adenosine (140 µg/kg per minute) and dobutamine (10-50 µg/kg per minute), separately. Exercise-stress-echocardiography test was positive for myocardial ischemia in 19/60 patients (32%). Conventional-FFR during adenosine and peak dobutamine had similar values (0.84±0.04 versus 0.84±0.06, P=0.852), but d-FFR during peak dobutamine was significantly lower than d-FFR during adenosine (0.76±0.08 versus 0.79±0.08, P=0.018). Diastolic-FFR during peak dobutamine was significantly lower in the exercise-stress-echocardiography test -positive group compared with the exercise- stress-echocardiography test -negative group (0.70±0.07 versus 0.79±0.06, P<0.001), but not during adenosine (0.79±0.07 versus 0.78±0.09, P=0.613). Among physiological indices, d-FFR during peak dobutamine was the only independent predictor of functionally significant MB (odds ratio, 0.870; 95% CI, 0.767-0.986, P=0.03). Receiver-operating characteristics curve analysis identifies the optimal d-FFR during peak dobutamine cut-off ≤0.76 (area under curve, 0.927; 95% CI, 0.833-1.000; P<0.001) with a sensitivity, specificity, and positive and negative predictive value of 95%, 95%, 90%, and 98%, respectively, for identifying MB associated with stress-induced ischemia. Conclusions Diastolic-FFR, but not conventional-FFR, during inotropic stimulation with high-dose dobutamine, in comparison to vasodilatation with adenosine, provides more reliable functional significance of MB in relation to stress-induced myocardial ischemia.

Randomized Controlled Comparison of Optimal Medical Therapy with Percutaneous Recanalization of Chronic Total Occlusion (COMET-CTO).

The aim of this randomized prospective study was to evaluate the quality of life (QoL) using the "Seattle Angina Questionnaire" (SAQ) in patients with chronic total occlusion (CTO) in coronary arteries treated with either percutaneous coronary intervention (PCI) or optimal medical therapy (OMT), or only with OMT.The potential benefits of recanalization of CTO by PCI have been controversial because of the scarcity of randomized controlled trials.A total of 100 patients with CTO were randomized (1:1) prospectively into the PCI CTO or the OMT group (50 patients in each group). There were no baseline differences in the SAQ scores between the groups, except for physical limitation scores (P = 0.03). During the mean follow-up (FUP) of 275 ± 88 days, patients in the PCI group reported less physical activity limitations (72.7 ± 21.3 versus 60.5 ± 27, P = 0.014), less frequent angina episodes (89.8 ± 17.6 versus 76.8 ± 27.1, P = 0.006), better QoL (79.9 ± 22.7 versus 62.5 ± 25.5, P = 0.001), greater treatment satisfaction (91.2 ± 13.6 versus 81.4 ± 18.4, P = 0.003), and borderline differences in angina stability (61.2 ± 26.5 versus 51.0 ± 23.7, P = 0.046) compared to patients in the OMT group. There were no significant differences in SAQ scores in the OMT group at baseline and during the FUP. There was a statistically significant increase in all five domains in the PCI group.Symptoms and QoL measured by the SAQ were significantly improved after CTO PCI compared to OMT alone.

Coronary Flow Velocity Reserve Using Dobutamine Test for Noninvasive Functional Assessment of Myocardial Bridging.

BACKGROUND: It has been shown that coronary flow velocity reserve (CFVR) measurement by transthoracic Doppler echocardiography (TTDE) during dobutamine (DOB) provocation provides a more accurate functional evaluation of myocardial bridging (MB) compared to adenosine. However; the cut-off value of CFVR during DOB for identification of MB associated with myocardial ischemia has not been fully clarified. PURPOSE: This prospective study aimed to determine the cut-off value of TTDE-CFVR during DOB in patients with isolated-MB, as compared with stress-induced wall motion abnormalities (VMA) during exercise stress-echocardiography (SE) as reference. METHODS: Eighty-one symptomatic patients (55 males [68%], mean age 56 ± 10 years; range: 27-74 years) with the existence of isolated-MB on the left anterior descending artery (LAD) and systolic MB-compression ≥50% diameter stenosis (DS) were eligible to participate in the study. Each patient underwent treadmill exercise-SE, invasive coronary angiography, and TTDE-CFVR measurements in the distal segment of LAD during DOB infusion (DOB: 10-40 µg/kg/min). Using quantitative coronary angiography, both minimal luminal diameter (MLD) and percent DS at MB-site at end-systole and end-diastole were determined. RESULTS: Stress-induced myocardial ischemia with the occurrence of WMA was found in 23 patients (28%). CFVR during peak DOB was significantly lower in the SE-positive group compared with the SE-negative group (1.94 ± 0.16 vs. 2.78 ± 0.53; p < 0.001). ROC analyses identified the optimal CFVR cut-off value ≤ 2.1 obtained during high-dose dobutamine (>20 µg/kg/min) for the identification of MB associated with stress-induced WMA, with a sensitivity, specificity, positive and negative predictive value of 96%, 95%, 88%, and 98%, respectively (AUC 0.986; 95% CI: 0.967-1.000; p < 0.001). Multivariate logistic regression analysis revealed that MLD and percent DS, both at end-diastole, were the only independent predictors of ischemic CFVR values ≤2.1 (OR: 0.023; 95% CI: 0.001-0.534; p = 0.019; OR: 1.147; 95% CI: 1.042-1.263; p = 0.005; respectively). CONCLUSIONS: Noninvasive CFVR during dobutamine provocation appears to be an additional and important noninvasive tool to determine the functional severity of isolated-MB. A transthoracic CFVR cut-off ≤2.1 measured at a high-dobutamine dose may be adequate for detecting myocardial ischemia in patients with isolated-MB.

Single prognostic cut-off value for admission glycemia in acute myocardial infarction has been used although high-risk stems from hyperglycemia as well as from hypoglycemia (a narrative review).

All original articles and meta-analysis use the single cut-off value to distinguish high-risk hyperglycemic from other acute myocardial infarction (AMI) patients. The mortality rate is 3.9 times higher in non-diabetic AMI patients with admission glycemia ≥6.1mmol compared to normoglycemic non-diabetic AMI patients. On the other hand, admission hypoglycemia in AMI is an important predictor of mortality. Because both admission hypo- and hyperglycemia correspond to higher in-hospital mortality, this graph is recognized as "J or U shaped curve". The review suggests two cut-off values for admission glycemia for risk assessment in AMI instead of single one because hypoglycemia as well as hyperglycemia represents a high-risk factor.

Prompt and consistent improvement of coronary flow velocity reserve following successful recanalization of the coronary chronic total occlusion in patients with viable myocardium.

BACKGROUND: Coronary chronic total occlusion (CTO) is characterized by the presence of collateral blood vessels which can provide additional blood supply to CTO-artery dependent myocardium. Successful CTO recanalization is followed by significant decrease in collateral donor artery blood flow and collateral derecruitment, but data on coronary hemodynamic changes in relation to myocardial function are limited. We assessed changes in coronary flow velocity reserve (CFVR) by echocardiography in collateral donor and recanalized artery following successful opening of coronary CTO. METHODS: Our study enrolled 31 patients (60 ± 9 years; 22 male) with CTO and viable myocardium by SPECT scheduled for percutaneous coronary intervention (PCI). Non-invasive CFVR was measured in collateral donor artery before PCI, 24 h and 6 months post-PCI, and 24 h and 6 months in recanalized artery following successful PCI of CTO. RESULTS: Collateral donor artery showed significant increase in CFVR 24 h after CTO recanalization compared to pre-PCI values (2.30 ± 0.49 vs. 2.71 ± 0.45, p = 0.005), which remained unchanged after 6-months (2.68 ± 0.24). Baseline blood flow velocity of the collateral donor artery significantly decreased 24 h post-PCI compared to pre-PCI (0.28 ± 0.06 vs. 0.24 ± 0.04 m/s), and remained similar after 6 months, with no significant difference in maximum hyperemic blood flow velocity pre-PCI, 24 h and 6 months post-PCI. CFVR of the recanalized coronary artery 24 h post-PCI was 2.55 ± 0.35, and remained similar 6 months later (2.62 ± 0.26, p = NS). CONCLUSIONS: In patients with viable myocardium, prompt and significant CFVR increase in both recanalized and collateral donor artery, was observed within 24 h after successful recanalization of CTO artery, which maintained constant during the 6 months. TRIAL REGISTRATION: ClinicalTrials.gov (Number NCT04060615 ).

Impairment of coronary flow velocity reserve and global longitudinal strain in women with cardiac syndrome X and slow coronary flow.

BACKGROUND: Microvascular dysfunction (MVD) is associated with adverse prognosis and may account for abnormal stress tests and angina symptoms in women with cardiac syndrome X (CSX). The aim of our study was to assess MVD by coronary flow velocity reserve (CFVR) and left ventricular (LV) contractile function by LV global longitudinal strain (LVGLS) in CSX patients with respect to presence of slow coronary flow (SCF). It was of additional importance to evaluate clinical status of CSX patients using Seattle Angina Questionnaire. METHODS AND RESULTS: Study population included 70 women with CSX (mean age 61 ± 7 years) and 34 age-matched controls. CSX group was stratified into two subgroups depending on SCF presence: CSX-Thrombolysis In Myocardial Infarction (TIMI) 3- normal flow subgroup (n = 38) and CSX-TIMI 2- SCF subgroup (n = 32) as defined by coronary angiography. LVGLS measurements and CFVR of left anterior descending (LAD) and posterior descending (PD) artery were performed. CFVR-LAD and PD were markedly impaired in CSX group compared to controls (2.34 ± 0.25 vs 3.05 ± 0.21, p < 0.001; 2.32 ± 0.24 vs 3.01 ± 0.13, p < 0.001), and furthermore decreased in CSX-TIMI 2 patients. Resting, peak, and ΔLVGLS were all significantly impaired in CSX group compared to controls (for all p < 0.001), and furthermore reduced in CSX-TIMI 2 subgroup. Strongest correlation was found between peak LVGLS and CFVR LAD (r = -0.784, p < 0.001) and PD (r = -0.772, p < 0.001). CSX-TIMI 2 subgroup had more frequent angina symptoms and more impaired quality of life. CONCLUSIONS: MVD in CSX patients is demonstrated by reduction in CFVR and LVGLS values. SCF implies more profound impairment of microvascular and LV systolic function along with worse clinical presentation.

Unsolved Problem: (Isolated) Systolic Hypertension with Diastolic Blood Pressure below the Safety Margin.

The problem of high systolic blood pressure (sBP) combined with low diastolic blood pressure (dBP) requires attention because sBP is directly and continuously related to the most important criterion, i.e., all-cause mortality, whereas dBP becomes inversely related to it after the age of 50-60 years. The European Society of Cardiology and European Society of -Hypertension (ESC/ESH) 2018 guidelines for hypertension (HTN) are helpful because they recommend a lower safety cut-off for in-treatment dBP. To prevent tissue hypoperfusion, these guidelines recommend that dBP should be ≥70 mm Hg during treatment. A patient with very elevated sBP (e.g., 220 mm Hg) and low dBP (e.g., 65 mm Hg) is difficult to treat if one strictly follows the guidelines. In this situation, the sBP is a clear indication for antihypertensive treatment, but the dBP is a relative contraindication (as it is <70 mm Hg, a safety margin recognized by the 2018 ESC/ESH guidelines). The dilemma about whether or not to treat isolated systolic hypertension (SH) patients with low dBP (<70 mm Hg) is evident from the fact that almost half (45%) remain untreated. This is a common occurrence and identifying this problem is the first step to solving it. We suggest that an adequate search and analysis should be performed, starting from the exploration of the prognosis of the isolated (I)SH subset of patients with a very low dBP (<70 mm Hg) at the beginning of already performed randomized clinical trials.

Beta blocker rebound phenomenon is important, but we do not know its definition, incidence or optimal prevention strategies.

The aim of this review is to analyze whether there is a need for scientific information about the beta blocker (BB) rebound phenomenon; whether such information is available; and, if it is, how detailed is the BB rebound phenomenon explained in the guidelines and papers? A narrative review is used due to the lack of valid randomized clinical trials (RCTs) on the topic, which are needed for a meta-analysis. The BB rebound phenomenon can have dangerous consequences. The discontinuation of a BB leads to a fourfold increased risk of events related to coronary artery disease in hypertensive patients; it increases in-hospital mortality in heart failure patients; it can precipitate angina pectoris attack; and it increases the risk for death and rehospitalization in patients who survive acute myocardial infarction. Consequently, being considered in the guidelines, the BB rebound phenomenon is believed to be clinically relevant (by experts in the field). This is in sharp contrast with the lack of any additional relevant information about the BB rebound phenomenon in the various important guidelines. For example, we lack a consensus about the precise definition. Moreover, data about the incidence and optimal prevention strategies are lacking for the phenomenon (which is sometimes life-threatening). The BB rebound phenomenon is an additional reason why it is very important to test the prognosis of patients following the cessation of long-term medicaments in RCTs, particularly for BBs.

Improved Propensity-Score Matched Long-Term Clinical Outcomes in Patients with Successful Percutaneous Coronary Interventions of Coronary Chronic Total Occlusion.

The objective of the study was to evaluate major adverse cardiovascular events (MACE) after successful versus failed percutaneous coronary intervention for chronic total occlusion (PCI-CTO).Limited data are available on long-term clinical follow-up in the treatment of chronic total occlusion (CTO).Between January 2009 and December 2010 PCI-CTO was attempted in 283 consecutive patients with 289 CTO lesions. Procedural success was 62.3% and clinical follow-up covered 83% (235/283) of the study population with a median follow-up of 66 months (range, 59-74).The total incidence of MACE was 57/235 (24.3%), and was significantly higher in the procedural failure group than in the procedural success group (33/87 (37.9%) versus 24/148 (16.2%), P < 0.001). All-cause mortality was significantly lower in patients with successful PCI-CTO compared to failed PCI-CTO (10.8% versus 20.7%, P < 0.05). Also, the rate of cardiovascular death in the procedural failure group (14.9%) was slightly higher than that in the procedural success group (7.4%, P = 0.066). The rate of TVR was statistically higher in the procedural failure group (P < 0.009). Propensity score-adjusted Cox regression showed that procedural success remained a significant predictor of MACE (adjusted HR 0.402; 95% CI 0.196-0.824; P = 0.013).Our study emphasizes the importance of CTO recanalization in improving long-term outcome including all-cause mortality with a borderline effect on cardiovascular mortality.

Endothelial cell markers from clinician's perspective.

Endothelial cell markers are membrane-bound or cytoplasmic molecules expressed by endothelial cells, which help their easier identification and discrimination from other cell types. During vasculogenesis, endothelial cells differentiate from hemangioblasts to form new blood vessels. With the discovery of endothelial progenitor cells (EPC) and their ability to form new blood vessels, the term vasculogenesis is not only reserved for the embryonic development. Possibility of de novo blood vessel formation from EPC is now widely explored in different ischemic conditions, especially in cardiovascular medicine. Numerous clinical trials have tested enhancing tissue vascularization by delivering hematopoietic cells that expressed endothelial markers. This therapeutic approach proved to be challenging and promising, particularly for patients who have exhausted all conventional therapeutic modalities. Angiogenesis, which refers to the formation of new blood vessels from existing vasculature, is indispensable process during tumor progression and metastasis. Blockage of tumor angiogenesis by targeting and inhibiting endothelial cell has emerged as novel safe and efficacious method to control many advanced malignant diseases. Numerous clinical studies are currently testing new antiangiogenic drugs which target and inhibit endothelial cell markers, receptors or molecules which transmit receptor-mediated signals, therefore inhibiting endothelial cell proliferation, migration and vascular tube formation. Many of these drugs are now widely used in clinical settings as first- or second-line chemotherapy in advanced malignant conditions. So far, these therapeutic approaches gave modest, yet encouraging clinical improvements, prolonging survival and improving functional capacity and quality of life for many terminally ill patients. Here we present the most commonly used endothelial cell markers along with their applicability in contemporary clinical practice.

Noninvasive assessment of myocardial bridging by coronary flow velocity reserve with transthoracic Doppler echocardiography: vasodilator vs. inotropic stimulation.

BACKGROUND: To consider hemodynamic assessment of myocardial bridging (MB) adequate, it is believed that inotropic stimulation with dobutamine should be estimated because its dynamic nature depends on the degree of extravascular coronary compression. This study evaluated comparative assessment of hemodynamic relevance of MB using coronary flow velocity reserve (CFVR) measurements by transthoracic Doppler echocardiography (TTDE) with vasodilatative and inotropic challenges. METHODS: This prospective study included forty-four patients with angiographic evidence of isolated MB of the left anterior descending coronary artery (LAD) and systolic compression of ≥50% diameter stenosis. All patients were evaluated by exercise stress-echocardiography (ExSE) test for signs of myocardial ischemia, and CFVR of the distal segment of LAD during iv.infusion of adenosine (ADO:140µg/kg/min) and iv.infusion of dobutamine (DOB:10-40µg/kg/min), separately. RESULTS: Exercise-SE was positive for myocardial ischemia in 8/44 (18%) of patients. CFVR during ADO was significantly higher than CFVR during peak DOB (2.85±0.68 vs. 2.44±0.48, p=0.002). CFVR during peak DOB was significantly lower in SE-positive group in comparison to SE-negative group (2.01±0.16 vs. 2.54±0.47, p<0.001), but not for ADO (2.47±0.51 vs. 2.89±0.70, p=0.168), respectively. Multivariable logistic analysis showed that CFVR peak DOB was the most significant predictor of functional significant MB (OR 0.011, 95%CI: 0.001-0.507, p=0.021). Receiver-operating characteristic curves have shown that TTDE-CFVR obtained by high-dose of dobutamine infusion is better than those by adenosine regarding to functional status of MB (AUC 0.861, p=0.004; AUC 0.674, p=0.179, respectively). CONCLUSIONS: Non-invasive CFVR measurement by TTDE during inotropic stimulation, in comparison to vasodilation, provides more reliable functional evaluation of MB.

Prediction of coronary plaque location on arteries having myocardial bridge, using finite element models.

This study was performed to evaluate the influences of the myocardial bridges on the plaque initializations and progression in the coronary arteries. The wall structure is changed due to the plaque presence, which could be the reason for multiple heart malfunctions. Using simplified parametric finite element model (FE model) of the coronary artery having myocardial bridge and analyzing different mechanical parameters from blood circulation through the artery (wall shear stress, oscillatory shear index, residence time), we investigated the prediction of "the best" position for plaque progression. We chose six patients from the angiography records and used data from DICOM images to generate FE models with our software tools for FE preprocessing, solving and post-processing. We found a good correlation between real positions of the plaque and the ones that we predicted to develop at the proximal part of the myocardial bridges with wall shear stress, oscillatory shear index and residence time. This computer model could be additional predictive tool for everyday clinical examination of the patient with myocardial bridge.