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.

Introduction: Landmark ISCHEMIA (ISCH) trial provided unique information, but the generalizability of its results into myocardial revascularization guidelines and practice has been met by unprecedented debate. Hypothesis: We aimed to compare the 5 year all-cause mortality (5y Mt) in our ISCH trial like patients (pts) with results in ISCH. Methods: After applying ISCH study inclusion/exclusion criteria we identified 854 pts from our prospective database of 2455 consecutive pts who had the first isolated CABG in 2012-2015 with complex CAD with 100% follow up (F-up) of 5y Mt. Results: Comparative characteristics of ISCH like and actual ISCH pts are presented in Table 1. Аll our pts underwent CABG, contrary to ISCH where CABG and PCI were used in 538 and 1532 pts, consecutively. Although in ISCH pts had high diversity of ethnicity, were older, had more DM2 (but less insulin dependent), and had previous PCI or CABG in 25%, our pts were strikingly sicker (lower LVEF, higher proportion of 3VD and proximal LAD, higher NYHA as well as more comorbidities) 5-year mortality was 8.9% compared to 9% in the Invasive arm of ISCH. Of note 48 h mortality from MI type 5 (post CABG) was 1.67% in ISCH, and 30-day Mt in our study was 1.30%, with complete revascularization in 95%. As expected by the disease severity treated by CABG early Mt was higher in our than ISCH pts (Figure 1). Conclusion: The present study findings outline that translation of results from the ISCHEMIA trial with practice-changing implications into recommendations for a local Heart Team discussion to advise the best treatment decision for patients with more complex forms of CAD is uncertain and requires further research activities.

Metabolic syndrome (Met Sy) as a highly debatable cluster of traditional risk factors is known to promote cardiometabolic-related morbidity and mortality, but its precise mechanisms remain to be determined. We sought to determine influence of MetSy on heart failure (HF) morbidity and mortality in the Seven Countries' Study as one of the oldest epidemiological studies. The Seven Countries Study encompassed 12,763 participants from 3 continents who were all healthy men of over 40 years at baseline and who underwent regular check ups every 5 years throughout over a 4 decades' span. Morbidity and mortality was adjudicated according to valid ICD and LPH coding. Using the IDF definition of the Metabolic Syndrome, 9,09% of participants were identified (Figure 1). HF was confirmed in 220 patients (16.4% alive at 40y follow up visit), while 8.2% died of HF as well in the same time-frame (Tables 1 & 2). Presence of MetSy has been shown to significantly influence HF mortality (Figures 2) with lowest survival of 22% for 300 months of follow up for patients with both MetSy and HF (Log rank test=4.405, p<0.0001). Metabolic syndrome treatment remains in the realm of risk factors' control that now we know influence both ischemic heart disease and heart failure of other origins. Historically, just emerging biomarkers' and targeted imaging weren't available to determine such at the time of HF diagnosis. Also, the sample consisted of men only, mainly Caucasian and a modest proportion of Asian and African-American now known to carry ethnic-specific burden of cardiovascular disease. All of the above, emphasizes the importance of more diversity, equity and inclusion-dedicated long term both observational, as well as interventional research. Type of funding sources: None.

Background The uneven lipid-lowering statin effects and statin intolerance raise interest regarding the involvement of coadministration of statins and dietary supplements. This study aimed to evaluate the effects of octacosanol supplementation on markers of redox status in cardiovascular patients on chronic atorvastatin therapy. Methods A double-blind, randomized, placebo-controlled, single-centre study was conducted. Redox status homeostasis parameters [i.e., advanced oxidation protein products (AOPP), pro-oxidant-antioxidant balance (PAB), total oxidant status (TOS), total antioxidant status (TAS), superoxide dismutase activity (SOD), total protein sulfhydryl (SHgroups), and paraoxonase 1 (PO N 1) activity] were assessed in 81 patients. According to favorable changes in lipid profile, patients were classified into two groups: responders (n = 35) and non-responders (n = 46), and followed for 13 weeks. A principal component analysis (PCA) was applied to explore the effect of octacosanol supplementation and the relationship between investigated parameters as predictors of responders' and non-responders' status. Results Significant decrease in Oxy-score value was found at the endpoint compared to baseline in responders' group (21.0 (13.4-25.5) versus 15.1 (12.4-18.0); P < 0.01). PCA analysis extracted 4 significant factors in the both groups, whereas extracted factors containing "octacosanol status" variable explained 14.7% and 11.5% of the variance in responders' and non-responders' subgroups, respectively. Conclusions Octacosanol supplementation leads to an improvement of lipid profile and markers of redox status in responders' group. New studies are needed to validate our results in order to find the best approach for personalized supplementation as a useful adjunct to standard statin therapy.

Evidence-based Clinical Guidelines (CGs) for Good Clinical Practice (GCP) have emerged to synthesize and systematize a wealth of knowledge from scientific journals that health professionals have been unable to follow. Today, the COVID 19 pandemic requires them more than ever. CGs are defined as a set of systematized claims, based on a systematic analysis of scientific evidence, that point to the performance of GCP; contain an assessment of the usefulness and harmfulness of various diagnostic and therapeutic options. "The Good": CG is necessary for health professionals, patients and society, because the knowledge gained in studies is insufficient to perform GCP in further practice. "The Bad": The shortcomings of the CG stem from; (a) there are still many unknowns in medicine, as funding for scientific research is inadequate; (b) the disunity of different institutions that make recommendations at the global, even local level results in different guidelines, although they are based on identical scientific papers as evidence; (c) most clinical scientific studies exclude groups of patients that make up a significant population in everyday practice and the guidelines more or less (do not) apply to them; (d) the impossibility of implementing the CG, because they are not backed by state regulatory bodies and / or the economy cannot follow them. "The Ugly": (a) the ambition of a large number of practitioners and researchers to be among the authors of the guidelines, although many do not have competence for the subject matter; (b) industry (equipment, drugs, supplements) most often funds scientific research and the interdependence of industry and the "dependence" of the authors of guidelines is often intertwined; and (c) publishing (un) intentionally falsified study results which then serve to "support" some guidelines. often in (un) intentional alliance with the editors of the world's elite medical journals.

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.

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.

With stress echo (SE) 2020 study, a new standard of practice in stress imaging was developed and disseminated: the ABCDE protocol for functional testing within and beyond CAD. ABCDE protocol was the fruit of SE 2020, and is the seed of SE 2030, which is articulated in 12 projects: 1-SE in coronary artery disease (SECAD); 2-SE in diastolic heart failure (SEDIA); 3-SE in hypertrophic cardiomyopathy (SEHCA); 4-SE post-chest radiotherapy and chemotherapy (SERA); 5-Artificial intelligence SE evaluation (AI-SEE); 6-Environmental stress echocardiography and air pollution (ESTER); 7-SE in repaired Tetralogy of Fallot (SETOF); 8-SE in post-COVID-19 (SECOV); 9: Recovery by stress echo of conventionally unfit donor good hearts (RESURGE); 10-SE for mitral ischemic regurgitation (SEMIR); 11-SE in valvular heart disease (SEVA); 12-SE for coronary vasospasm (SESPASM). The study aims to recruit in the next 5 years (2021–2025) ≥10,000 patients followed for ≥5 years (up to 2030) from ≥20 quality-controlled laboratories from ≥10 countries. In this COVID-19 era of sustainable health care delivery, SE2030 will provide the evidence to finally recommend SE as the optimal and versatile imaging modality for functional testing anywhere, any time, and in any patient.

Background: Two-dimensional volumetric exercise stress echocardiography (ESE) provides an integrated view of left ventricular (LV) preload reserve through end-diastolic volume (EDV) and LV contractile reserve (LVCR) through end-systolic volume (ESV) changes. Purpose: To assess the dependence of cardiac reserve upon LVCR, EDV, and heart rate (HR) during ESE. Methods: We prospectively performed semi-supine bicycle or treadmill ESE in 1344 patients (age 59.8 ± 11.4 years; ejection fraction = 63 ± 8%) referred for known or suspected coronary artery disease. All patients had negative ESE by wall motion criteria. EDV and ESV were measured by biplane Simpson rule with 2-dimensional echocardiography. Cardiac index reserve was identified by peak-rest value. LVCR was the stress-rest ratio of force (systolic blood pressure by cuff sphygmomanometer/ESV, abnormal values ≤2.0). Preload reserve was defined by an increase in EDV. Cardiac index was calculated as stroke volume index * HR (by EKG). HR reserve (stress/rest ratio) <1.85 identified chronotropic incompetence. Results: Of the 1344 patients, 448 were in the lowest tertile of cardiac index reserve with stress. Of them, 303 (67.6%) achieved HR reserve <1.85; 252 (56.3%) had an abnormal LVCR and 341 (76.1%) a reduction of preload reserve, with 446 patients (99.6%) showing ≥1 abnormality. At binary logistic regression analysis, reduced preload reserve (odds ratio [OR]: 5.610; 95% confidence intervals [CI]: 4.025 to 7.821), chronotropic incompetence (OR: 3.923, 95% CI: 2.915 to 5.279), and abnormal LVCR (OR: 1.579; 95% CI: 1.105 to 2.259) were independently associated with lowest tertile of cardiac index reserve at peak stress. Conclusions: Heart rate assessment and volumetric echocardiography during ESE identify the heterogeneity of hemodynamic phenotypes of impaired chronotropic, preload or LVCR underlying a reduced cardiac reserve.

Background We are facing the outburst of coronavirus disease 2019 (COVID-19) defined as a serious, multisystem, disorder, including various neurological manifestations in its presentation. So far, autonomic dysfunction (AD) has not been reported in patients with COVID-19 infection. Aim Assessment of AD in the early phase of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus). Patients and methods We analyzed 116 PCR positive COVID-19 patients. After the exclusion of 41 patients with associate diseases (CADG), partitioned to patients with diabetes mellitus, hypertension, and syncope, the remaining patients were included into a severe group (45 patients with confirmed interstitial pneumonia) and mild group (30 patients). Basic cardiovascular autonomic reflex tests (CART) were performed, followed by beat-to-beat heart rate variability (HRV) and systolic and diastolic blood pressure variability (BPV) analysis, along with baroreceptor sensitivity (BRS). Non-linear analysis of HRV was provided by Poincare Plot. Results were compared to 77 sex and age-matched controls. Results AD (sympathetic, parasympathetic, or both) in our study has been revealed in 51.5% of severe, 78.0% of mild COVID-19 patients, and the difference compared to healthy controls was significant (p = 0.018). Orthostatic hypotension has been established in 33.0% COVID-19 patients compared to 2.6% controls (p = 0.001). Most of the spectral parameters of HRV and BPV confirmed AD, most prominent in the severe COVID-19 group. BRS was significantly lower in all patients (severe, mild, CADG), indicating significant sudden cardiac death risk. Conclusion Cardiovascular autonomic neuropathy should be taken into account in COVID-19 patients’ assessment. It can be an explanation for a variety of registered manifestations, enabling a comprehensive diagnostic approach and further treatment.

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.

Background In ST‐segment–elevation myocardial infarction, angiography‐based complete revascularization is superior to culprit‐lesion‐only percutaneous coronary intervention. Quantitative flow ratio (QFR) is a novel, noninvasive, vasodilator‐free method used to assess the hemodynamic significance of coronary stenoses. We aimed to investigate the incremental value of QFR over angiography in nonculprit lesions in patients with ST‐segment–elevation myocardial infarction undergoing angiography‐guided complete revascularization. Methods and Results This was a retrospective post hoc QFR analysis of untreated nontarget vessels (any degree of diameter stenosis [DS]) from the randomized multicenter COMFORTABLE AMI (Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST‐Elevation Myocardial Infarction) trial by assessors blinded for clinical outcomes. The primary end point was cardiac death, spontaneous nontarget vessel myocardial infarction, and clinically indicated nontarget vessel revascularization (ie, ≥70% DS by 2‐dimensional quantitative coronary angiography or ≥50% DS and ischemia) at 5 years. Of 1161 patients with ST‐segment–elevation myocardial infarction, 946 vessels in 617 patients were analyzable by QFR. At 5 years, the rate of the primary end point was significantly higher in patients with QFR ≤0.80 (n=35 patients, n=36 vessels) versus QFR >0.80 (n=582 patients, n=910 vessels) (62.9% versus 12.5%, respectively; hazard ratio [HR], 7.33 [95% CI, 4.54–11.83], P<0.001), driven by higher rates of nontarget vessel myocardial infarction (12.8% versus 3.1%, respectively; HR, 4.38 [95% CI, 1.47–13.02], P=0.008) and nontarget vessel revascularization (58.6% versus 7.7%, respectively; HR, 10.99 [95% CI, 6.39–18.91], P<0.001) with no significant differences for cardiac death. Multivariable analysis identified QFR ≤0.80 but not ≥50% DS by 3‐dimensional quantitative coronary angiography as an independent predictor of the primary end point. Results were consistent, including only >30% DS by 3‐dimensional quantitative coronary angiography. Conclusions Our study suggests incremental value of QFR over angiography‐guided percutaneous coronary intervention for nonculprit lesions among patients with ST‐segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention.

Dietary supplementation with sugar cane derivates may modulate low-density lipoprotein cholesterol (LDL-C) and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. The purpose of this study was to determine if dietary supplement (DS), containing Octacosanol (20 mg) and vitamin K2 (45 µg), could restore the disrupted physiologic relation between LDL-C and serum PCSK9. Double-blind, randomized, placebo-controlled, single-center study including 87 patients on chronic atorvastatin therapy was conducted. Eighty-seven patients were randomized to receive DS (n = 42) or placebo (n = 45), and followed for 13 weeks. Serum PCSK9 levels, lipid parameters and their relationship were the main efficacy endpoints. The absolute levels of PCSK9 and LDL-C were not significantly different from baseline to 13 weeks. However, physiologic correlation between % change of PCSK9 and % change of LDL-C levels was normalized only in the group of patients treated with DS (r = 0.409, p = 0.012). This study shows that DS can restore statin disrupted physiologic positive correlation between PCSK9 and LDL-C. Elevated PCSK9 level is an independent risk factor so controlling its rise by statins may be important in prevention of cardiovascular events.

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.