Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

Influence of atrial fibrillation on efficacy and safety of omecamtiv mecarbil in heart failure: the GALACTIC-HF trial.

AIMS: In GALACTIC-HF, the cardiac myosin activator omecamtiv mecarbil compared with placebo reduced the risk of heart failure events or cardiovascular death in patients with heart failure with reduced ejection fraction. We explored the influence of atrial fibrillation or flutter (AFF) on the effectiveness of omecamtiv mecarbil. METHODS AND RESULTS: GALACTIC-HF enrolled patients with New York Heart Association (NYHA) Class II-IV heart failure, left ventricular ejection fraction ≤35%, and elevated natriuretic peptides. We assessed whether the presence or absence of AFF, a pre-specified subgroup, modified the treatment effect for the primary and secondary outcomes, and additionally explored effect modification in patients who were or were not receiving digoxin. Patients with AFF (n = 2245, 27%) were older, more likely to be randomized as an inpatient, less likely to have a history of ischaemic aetiology or myocardial infarction, had a worse NYHA class, worse quality of life, lower estimated glomerular filtration rate, and higher N-terminal pro-B-type natriuretic peptide. The treatment effect of omecamtiv mecarbil was modified by baseline AFF (interaction P = 0.012), with patients without AFF at baseline deriving greater benefit. The worsening of the treatment effect by baseline AFF was significantly more pronounced in digoxin users than in non-users (interaction P = 0.007); there was minimal evidence of effect modification in those patients not using digoxin (P = 0.47) or in digoxin users not in AFF. CONCLUSION: Patients in AFF at baseline were less likely to benefit from omecamtiv mecarbil than patients without AFF, although the attenuation of the treatment effect was disproportionally concentrated in patients with AFF who were also receiving digoxin.Clinical Trial Registration: NCT02929329.

Reperfusion therapies and in-hospital outcomes for ST-elevation myocardial infarction in Europe: the ACVC-EAPCI EORP STEMI Registry of the European Society of Cardiology.

AIMS: The aim of this study was to determine the contemporary use of reperfusion therapy in the European Society of Cardiology (ESC) member and affiliated countries and adherence to ESC clinical practice guidelines in patients with ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Prospective cohort (EURObservational Research Programme STEMI Registry) of hospitalized STEMI patients with symptom onset <24 h in 196 centres across 29 countries. A total of 11 462 patients were enrolled, for whom primary percutaneous coronary intervention (PCI) (total cohort frequency: 72.2%, country frequency range 0-100%), fibrinolysis (18.8%; 0-100%), and no reperfusion therapy (9.0%; 0-75%) were performed. Corresponding in-hospital mortality rates from any cause were 3.1%, 4.4%, and 14.1% and overall mortality was 4.4% (country range 2.5-5.9%). Achievement of quality indicators for reperfusion was reported for 92.7% (region range 84.8-97.5%) for the performance of reperfusion therapy of all patients with STEMI <12 h and 54.4% (region range 37.1-70.1%) for timely reperfusion. CONCLUSIONS: The use of reperfusion therapy for STEMI in the ESC member and affiliated countries was high. Primary PCI was the most frequently used treatment and associated total in-hospital mortality was below 5%. However, there was geographic variation in the use of primary PCI, which was associated with differences in in-hospital mortality.

High-Sensitivity Cardiac Troponin Impact on the Differential Diagnosis of Non-ST Segment Elevation Coronary Syndromes-Is It Helping?

Background and Objectives: Increased levels of high-sensitivity cardiac troponin (hs-cTn) are the main criteria that differentiate non-ST segment elevation myocardial infarction (NSTEMI) from unstable angina (UA). How are these implemented in clinical practices? This study aims to detect cases of misdiagnosed UA instead of NSTEMI. Materials and Methods: We analysed discharge summaries of 840 patients admitted to Vilnius University Hospital Santaros Klinikos with the diagnosis of UA in 2017-2018. We retrospectively checked symptoms, levels of hs-cTn, coronary angiography and electrocardiogram changes with an aim to differentiate UA and type 1 NSTEMI, according to the Fourth Universal Definition of Myocardial Infarction. We excluded patients with missing hs-cTn levels or coronary angiography. Results: We found that 46.71% (n = 334) of patients met the diagnostic criteria of UA according to the Fourth Universal Definition, whereas 19.16% of patients (n = 137) could have been diagnosed with type 1 NSTEMI instead of UA. In the group of patients who could be reclassified to type 1 NSTEMI, the median level of hs-cTn was 184.32 [226.15] ng/L on admission. The median of the lowest level during the hospitalization was 114.0 [207.4] ng/L. Median highest-304.0 [257.6] ng/L. Myocardial infarction with non-obstructive coronary arteries could have been diagnosed in 3.36% (n = 24) of patients. Conclusions: Only less than half of patients met the diagnostic UA criteria. Almost one-fifth of patients with a diagnosis of UA could be reclassified to type 1 NSTEMI.

One-Year Outcomes after PCI Strategies in Cardiogenic Shock.

BACKGROUND: Among patients with acute myocardial infarction, cardiogenic shock, and multivessel coronary artery disease, the risk of a composite of death from any cause or severe renal failure leading to renal-replacement therapy at 30 days was found to be lower with percutaneous coronary intervention (PCI) of the culprit lesion only than with immediate multivessel PCI. We evaluated clinical outcomes at 1 year. METHODS: We randomly assigned 706 patients to either culprit-lesion-only PCI or immediate multivessel PCI. The results for the primary end point of death or renal-replacement therapy at 30 days have been reported previously. Prespecified secondary end points at 1 year included death from any cause, recurrent myocardial infarction, repeat revascularization, rehospitalization for congestive heart failure, the composite of death or recurrent infarction, and the composite of death, recurrent infarction, or rehospitalization for heart failure. RESULTS: As reported previously, at 30 days, the primary end point had occurred in 45.9% of the patients in the culprit-lesion-only PCI group and in 55.4% in the multivessel PCI group (P=0.01). At 1 year, death had occurred in 172 of 344 patients (50.0%) in the culprit-lesion-only PCI group and in 194 of 341 patients (56.9%) in the multivessel PCI group (relative risk, 0.88; 95% confidence interval [CI], 0.76 to 1.01). The rate of recurrent infarction was 1.7% with culprit-lesion-only PCI and 2.1% with multivessel PCI (relative risk, 0.85; 95% CI, 0.29 to 2.50), and the rate of a composite of death or recurrent infarction was 50.9% and 58.4%, respectively (relative risk, 0.87; 95% CI, 0.76 to 1.00). Repeat revascularization occurred more frequently with culprit-lesion-only PCI than with multivessel PCI (in 32.3% of the patients vs. 9.4%; relative risk, 3.44; 95% CI, 2.39 to 4.95), as did rehospitalization for heart failure (5.2% vs. 1.2%; relative risk, 4.46; 95% CI, 1.53 to 13.04). CONCLUSIONS: Among patients with acute myocardial infarction and cardiogenic shock, the risk of death or renal-replacement therapy at 30 days was lower with culprit-lesion-only PCI than with immediate multivessel PCI, and mortality did not differ significantly between the two groups at 1 year of follow-up. (Funded by the European Union Seventh Framework Program and others; CULPRIT-SHOCK ClinicalTrials.gov number, NCT01927549 .).

Long-Term Effects of Renal Artery Denervation.

Background and Objectives: Renal artery denervation (RDN) procedure is a broadly discussed method in the treatment of resistant hypertension. Many studies report short-term (3-12 months) results for blood pressure and arterial stiffness. The primary endpoints were changes in 24 h mean systolic blood pressure (BP) and office systolic BP 48 months after RDN. The secondary endpoints were changes in aortic pulse wave velocity and impact of polypharmacy on these variables. Materials and Methods: Renal artery denervation was performed in 73 patients treated for resistant hypertension; 49 patients remained in final analysis. Patient examination was carried out before the procedure, and subsequently at 3, 6, 12, 24, and 48 months later. Patients' antihypertensive and overall medication regimens were carefully analysed. Results: Mean 24 h arterial blood pressure lowered and was sustained at lower levels for up to 48 months; median (interequartile range-IQR) from 158(23.5)/100(14.2) to 140(26.5)/86(16.2) mmHg. Mean reduction in 24 h ambulatory systolic BP was -11 ± 25 mmHg (95% CI, -20 to -2; p < 0.001), while office systolic BP reduced by -7 ± 23 mmHg (95%CI, -24 to -1; p < 0.02). A significant reduction in median aortic pulse wave velocity 12 months after the procedure (drop from baseline 11.2 [3.15] m/s (95%CI 6.1 to 16.2) to 9.8 [2.1] m/s (95%CI 6.1 to 13.7; p = 0.002)). After 48 months, there was no worsening compared to the baseline level of 10.3 [4.0] m/s (95% CI 6.9 to 17.8) (p > 0.05). The total mean number of antihypertensive drugs remained unchanged: 5.97(±1.1) vs. 5.24 (±1.45). A higher number of pills after 48 months was associated with higher aortic pulse wave velocity (1-5 pill group: 8.1 ± 1.6 m/s; 6-10 pill group: 10.9 ± 1.8 m/s; >11 pill group: 15.1 ± 2.6 m/s) (p = 0.003). Conclusions: Antihypertensive effect after renal denervation lasts up to 48 months with no worsening of arterial stiffness compared to baseline. In our study, polypharmacy was associated with increased arterial stiffness 48 months after the procedure.

Increase of Myocardial Ischemia Time and Short-Term Prognosis of Patients with Acute Myocardial Infarction during the First COVID-19 Pandemic Wave.

Background and objectives: early reports showed a decrease in admission rates and an increase in mortality of patients with acute myocardial infarction (AMI) during the first wave of COVID-19 pandemic. We sought to investigate whether the COVID-19 pandemic and associated lockdown had an impact on the ischemia time and prognosis of patients suffering from AMI in the settings of low COVID-19 burden. Materials and Methods: we conducted a retrospective data analysis from a tertiary center in Lithuania of 818 patients with AMI. Data were collected from 1 March to 30 June in 2020 during the peri-lockdown period (2020 group; n = 278) and compared to the same period last year (2019 group; n = 326). The primary study endpoint was all-cause mortality during 3 months of follow-up. Secondary endpoints were heart failure severity (Killip class) on admission and ischemia time in patients with acute ST segment elevation myocardial infarction (STEMI). Results: there was a reduction of 14.7% in admission rate for acute myocardial infarction (AMI) during the peri-lockdown period. The 3-month mortality rate did not differ significantly (6.9% in 2020 vs. 10.5% in 2019, p = 0.341 for STEMI patients; 5.3% in 2020 vs. 2.6% in 2019, p = 0.374 for patients with acute myocardial infarction without ST segment elevation (NSTEMI)). More STEMI patients presented with Killip IV class in 2019 (13.5% vs. 5.5%, p = 0.043, respectively). There was an increase of door-to-PCI time (54.0 [42.0-86.0] in 2019; 63.5 [48.3-97.5] in 2020, p = 0.018) and first medical contact (FMC)-to-PCI time (101.0 [82.5-120.8] in 2019; 115 [97.0-154.5] in 2020, p = 0.01) during the pandemic period. Conclusions: There was a 14.7% reduction of admissions for AMI during the first wave of COVID-19. FMC-to-PCI time increased during the peri-lockdown period, however, it did not translate into worse survival during follow-up.

PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock.

BACKGROUND: In patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention (PCI) improves outcomes. However, the majority of patients with cardiogenic shock have multivessel disease, and whether PCI should be performed immediately for stenoses in nonculprit arteries is controversial. METHODS: In this multicenter trial, we randomly assigned 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock to one of two initial revascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate multivessel PCI. The primary end point was a composite of death or severe renal failure leading to renal-replacement therapy within 30 days after randomization. Safety end points included bleeding and stroke. RESULTS: At 30 days, the composite primary end point of death or renal-replacement therapy had occurred in 158 of the 344 patients (45.9%) in the culprit-lesion-only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group (relative risk, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P=0.01). The relative risk of death in the culprit-lesion-only PCI group as compared with the multivessel PCI group was 0.84 (95% CI, 0.72 to 0.98; P=0.03), and the relative risk of renal-replacement therapy was 0.71 (95% CI, 0.49 to 1.03; P=0.07). The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups. CONCLUSIONS: Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of a composite of death or severe renal failure leading to renal-replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate multivessel PCI. (Funded by the European Union 7th Framework Program and others; CULPRIT-SHOCK ClinicalTrials.gov number, NCT01927549 .).

Correction to: Prevalence and prognostic value of late gadolinium enhancement on CMR in aortic stenosis: meta-analysis.

The original version of this article, published on 12 August 2019, unfortunately contained a mistake. The funding note was incorrect; the correct funding note is given below.

Prevalence and prognostic value of late gadolinium enhancement on CMR in aortic stenosis: meta-analysis.

OBJECTIVES: The aim of this study was to investigate the prevalence and prognostic value of late gadolinium enhancement (LGE), as assessed by cardiovascular magnetic resonance (CMR) imaging, in patients with aortic stenosis. METHODS AND RESULTS: A systematic search of PubMed and EMBASE was performed, and observational cohort studies that analysed the prevalence of LGE and its relation to clinical outcomes in patients with aortic stenosis were included. Odds ratios were used to measure an effect of the presence of LGE on both all-cause and cardiovascular mortality. Nineteen studies were retrieved, accounting for 2032 patients (mean age 69.8 years, mean follow-up 2.8 years). We found that LGE is highly prevalent in aortic stenosis, affecting half of all patients (49.6%), with a non-infarct pattern being the most frequent type (63.6%). The estimated extent of focal fibrosis, expressed in % of LV mass, was equal to 3.83 (95% CI [2.14, 5.52], p < 0.0001). The meta-analysis showed that the presence of LGE was associated with increased all-cause (pooled OR [95% CI] = 3.26 [1.72, 6.18], p = 0.0003) and cardiovascular mortality (pooled OR [95% CI] = 2.89 [1.90, 4.38], p < 0.0001). CONCLUSIONS: LGE by CMR is highly prevalent in aortic stenosis patients and exhibits a substantial value in all-cause and cardiovascular mortality prediction. These results suggest a potential role of LGE in aortic stenosis patient risk stratification. KEY POINTS: • Up to the half of aortic stenosis patients are affected by myocardial focal fibrosis. • Sixty-four percent of focal fibrosis detected by LGE-CMR is non-infarct type. • The presence of focal fibrosis triples all-cause and cardiovascular mortality.

Prognostic value of myocardial fibrosis in severe aortic stenosis: study protocol for a prospective observational multi-center study (FIB-AS).

BACKGROUND: Adverse cardiac remodeling with a myocardial fibrosis as a key pathophysiologic component may be associated to worse survival in aortic stenosis (AS) patients. Therefore, with the application of advanced cardiac imaging we aim to investigate left ventricular myocardial fibrosis in severe AS patients undergoing aortic valve replacement (AVR) and determine its impact with post-intervention clinical outcomes. METHODS: In a prospective, observational, cohort study patients with severe AS scheduled either for surgical or transcatheter AVR will be recruited from two tertiary heart centers in Denmark and Lithuania. All patients will receive standard of care in accordance with the current guidelines and will undergo additional imaging testing before and after AVR: echocardiography with deformation analysis and cardiovascular magnetic resonance (CMR) with T1 parametric mapping. Those undergoing surgical AVR will also have a myocardial biopsy sampled at the time of a surgery for histological validation. Patients will be recruited over a 2-year period and followed up to 2 years to ascertain clinical outcomes. Follow-up CMR will be performed 12 months following AVR, and echocardiography with deformation analysis will be performed 3, 12, and 24 months following AVR. The study primary outcome is a composite of all-cause mortality and major adverse cardiovascular events. DISCUSSION: Despite continuous effort of research community there is still a lack of early predictors of left ventricular decompensation in AS, which could improve patient risk stratification and guide the optimal timing for aortic valve intervention, before irreversible left ventricular damage occurs. Advanced cardiac imaging and CMR derived markers of diffuse myocardial fibrosis could be utilized for this purpose. FIB-AS study is intended to invasively and non-invasively assess diffuse myocardial fibrosis in AS patients and investigate its prognostic significance in post-interventional outcomes. The results of the study will expand the current knowledge of cardiac remodeling in AS and will bring additional data on myocardial fibrosis and its clinical implications following AVR. ETHICS/DISSEMINATION: The study has full ethical approval and is actively recruiting patients. The results will be disseminated through scientific journals and conference presentations. TRIAL REGISTRATION: ClinicalTrials.govNCT03585933. Registered on 02 July 2018.

Evaluation of risk factors for adverse outcome in extracorporeal membrane oxygenation-supported elderly postcardiotomy patients.

BACKGROUND: Recently extracorporeal membrane oxygenation is becoming the commonly used mechanical assist device for the treatment of severe cardiogenic shock in postcardiotomy patients. Evaluation of risk factors of negative outcome would be beneficial in decision-making in the elderly patient population. METHODS: This was a retrospective single-centre analysis of elderly patients who underwent extracorporeal membrane oxygenation treatment for refractory cardiogenic shock in a tertiary care centre. Demographic data, comorbidities and perioperative parameters were collected to evaluate their impact on the outcome of extracorporeal membrane oxygenation treatment in this patient group. Logistic regression analysis of the variables was performed to identify factors predicting an adverse outcome. RESULTS: Forty consecutive elderly patients underwent extracorporeal membrane oxygenation treatment during the study period. The mean age was 76.7 ± 3.8 years, 27 (68%) were male. The mean Survival after Veno-Arterial extracorporeal membrane oxygenation score before initiating extracorporeal membrane oxygenation support was - 11 ± 6. Intra-aortic counterpulsation was used as the first-line mechanical support in 31 (77%) patients. The mean duration of extracorporeal membrane oxygenation support was 172 ± 128 hours. Twenty-four patients (56%) were successfully weaned from extracorporeal membrane oxygenation, and 8 (20%) survived to hospital discharge. Lactate level before extracorporeal membrane oxygenation initiation was the only predictor of unfavourable outcome in multivariate analysis (p < 0.05). CONCLUSION: High lactate level before initiation of extracorporeal membrane oxygenation was the most important prognostic values of an unfavourable outcome.

Association of aortic stiffness, carotid intima-media thickness and endothelial function with cardiovascular events in metabolic syndrome subjects.

PURPOSE: The objective of this study was to assess predictive value of various arterial markers for cardiovascular (CV) events in patients with metabolic syndrome (MetS). MATERIALS AND METHODS: A longitudinal study with the follow-up period of 3.9 ± 1.7 years investigated 2728 middle-aged (53.9 ± 6.2 years old, 63% women) MetS subjects without overt CV disease. The study cohort was comprised of the participants of the Lithuanian High Cardiovascular Risk primary prevention program. The baseline assessment included the evaluation of brachial flow-mediated dilatation (FMD), carotid intima-media thickness (cIMT), carotid stiffness index, aortic pulse wave velocity (aPWV), aortic augmentation index (AIx), and cardio-ankle vascular index). The data on the cardiovascular outcome (fatal or non-fatal myocardial infarction or stroke) was collected by using the databases of the two major national registries. RESULTS: Over the follow-up period, 83 (3%) patients had at least one cardiovascular event. In a univariate analysis, occurrence of CV events was associated with the following parameters: higher mean blood pressure, aPWV, AIx and cIMT, and lower FMD (all p < .05). In Cox proportional hazard regression analysis, the occurrence of CV event was associated with an increase in aPWV (HR 1.29, 95% CI 1.04-1.60, p = .019), AIx (HR 1.53, 95% CI 1.16-2.02, p = .003), and cIMT (HR 1.31, 95% CI 1.14-1.50, p < .001), and with the decrease in FMD (HR 0.83, 95% CI 0.71-0.97, p = .016) even after the adjustment for age, gender, and common cardiometabolic risk factors. In a two-level survival trees analysis, we established that patients with cIMT > 794 mcm had higher CV risk (p < .001) and their prognosis was further compromised by aPWV > 11.1 m/s (p = .023). Meanwhile, in patients with cIMT ≤ 794mcm, the FMD cut-off point of 6.5% further stratified the risk (p = .003). CONCLUSIONS: In our prospective study, CV risk in the middle-aged patients with MetS was associated with an increase in cIMT and aPWV, and with a decrease in FMD.

Long-term quality of life in patients treated with extracorporeal membrane oxygenation for postcardiotomy cardiogenic shock.

OBJECTIVE: The aim of our study was to explore long-term health-related quality of life (HRQOL) and incidence of post-traumatic stress disorder (PTSD) in extracorporeal membrane oxygenation (ECMO) survivors. METHODS: Single-center prospective follow-up study. All patients in whom ECMO was initiated due to refractory cardiogenic shock between 2009 and 2014 were included in the study. We used Medical Outcomes Study 36-Item Short-Form Health Survey to evaluate HRQOL and IES-R questionnaire to assess incidence of PTSD. RESULTS: Sixty-nine patients were treated with venoarterial (VA) ECMO during the study period. Nineteen patients survived until hospital discharge and 15 patients were alive at the study cut-off point in June 2017; mean follow-up time was 70.6 ± 10 months. The average Physical Component Summary and Mental Component Summary scores amongst long-term survivors were 46.1 ± 7 and 47.1 ± 8, respectively. PTSD was evident in 4 out of 15 participants. CONCLUSIONS: Despite the complex clinical course and prolonged recovery, ECMO survivors achieved satisfactory levels of both mental and physical recovery, which were comparable to the age- and pathology-adjusted population means.

Cardiovascular risk assessment of dyslipidemic middle-aged adults without overt cardiovascular disease over the period of 2009-2016 in Lithuania.

BACKGROUND: Cardiovascular mortality in Lithuania is extremely high and abnormal lipid levels are very common among Lithuanian adults. Dyslipidemia is one of the main independent risk factors for cardiovascular diseases (CVD) leading to high absolute CVD risk. The aim of this study was to assess CVD risk in dyslipidemic middle-aged subjects. METHODS: During the period of 2009-2016 a total of 92,373 people (58.4% women and 41.6% men) were evaluated. This study included men aged 40-54 and women aged 50-64 without overt CVD. RESULTS: Any type of dyslipidemia was present in 89.7% of all study population. 7.5% of dyslipidemic patients did not have any other conventional risk factors. Three and more risk factors were detected in 60.1% of dyslipidemic subjects. All analyzed risk factors, except smoking, were more common in dyslipidemic adults compared to subjects without dyslipidemia: arterial hypertension (55.8% vs. 43.3%, p < 0.001), diabetes (11.1% vs. 7.3%, p < 0.001), abdominal obesity (45.3% vs. 30.2%, p < 0.001), BMI ≥30 kg/m2 (35.8% vs. 23.7%, p < 0.001), metabolic syndrome (34.0% vs. 9.2%, p < 0.001), family history of coronary heart disease (26.3% vs. 23.1%, p < 0.001), unbalanced diet (62.5% vs. 52.9%, p < 0.001) and insufficient physical activity (52.0% vs. 44.2%, p < 0.001). The prevalence of all evaluated risk factors, except smoking, increased with age. Average SCORE index was 1.87 in all study population, while dyslipidemic subjects had higher SCORE compared to control group (1.95 vs 1.20, p < 0.001). CONCLUSIONS: Almost two thirds of dyslipidemic middle-aged Lithuanian adults without overt cardiovascular disease had three or more other CVD risk factors, which synergistically increase absolute risk of CVD. The average 10-year risk of CVD death in patients with dyslipidemia was 1.95%. The importance of managing dyslipidemia as well as other risk factors in order to reduce burden of cardiovascular disease in Lithuania is evident.

Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial.

BACKGROUND: Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil. METHODS: In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov, number NCT01786512. FINDINGS: From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18-32, p<0·0001), stroke volume 3·6 mL (0·5-6·7, p=0·0217), left ventricular end-systolic diameter -1·8 mm (-2·9 to -0·6, p=0·0027), left ventricular end-diastolic diameter -1·3 mm, (-2·3 to 0·3, p=0·0128), heart rate -3·0 beats per min (-5·1 to -0·8, p=0·0070), and N-terminal pro B-type natriuretic peptide concentration in plasma -970 pg/mL (-1672 to -268, p=0·0069). The frequency of adverse clinical events did not differ between groups. INTERPRETATION: Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter. FUNDING: Amgen.

Cardiac shock-wave therapy in the treatment of coronary artery disease: systematic review and meta-analysis.

AIM: To systematically review currently available cardiac shock-wave therapy (CSWT) studies in humans and perform meta-analysis regarding anti-anginal efficacy of CSWT. METHODS: The Cochrane Controlled Trials Register, Medline, Medscape, Research Gate, Science Direct, and Web of Science databases were explored. In total 39 studies evaluating the efficacy of CSWT in patients with stable angina were identified including single arm, non- and randomized trials. Information on study design, subject's characteristics, clinical data and endpoints were obtained. Assessment of publication risk of bias was performed and heterogeneity across the studies was calculated by using random effects model. RESULTS: Totally, 1189 patients were included in 39 reviewed studies, with 1006 patients treated with CSWT. The largest patient sample of single arm study consisted of 111 patients. All selected studies demonstrated significant improvement in subjective measures of angina symptoms and/or quality of life, in the majority of studies left ventricular function and myocardial perfusion improved. In 12 controlled studies with 483 patients included (183 controls) angina class, Seattle Angina Questionnaire (SAQ) score, nitrates consumption were significantly improved after the treatment. In 593 participants across 22 studies the exercise capacity was significantly improved after CSWT, as compared with the baseline values (in meta-analysis standardized mean difference SMD = -0.74; 95% CI, -0.97 to -0.5; p < 0.001). CONCLUSIONS: Systematic review of CSWT studies in stable coronary artery disease (CAD) demonstrated consistent improvement of clinical variables. Meta-analysis showed a moderate improvement of exercise capacity. Overall, CSWT is a promising non-invasive option for patients with end-stage CAD, but evidence is limited to small sample single-center studies. Multi-center adequately powered randomised double blind studies are warranted.

Multivessel versus culprit lesion only percutaneous revascularization plus potential staged revascularization in patients with acute myocardial infarction complicated by cardiogenic shock: Design and rationale of CULPRIT-SHOCK trial.

BACKGROUND: In acute myocardial infarction complicated by cardiogenic shock (CS), up to 80% of patients present with multivessel coronary artery disease. Currently, the best revascularization strategy is unknown. Therefore, a prospective randomized adequately powered clinical trial is warranted. STUDY DESIGN: The CULPRIT-SHOCK study is a 706-patient controlled, international, multicenter, randomized, open-label trial. It is designed to compare culprit lesion only percutaneous coronary intervention (PCI) with possible staged non-culprit lesion revascularization versus immediate multivessel PCI in patients with CS complicating acute myocardial infarction. Patients will be randomized in a 1:1 fashion to one of the two treatment arms. The primary efficacy endpoint of CULPRIT-SHOCK is 30-day mortality and severe renal failure requiring renal replacement therapy. Secondary outcome measures such as hemodynamic, laboratory, and clinical parameters will serve as surrogate endpoints for prognosis. Furthermore, an intermediate- and long-term follow-up at 6 and 12 months will be performed. Safety endpoints include the assessment of bleeding and stroke. CONCLUSIONS: The CULPRIT-SHOCK trial will address the question of optimal revascularization strategy in patients with multivessel disease and acute myocardial infarction complicated by CS.

Prediction of long-term segmental and global functional recovery of hibernating myocardium after revascularisation based on low dose dobutamine and late gadolinium enhancement cardiovascular magnetic resonance.

BACKGROUND: This study sought to evaluate the relation between long-term segmental and global functional outcome after revascularisation in patients with chronic ischaemic left ventricular dysfunction (LVD) and baseline markers of viability: late gadolinium enhancement (LGE) transmurality and contractile reserve (CR). METHODS: Forty-two patients with chronic ischaemic LVD underwent low-dose dobutamine- (LDD) and late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) before surgical or percutaneous revascularisation. Regional and global left ventricular (LV) functions and LGE were repeatedly assessed 6 ± 1 and 35 ± 6 months after revascularisation. In total, 319 at baseline dysfunctional and successfully revascularised segments were available for statistical analysis. RESULTS: The likelihood of long-term functional improvement was directly related to the presence of CR and inversely related to both the LGE and the degree of contractile dysfunction at baseline. The time course of functional improvement was protracted, with significantly more delay in segments with more extensive LGE (p = 0.005) and more severe contractile dysfunction at baseline (p = 0.002). The presence of CR was the predictor of earlier functional improvement (p < 0.0001). Using a definition of viable segment as a segment without any LGE or with any LGE and producing CR during LDD stimulation, ≥ 55% of viable segments from all dysfunctional and revascularised segments in a patient was the only independent predictor of significant improvement (≥ 5%) in the left ventricular ejection fraction (LVEF) after revascularisation, with a 72% sensitivity and an 80% specificity (AUC 0.76, p = 0.014). Reverse LV remodelling was observed in patients who had a significant amount of viable myocardium successfully revascularised. CONCLUSIONS: In patients with chronic ischaemic LVD, improvement of dysfunctional but viable myocardium can be considerably delayed. Both the likelihood and the time course of functional improvement are related to the LGE, CR and the degree of contractile dysfunction at baseline. At 35 ± 6 months after revascularisation, patients with ≥55% of viable segments from all dysfunctional and revascularised segments significantly improve LVEF and experience reverse LV remodelling. A combination of LDD-CMR and LGE-CMR is a simple and powerful tool for identifying which patients with impaired LV function will benefit from revascularisation.

Current spectrum and outcomes of infarct-related cardiogenic shock: insights from the CULPRIT-SHOCK registry and randomized controlled trial.

AIMS: We analysed consecutive patients with acute myocardial infarction complicated by cardiogenic shock (CS) who were enrolled into the CULPRIT-SHOCK randomized controlled trial (RCT) and those with exclusion criteria who were included into the accompanying registry. METHODS AND RESULTS: In total, 1075 patients with infarct-related CS were screened for CULPRIT-SHOCK in 83 specialized centres in Europe; 369 of them had exclusion criteria for the RCT and were enrolled into the registry. Patients were followed over 1 year. The mean age was 68 years and 260 (25%) were women. 13.5%, 30.9%, and 55.6% had one-vessel, two-vessel, and three-vessel coronary artery disease (CAD), respectively. Significant left main (LM) coronary artery stenosis was present in 8.0%. 54.2% of the patients had cardiac arrest before admission. Thrombolysis in myocardial infarction (TIMI) 3 patency of the infarct vessel after percutaneous coronary intervention was achieved in 83.6% of all patients. Mechanical circulatory support was applied in one-third of patients. Total mortality after 30 days and 1 year was 47.6% and 52.9%. Mortality after 1 year was highest in patients with LM coronary artery stenosis (63.5%), followed by three-vessel (56.6%), two-vessel (49.8%), and one-vessel CAD (38.6%), respectively. Mechanical complications were rare (21/1008; 2.1%) but associated with a high mortality of 66.7% after 1 year. CONCLUSION: In specialized centres in Europe, short- and long-term mortality of patients with infarct-related CS treated with an invasive strategy is still high and mainly depends on the extent of CAD. Therefore, there is still a need for improvement of care to improve the prognosis of infarct-related CS.