Correlation between electromechanical parameters (NOGA XP) and changes of myocardial ischemia in patients with refractory angina.

INTRODUCTION: Cell therapy has the potential to improve symptoms and clinical outcomes in refractory angina (RFA). Further analyses are needed to evaluate factors influencing its therapeutic effectiveness. AIM: Assessment of electromechanical (EM) parameters of the left ventricle (LV) and investigation of correlation between EM parameters of the myocardium and response to CD133+ cell therapy. MATERIAL AND METHODS: Thirty patients with RFA (16 active and 14 placebo individuals) enrolled in the REGENT-VSEL trial underwent EM evaluation of the LV with intracardiac mapping system. The following parameters were analyzed: unipolar voltage (UV), bipolar voltage (BV), local linear shortening (LLS). Myocardial ischemia was evaluated with single-photon emission computed tomography (SPECT). The median value of each EM parameter was used for intra-group comparisons. RESULTS: Global EM parameters (UV, BV, LLS) of LV in active and placebo groups were 11.28 mV, 3.58 mV, 11.12%, respectively; 13.00 mV, 3.81 mV, 11.32%, respectively. EM characteristics analyzed at global and segmental levels did not predict response to CD133+ cell therapy in patients with RFA (Global UV, BV and LLS at rest R = -0.06; R = 0.2; R = -0.1 and at stress: R = 0.07, R = 0.09, R = -0.1, respectively; Segmental UV, BV, LLS at rest R = -0.2, R = 0.03, R = -0.4 and at stress R = 0.02, R = 0.2, R = -0.2, respectively). Multiple linear regression of the treated segments showed that only pre-injection SPECT levels were significantly correlated with post-injection SPECT, either at rest or stress (p < 0.05). CONCLUSIONS: Electromechanical characteristics of the left ventricle do not predict changes of myocardial perfusion by SPECT after cell therapy. Baseline SPECT results are only predictors of changes of myocardial ischemia observed at 4-month follow-up.

Rationale and design of the European multicentre study on Stem Cell therapy in IschEmic Non-treatable Cardiac diseasE (SCIENCE).

AIMS: Ischaemic heart failure (IHF) patients have a poor prognosis even with current guideline-derived therapy. Intramyocardial injections of autologous or allogeneic mesenchymal stromal cells might improve cardiac function leading to better clinical outcome. METHODS: The SCIENCE (Stem Cell therapy in IschEmic Non-treatable Cardiac diseasE) consortium has initiated a Horizon 2020 funded multicentre phase II study in six European countries. It is a double-blind, placebo-controlled trial testing the safety and efficacy of allogeneic Cardiology Stem Cell Centre Adipose-derived Stromal Cells (CSCC_ASC) from healthy donors or placebo in 138 symptomatic IHF patients. Main inclusion criteria are New York Heart Association class II-III, left ventricular ejection fraction < 45% and N-terminal pro-B-type natriuretic peptide levels > 300 pg/mL. Patients are randomized in a 2:1 pattern to receive intramyocardial injections of either CSCC_ASC or placebo. CSCC_ASC and placebo treatments are prepared centralized at Rigshospitalet in 5 mL vials as an off-the-shelf product. Vials are distributed to all clinical partners and stored in nitrogen vapour tanks ready to be used directly after thawing. A total of 100 × 106 CSCC_ASC or placebo are injected directly into viable myocardium in the infarct border zone using the NOGA XP system (BDS, Cordis, Johnson & Johnson, USA). Primary endpoint is a centralized core-laboratory assessed change in left ventricular end-systolic volume at 6-month follow-up measured by echocardiography. The trial started in January 2017, 58 patients were included and treated until July 2018. CONCLUSION: The SCIENCE trial will provide clinical data on efficacy and safety of intramyocardial cell therapy of allogeneic adipose-derived stromal cells from healthy donors in patients with IHF.

Effects of trans-endocardial delivery of bone marrow-derived CD133+ cells on angina and quality of life in patients with refractory angina: A sub-analysis of the REGENT-VSEL trial.

BACKGROUND: The REGENT-VSEL trial demonstrated a neutral effect of transendocardial injection of autologous bone marrow (BM)-derived CD133+ in regard to myocardial ischemia. The current sub-analysis of the REGENT VSEL trial aims to assess the effect stem cell therapy has on quality of life (QoL) in patients with refractory angina. METHODS: Thirty-one patients (63.0 ± 6.4 years, 70% male) with recurrent CCS II-IV angina, despite optimal medical therapy, enrolled in the REGENT-VSEL single center, randomized, double-blinded, and placebo-controlled trial. Of the 31 patients, 16 individuals were randomly assigned to the active stem cell group and 15 individuals were randomly assigned to the placebo group on a 1:1 basis. The inducibility of ischemia, (≥ one myocardial segment) was confirmed for each patient using Tc-99m SPECT. QoL was measured using the Seattle Angina Questionnaire. Each patient completed the questionnaire prior to treatment and at the time of their outpatient follow-up visits at 1, 4, 6, and 12 months after cell/placebo treatment. RESULTS: The main finding of the REGENT-VSEL trial sub-analysis was that transendocardial injection of autologous BM-derived CD133+ stem cells in patients with chronic refractory angina did not show significant improvement in QoL in comparison to the control group. Moreover, there was no significant difference between cell therapy and placebo in a number of patients showing improvement of at least 1 Canadian Cardiovascular Society class during the follow-up period. CONCLUSIONS: Intra-myocardial delivery of autologous CD133+ stem cells is safe and feasible but does not show a significant improvement in the QoL or angina pectoris symptoms in patients with chronic myocardial ischemia.

Effects of Transendocardial Delivery of Bone Marrow-Derived CD133+ Cells on Left Ventricle Perfusion and Function in Patients With Refractory Angina: Final Results of Randomized, Double-Blinded, Placebo-Controlled REGENT-VSEL Trial.

RATIONALE: New therapies for refractory angina are needed. OBJECTIVE: Assessment of transendocardial delivery of bone marrow CD133+ cells in patients with refractory angina. METHODS AND RESULTS: Randomized, double-blinded, placebo-controlled trial enrolled 31 patients with recurrent Canadian Cardiovascular Society II-IV angina, despite optimal medical therapy, ≥1 myocardial segment with inducible ischemia in Tc-99m SPECT who underwent bone marrow biopsy and were allocated to cells (n=16) or placebo (n=15). Primary end point was absolute change in myocardial ischemia by SPECT. Secondary end points were left ventricular function and volumes by magnetic resonance imaging and angina severity. After 4 months, there were no significant differences in extent of inducible ischemia between groups (summed difference score mean [±SD]: 2.60 [2.6] versus 3.63 [3.6], P=0.52; total perfusion deficit: 3.60 [3.6] versus 5.01 [4.3], P=0.32; absolute changes of summed difference score: -1.38 [5.2] versus -0.73 [1.9], P=0.65; and total perfusion deficit: -1.33 [3.3] versus -2.19 [6.6], P=0.65). There was a significant reduction of left ventricular volumes (end-systolic volume: -4.3 [11.3] versus 7.4 [11.8], P=0.02; end-diastolic volume: -9.1 [14.9] versus 7.4 [15.8], P=0.02) and no significant change of left ventricular ejection fraction in the cell group. There was no difference in number of patients showing improvement of ≥1 Canadian Cardiovascular Society class after 1 (41.7% versus 58.3%; P=0.68), 4 (50% versus 33.3%; P=0.63), 6 (70% versus 50.0%; P=0.42), and 12 months (55.6% versus 81.8%; P=0.33) and use of nitrates after 12 months. CONCLUSION: Transendocardial CD133+ cell therapy was safe. Study was underpowered to conclusively validate the efficacy, but it did not show a significant reduction of myocardial ischemia and angina versus placebo. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01660581.

Exercise-induced mobilisation of endothelial progenitor cells in patients with premature coronary heart disease.

BACKGROUND: Endothelial progenitor cells (EPC) derive from bone marrow and participate in both endothelial regeneration and development of new blood vessels. EPC also play a role in the atherosclerotic process, and their number correlates negatively with the presence of classical risk factors. AIM: To evaluate circulating EPC count and their exercise-induced mobilisation in patients with premature coronary artery disease (CAD). METHODS: The study group included 60 patients with stable CAD diagnosed before 45 years of age. The control group consisted of 33 healthy age- and gender-matched volunteers. Venous blood was sampled 3 times in order to assess circulating EPC count immediately before an exercise test (EPC 0) and at 15 min (EPC 15) and 60 min (EPC 60) after the exercise test. RESULTS: Circulating EPC count in the study group at rest and at 15 min after exercise was comparable (2.1 vs. 2.1 cell/µL, p = 0.35) and increased significantly at 60 min after exercise in comparison to resting values (2.1 vs. 3.2 cell/µL, p < 0.00001). In the control group, circulating EPC count increased significantly at 15 min after exercise (2.0 vs. 3.5 cell/µL, p < 0.0001) but later decreased at 60 min after exercise, although it remained greater than at rest (2.7 vs. 2.0 cell/µL, p < 0.0002). Circulating EPC count at rest and at 60 min after exercise was comparable in the two groups (2.1 vs. 2.0 cell/µL, p = 0.96; and 3.2 vs. 2.7 cell/µL, p = 0.13, respectively) but it was significantly lower in the study group compared to the control group at 15 min after exercise (2.1 vs. 3.5 cell/µL, p < 0.00001). Circulating EPC count at rest and at 15 min after exercise did not correlate with the number of stenosed coronary arteries but at 60 min after exercise it was greater in patients with one-vessel disease compared to those with two- or three-vessel disease (4.2 vs. 3.4 cell/µL, p = 0.01; and 4.2 vs. 2.3 cell/µL, p = 0.00003). However, no difference in circulating EPC count was seen at 60 min after exercise between patients with two- or three-vessel disease (3.4 vs. 2.3 cell/µL, p = 0.3). CONCLUSIONS: 1. Circulating EPC count at rest is comparable between subjects with premature atherosclerosis and healthy volunteers. 2. A single bout of physical exercise causes a significant increase in circulating EPC count in both groups, but the dynamics of exercise-induced EPC mobilisation is different, with delayed exercise-induced EPC mobilisation in subjects with premature CAD. 3. The extent of atherosclerotic coronary lesions does not influence circulating EPC count at rest.

Effect of a significant asymptomatic unilateral carotid artery stenosis on outcomes in patients undergoing coronary artery bypass grafting.

BACKGROUND: Occurrence of a stroke is a major concern in patients undergoing coronary artery bypass grafting (CABG). It remains uncertain whether significant asymptomatic carotid artery stenosis (CAS) is associated with stroke incidence in such patients. AIM: To investigate the incidence of cerebrovascular events, myocardial infarction (MI), and death in patients with a significant asymptomatic CAS undergoing CABG. METHODS: We prospectively evaluated 123 consecutive patients with documented carotid artery duplex Doppler ultrasound examination who underwent isolated CABG. Patients with a significant (≥ 60%) asymptomatic unilateral CAS (n = 35) were compared with those without a significant CAS (n = 88) to assess the rates of stroke, MI and mortality after CABG. RESULTS: No significant differences between patients with a significant asymptomatic unilateral CAS and those without a significant CAS in regard to age (p = 0.5955), presence of hypertension (p = 0.2343), diabetes (p = 0.5495), smoking (p = 0.7891), serum creatinine (p = 0.47) and left ventricular systolic function as evaluated by ejection fraction (p = 0.3789). No cerebrovascular events, MI and deaths occurred during the first 30 days postoperatively. At 12 months, no differences were seen between the groups in the incidence of MI (p = 0.1005) and mortality (p = 0.3959). However, a trend towards higher stroke incidence was noted among patients with a significant asymptomatic unilateral CAS (p = 0.0692). The primary combined endpoint (stroke, MI, and mortality) occurred in 40% of patients with a significant asymptomatic unilateral CAS and 17.05% of patients without a significant CAS (p = 0.0097). Linear regression analysis showed an association between significant asymptomatic unilateral CAS and stroke (p = 0.0041), and between significant asymptomatic unilateral CAS and the primary end point (p = 0.0475). CONCLUSIONS: The presence of a significant asymptomatic unilateral CAS does not increase the risk of stroke, MI and mortality within 30 days after CABG but is was associated with an increased risk of cardiovascular events during the first 12 months postoperatively.

A myomesin mutation associated with hypertrophic cardiomyopathy deteriorates dimerisation properties.

Myomesin plays an important structural and functional role in the M-band of striated muscles. The C-terminal domain 13 of myomesin dimerises and forms antiparallel strands which cross-link neighboring Myosin filaments and titin in the M-line of the sarcomeres. These interactions stabilise the contractile apparatus during striated muscle contraction. Since myomesin is an important component of the M-band we screened the myomesin gene for genetic variants in patients with hypertrophic cardiomyopathy (HCM). We identified the missense mutation V1490I in domain 12 of myomesin in a family with inherited HCM. Analytical ultracentrifugation experiments, circular dichroism spectra, and surface plasmon resonance spectroscopy of myomesin fragments were carried out to investigate the effects of the mutation V1490I on structure and function of myomesin domains 11-13 and 12-13. Both the wild type and mutated myomesin domains My11-13 revealed similar secondary structures and formed stable dimers. Mutated myomesin domains My11-13 and My12-13 dimers revealed a reduced thermal stability and a significantly decreased dimerisation affinity, showing disturbed functional properties of V1490I mutated myomesin. However, monomeric myomesin domains My11-12, i.e. without dimerisation domain 13 showed no difference in thermal stability between wild type and V1490I mutated myomesin. In conclusion, the V1490I mutation associated with HCM lead to myomesin proteins with abnormal functional properties which affect dimerisation properties of myomesin domain 13. These effects may contribute to the pathogenesis of HCM.

Diagnostic value of flow mediated dilatation measurement for coronary artery lesions in men under 45 years of age.

BACKGROUND: In those without symptoms of coronary artery disease (CAD), the incidence of coronary events is still high. The aim of this study was to evaluate whether flow mediated dilatation (FMD) is a useful tool in identifying those with CAD in who are under 45 years of age. METHODS AND RESULTS: Seventy five men below 45 years of age, hospitalized in order to perform elective coronary angiography, were enrolled into the study. Based on coronary angiography findings, they were divided into two groups: study group (Group A, n = 55) with obstructive coronary lesions and the control group (Group B, n = 20) without significant lesions in coronary arteries. In all subjects atherosclerosis risk factors were analyzed. Endothelial dysfunction was assessed in ultrasound via FMD. FMD was significantly lower in the study group than in the control group (3.92 +/- 1.1 vs 6.51 +/- 1.1, p < 0.001). FMD, as well as age, diabetes and positive family history, appeared to be statistically significant CAD risk factors. AUROC for FMD was 0.957 (p < 0.001), meaning this model had an almost complete ability to predict the presence of CAD. AUROC for CAD diagnosis on the basis of significant clinical parameters was 0.992 (p < 0.001), also representing almost complete ability of this model to identify asymptomatic subjects with CAD risk. CONCLUSIONS: The evaluation of endothelial function by the use of FMD in the population of men below 45 years of age with diabetes and positive family history can help in identifying subjects at high risk of coronary artery disease.

Intima-media thickness and flow-mediated dilatation in the diagnosis of coronary artery disease in perimenopausal women.

INTRODUCTION: Noninvasive diagnosis of coronary artery disease (CAD) in perimenopausal women is a considerable challenge for the clinical practice. OBJECTIVES: The aim of the study was to investigate whether ultrasound examination of the endothelial function and arterial remodeling can be useful for CAD risk assessment in perimenopausal women. PATIENTS AND METHODS: The study involved 65 women with chest pain and positive stress test. Based on the results of coronary angiography, they were divided into 2 groups: a study group with coronary lesions (n = 32) and a control group without coronary lesions (n = 33). The mean age was 50.3 +/-3.2 years (study group: 50.3 +/-3.5 years; control group: 50.2 +/-3.0 years; P = 0.9). Atherosclerotic risk factors were analyzed in all patients. The ultrasound examination was used to assess early atherosclerotic remodeling of the artery by measuring the intima-media thickness (IMT) and endothelial dysfunction by measuring the flow-mediated dilatation (FMD). RESULTS: The IMT was significantly higher in the study group compared with controls (0.059 +/-0.01 mm vs. 0.049 +/-0.01 mm, respectively; P <0.001); FMD was significantly lower in the study group compared with controls (6.53 +/-0.98 vs. 7.89 +/-0.85, respectively; P <0.001). For IMT, the area under the receiver operating characteristic curve (AUROC) was 0.73 (95% confidence interval [CI] 0.6-0.85; P <0.001); therefore, this parameter cannot be used as a predictor of CAD. FMD with the AUROC of 0.85 (95% CI 0.76-0.94; P <0.001) had a good predictive value for CAD. CONCLUSIONS: Evaluation of IMT and FMD in perimenopausal women can be a useful noninvasive diagnostic tool for CAD risk assessment.

[Massive pulmonary embolism without echocardiographic features of right ventricular overload]. / Masywny zator tetnicy plucnej bez cech przeciazenia prawej komory w badaniu echokardiograficznym.

A case of 70-year-old patient with massive pulmonary embolism confirmed in CT, but without changes in right ventricle size and function in echocardiography is presented. This case is consistent with literature data that echocardiography has relatively low sensitivity in the diagnosis of acute pulmonary embolism.

Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy.

The familial form of dilated cardiomyopathy (DCM) occurs in about 20%-50% of DCM cases. It is a heterogeneous genetic disease: mutations in more than 20 different genes have been shown to cause familial DCM. LMNA, encoding the nuclear membrane protein lamin A/C, is one of the most important disease gene for that disease. Therefore, we analyzed the LMNA gene in a large cohort of 73 patients with familial DCM. Clinical examination (ECG, echocardiography, and catheterization) was followed by genetic characterization of LMNA by direct sequencing. We detected five heterozygous missense mutations (prevalence 7%) in five different families characterized by severe DCM and heart failure with conduction system disease necessitating pacemaker implantation and heart transplantation. Four of these variants clustered in the protein domain coil 1B, which is important for lamin B interaction and lamin A/C dimerization. Although we identified two novel mutations (E203V, K219T) besides three known ones (E161K, R190Q, R644C), it was remarkable that four mutations represent LMNA hot spots. DCM patients with LMNA mutations show a notable homogenous severe phenotype as we could confirm in our study. Testing LMNA in such families seems to be recommended because genotype information in an individual could definitely be useful for the clinician.