Zofia Parma

Mobilization of CD34+CXCR4+ Stem/Progenitor Cells and the Parameters of Left Ventricular Function and Remodeling in 1-Year Follow-up of Patients with Acute Myocardial Infarction

Mobilization of stem cells in acute MI might signify the reparatory response. Aim of the Study. Prospective evaluation of correlation between CD34+CXCR4+ cell mobilization and improvement of LVEF and remodeling in patients with acute MI in 1-year followup. Methods. 50 patients with MI, 28 with stable angina (SAP), and 20 individuals with no CAD (CTRL). CD34+CXCR4+ cells, SDF-1, G-CSF, troponin I (TnI) and NT-proBNP were measured on admission and 1 year after MI. Echocardiography and ergospirometry were carried out after 1 year. Results. Number of CD34+CXCR4+ cells in acute MI was significantly higher in comparison with SAP and CTRL, but lower in patients with decreased LVEF ≤40%. In patients who had significant LVEF increase ≥5% in 1 year FU the number of cells in acute MI was significantly higher versus patients with no LVEF improvement. Number of cells was positively correlated (r = 0,41, P = 0,031) with absolute LVEF change and inversely with absolute change of ESD and EDD in 1-year FU. Mobilization of CD34+CXCR4+ cells in acute MI was negatively correlated with maximum TnI and NT-proBNP levels. Conclusion. Mobilization of CD34+CXCR4+ cells in acute MI shows significant positive correlation with improvement of LVEF after 1 year.

ARISTOTLE RE-LYs on the ROCKET. What’s new in stroke prevention in patients with atrial fibrillation?

Warfarin has long been considered the gold standard for stroke prevention in patients with atrial fibrillation (AF). Recently, three major trials comparing the efficacy and safety of new drugs: a thrombin inhibitor dabigatran and two inhibitors of factor Xa - rivaroxaban and apixaban, with that of warfarin, have been published. The aim of this paper is to present the main results of the RE-LY, ROCKET AF and ARISTOTLE trials, compare study populations and outcomes, and discuss clinical implications of their results for the long-term anticoagulation in patients with nonvalvular AF.

Effects of Trans-Endocardial 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.

Traditional risk factors and coronary artery calcium in young adults.

BACKGROUND AND METHODS 362 symptomatic subjects of 45 years of age or younger were selected from a large database of around 4100 persons who underwent coronary artery calcium (CAC) scoring by means of a 64-multidetector computed tomography (MDCT). Amongst them, a group with the CAC > 0 Agatston units (n = 65) and a group with no detectable calcium (CAC = 0, n = 297) were compared in terms of risk factors presence. Risk factors considered were gender, body mass index, smoking habits, blood pressure level, blood lipids, presence of diabetes mellitus, family history of cardiovascular disease, and physical activity. RESULTS The vast majority of subjects with a positive CAC were males (54, 83.1%) compared to those with a negative CAC (147, 49.5%, p < 0.001, χ2). More frequent results of CAC < 0 were observed in obese subjects (38.5% vs. 24.2%, p < 0.05), among smokers (41.5% vs. 27.6%, p < 0.05). Presence of arterial hypertension coexisted with a more frequent CAC > 0 (76.9% vs. 60.6%, p < 0.05). Also, the frequency of a positive CAC was significantly higher in patients with diabetes mellitus (10.8%), compared to those without diabetes mellitus (4.0%, p < 0.05). Effects of high lipids, family history, and physical activity were not observed. Accumulation of at least 4 risk factors was associated with more frequent positive CAC (26.0 vs. 15.9%, p < 0.05). Multivariate regression analysis showed that only male gender and presence of diabetes mellitus were independent predictors of a positive CAC in younger subjects (F = 5.06, p < 0.001, multiple R = 0.321). CONCLUSIONS Traditional risk factors, apart from gender and diabetes mellitus, do not seem to allow for distinguishing young persons with a premature coronary atherosclerosis. Therefore, CAC scoring might be considered justified in symptomatic young men with diabetes mellitus.

Effects of Transendocardial Delivery of Bone Marrow–Derived CD133 + Cells on Left Ventricle Perfusion and Function in Patients With Refractory Angina

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.

Transcatheter paravalvular leak closure and hemolysis – a prospective registry

Introduction Paravalvular leak (PVL) related to a surgical prosthetic valve may be associated with clinically significant hemolysis. The influence of transcatheter PVL closure (TPVLC) on hemolysis remains uncertain. Material and methods The prospective registry included patients undergoing TPVLC due to PVL-related heart failure and/or hemolysis. Procedural data, laboratory markers of hemolysis and heart failure status were recorded at baseline, discharge and at 1- and 6-month follow-up. Results Of 116 patients from all those qualified for TPVLC, 79 fulfilled the inclusion/exclusion criteria. Hemolysis was significantly more frequent in patients with mitral location of PVL and with calcifications in its channel. After TPVLC prompt reduction of lactate dehydrogenase activity (617.0 (342.0–899.0) vs. 397 (310.0–480.5) IU/l, p < 0.05) and gradual resolution of anemia (hemoglobin (HGB) 11.7 (10.4–13.8) vs. 13.4 (12.9–13.8) g%, p < 0.05) over 6 months were noted. Effective closure of PVL (> 90% reduction of PVL cross-sectional area) resulted in a more prominent increase of red blood cell count and HGB than in patients with residual regurgitation. The TPVLC-related exacerbation of hemolysis was recorded in 14 patients. Its risk was aggravated by presence of significant hemolysis at baseline or residual flow either by a partially uncovered channel or across the occluder. Reduction of hemolysis after successful TPVLC was sustained in 6-month follow-up. Conclusions Risk factors for PVL-related hemolysis were the presence of calcifications in the defect and mitral location of PVL. The TPVLC effectively reduced hemolysis if at least 90% reduction of PVL cross sectional area was achieved. The effect was sustained in 6-month follow-up. Incomplete closure of PVL may increase the magnitude of hemolysis after TPVLC, but it occurred rarely.

Secular trends in first-time hospitalization for heart failure with following one-year readmission and mortality rates in the 3.8 million adult population of Silesia, Poland between 2010 and 2016. The SILCARD database

BACKGROUND Heart failure (HF) continues to be an important medical and social problem, with high morbidity and mortality. Data on the trends in hospitalizations, hospital readmissions and mortality is of great importance both from the epidemiological and clinical points of view. METHODS AND RESULTS We analyzed the secular trends in first-time hospital admissions for heart failure between 2010 and 2016, derived from SILCARD database, covering a population of 3.8 million adults. Patient characteristics as well as data on in-hospital and 12-month outcomes were recorded for each year. The total number of first-time hospitalizations for HF as the primary diagnosis showed a downward trend during the study period (reduction by 12%, p = 0.07), with a constant patient age (mean 74.3 ± 11.3 years). The length of hospital stay shortened from 10.9 to 9.6 days (p = 0.003). Crude in-hospital mortality remained constant at around 14% (p = 0.55), but after adjustment for sex and age, mortality rates tended to decrease from 17.2% in 2010 to 11.5% in 2016 (p = 0.007). All-cause hospital readmission rates in 12-month follow-up increased which was due to non-CV hospitalizations, since both CV- and HF-related readmissions were constant throughout the years. Crude 12-month mortality was constant, but after adjustment for age and sex absolute reduction by about 10% was found (p = 0.02). CONCLUSIONS Despite the decreasing duration of hospital stay, significant improvement in both in-hospital and long-term survival was observed, with constant rates of hospital readmissions related to HF.

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 AnginaNovelty and Significance: 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.

Electromechanical mapping of the left ventricle for stem cell injection in a patient with permanent atrial fibrillation.

Stem cell therapies for improvement of the ischaemic myocardium are an emerging and promising therapeutic option. Three-dimensional NOGA mapping allows simultaneous registration of left ventricle (LV) mechanical and electrical activity, enabling assessment of myocardial viability and targeted cell delivery. However, LV mapping in patients during atrial fibrillation (AF) is considered time consuming and difficult. A 77-year-old man was admitted to our centre presenting with refractory angina. His risk factors included hypertension, hyperlipidaemia, and advanced chronic renal failure, he also had a history of permanent AF. In the past he had undergone coronary artery bypass grafting twice: in 1985 and 2002, he had also suffered from a non-ST-elevation myocardial infarction treated with percutaneous coronary intervention with a drug eluting stent implantation in 2010. At the moment of admission, he was in CCS class III despite optimal medical treatment. The patient had previously been disqualified from any further revascularisation by the Heart Team. Echocardiography revealed a mild impairment of the LV ejection fraction (LVEF 45%), with hypokinesia of the intraventricular septum and inferior wall. Single-photon emission computed tomography (SPECT) showed reversible perfusion defects in the anterolateral region. AF with short QRS duration (80 ms) and relatively good rate control (80 bpm) was observed in an electrocardiogram. The patient was enrolled to the REGENT (autologous CD133+ cells vs. placebo, double-blind, placebo-controlled RCT) trial to undergo targeted transendocardial treatment. We used a NOGA-XP System to perform electromechanical mapping and direct transendocardial cell injection. A diagnostic NOGA STAR catheter was placed in the LV under fluoroscopic guidance, and LV electromechanical mapping was performed. Completing the data necessary to build the map and localise the target area took about 60 min. The regions of hibernating myocardium defined by preserved electrical and decreased mechanical activity correlated with reversible perfusion defects detected by SPECT. Time volume graphs showed evident dyssynchrony of the hibernating areas (Fig. 1). Following the standardised NOGA injection criteria, twelve 0.2 mL injections of autologous CD133+ bone marrow stem cells or placebo (procedure double-blinded) were placed into the anterolateral viable area (> 5 mV unipolar) with low wall movement (< 6% LLS) (Fig. 2). Only limited premature ventricular contractions were detectable at injections, which can probably be explained by a reduced time window for excitation after the electrical refractory period. Total injection time was 20 min. Mapping and injection were completed within 80 min despite permanent AF. No raise in creatinine levels, pericardial effusion, and no local complications were observed in the days following the procedure. To conclude, despite technical difficulties due to irregular rhythm, electromechanical mapping on AF is feasible. Completing the procedure in patients with AF and good heart rate control does not have to be more time consuming than in patients on sinus rhythm. Additionally, time volume graphs display differences in wall movement of hibernating and normal tissue even during AF, providing us with additional information on segmental ventricular contraction synchrony.