Kari Ylitalo

Effects of intracoronary injection of mononuclear bone marrow cells on left ventricular function, arrhythmia risk profile, and restenosis after thrombolytic therapy of acute myocardial infarction

AIMS To assess the efficacy and safety of bone marrow cell (BMC) therapy after thrombolytic therapy of an acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS Patients with STEMI treated with thrombolysis followed by percutaneous coronary intervention (PCI) 2-6 days after STEMI were randomly assigned to receive intracoronary BMCs (n = 40) or placebo medium (n = 40), collected and prepared 3-6 h prior PCI and injected into the infarct artery immediately after stenting. Efficacy was assessed by the measurement of global left ventricular ejection fraction (LVEF) by left ventricular angiography and 2-D echocardiography, and safety by measuring arrhythmia risk variables and restenosis of the stented vessel by intravascular ultrasound. At 6 months, BMC group had a greater absolute increase of global LVEF than placebo group, measured either by angiography (mean +/- SD increase 7.1 +/- 12.3 vs. 1.2 +/- 11.5%, P = 0.05) or by 2-D echocardiography (mean +/- SD increase 4.0 +/- 11.2 vs. -1.4 +/- 10.2%, P = 0.03). No differences were observed between the groups in the adverse clinical events, arrhythmia risk variables, or the minimal lumen diameter of the stented coronary lesion. CONCLUSION Intracoronary BMC therapy is associated with an improvement of global LVEF and neutral effects on arrhythmia risk profile and restenosis of the stented coronary lesions in patients after thrombolytic therapy of STEMI.

Mechanisms of Ischemic Preconditioning in Rat Myocardium

BACKGROUND Adenosine has been proposed as one mediator for the preconditioning effect in the myocardium of some animals, but recent investigations have shown that this may not be the mechanism in the rat heart, although the effect itself is clearly demonstrable. The cellular energy state has been shown to be better in preconditioned hearts, and the role of ATP consumption has been discussed. The role of inhibition of mitochondrial F1F0-ATPase as a mechanism for the preservation of ATP in preconditioned hearts remains controversial. METHODS AND RESULTS Three-minute global ischemia followed by 9 minutes of reperfusion was used to precondition Langendorff-perfused rat hearts, and control hearts were perfused under normoxic conditions for the same time. The duration of sustained ischemia in both groups of hearts was 21 minutes, after which the hearts were reperfused for 15 minutes to evaluate their mechanical and metabolic recovery. Separate experiments were performed for tissue metabolite determinations, mitochondrial ATPase activity measurements, and 31P nuclear magnetic resonance studies. The recovery of the rate-pressure product was better in the preconditioned group. Three-minute preconditioning ischemia caused inhibition of the mitochondrial ATPase that persisted throughout the 9-minute intervening reperfusion so that at the early stages of sustained ischemia the enzyme activity was still more inhibited in preconditioned hearts. ATP was better preserved in preconditioned hearts than in control hearts during sustained ischemia. The accumulation of adenosine and its degradation products during sustained ischemia was greater in the control group. More lactate and H+ ions accumulated in this group, indicating higher anaerobic glycolysis. Also, inhibition of mitochondrial ATPase by oligomycin slowed ATP depletion during ischemia. CONCLUSIONS The results indicate that preconditioning causes inhibition of rat heart mitochondrial ATPase that persists during reperfusion so that the enzyme is inhibited from the very beginning of the sustained ischemia. This inhibition leads to sparing of high-energy phosphates and improves the time-averaged energy state during ischemia. Although a causal relationship is difficult to prove, this reversible inhibition may contribute to postischemic recovery of the heart.

Randomized Comparison of Coronary Bifurcation Stenting With the Crush Versus the Culotte Technique Using Sirolimus Eluting Stents The Nordic Stent Technique Study

Background—In a number of coronary bifurcation lesions, both the main vessel and the side branch need stent coverage. Using sirolimus eluting stents, we compared 2 dedicated bifurcation stent techniques, the crush and the culotte techniques in a randomized trial with separate clinical and angiographic end-points. Methods and Results—A total of 424 patients with a bifurcation lesion were randomized to crush (n=209) and culotte (n=215) stenting. The primary end point was major adverse cardiac events; cardiac death, myocardial infarction, target vessel revascularization, or stent thrombosis after 6 months. At 6 months there were no significant differences in major adverse cardiac event rates between the groups; crush 4.3%, culotte 3.7% (P=0.87). Procedure and fluoroscopy times and contrast volumes were similar in the 2 groups. The rates of procedure-related increase in biomarkers of myocardial injury were 15.5% in crush versus 8.8% in culotte group (P=0.08). A total of 324 patients had a quantitative coronary assessment at the index procedure and after 8 months. The angiographic end-points of in-segment and in-stent restenosis of main vessel and/or side branch after 8 months were found in 12.1% versus 6.6% (P=0.10) and in 10.5% versus 4.5% (P=0.046) in the crush and culotte groups, respectively. Conclusions—Both the crush and the culotte bifurcation stenting techniques were associated with similar and excellent clinical and angiographic results. Angiographically, there was a trend toward less in-segment restenosis and significantly reduced in-stent restenosis following culotte stenting.

Cardiac Sarcoidosis: Epidemiology, Characteristics and Outcome over 25 Years in a Nationwide Study

Background— This study was designed to assess the epidemiology, characteristics, and outcome of cardiac sarcoidosis (CS) in Finland. Methods and Results— We identified in retrospect all adult (>18 years of age) patients diagnosed with histologically confirmed CS in Finland between 1988 and 2012. A total of 110 patients (71 women) 51±9 years of age (mean±SD) were found and followed up for outcome events to the end of 2013. The annual detection rate of CS increased >20-fold during the 25-year period, reaching 0.31 in 1×105 adults between 2008 and 2012. The 2012 prevalence of CS was 2.2 in 1×105. Nearly two thirds of patients had clinically isolated CS. Altogether, 102 of the 110 patients received immunosuppressive therapy, and 56 received an intracardiac defibrillator. Left ventricular function was impaired (ejection fraction <50%) in 65 patients (59%) at diagnosis and showed no overall change over 12 months of steroid therapy. During follow-up (median, 6.6 years), 10 patients died of a cardiac cause, 11 patients underwent transplantation, and another 11 patients suffered an aborted sudden cardiac death. The Kaplan–Meier estimates for 1-, 5-, and 10-year transplantation-free cardiac survival were 97%, 90%, and 83%, respectively. Heart failure at presentation predicted poor outcome (log-rank P=0.0001) with a 10-year transplantation-free cardiac survival of only 53%. Conclusions— The detection rate of CS has increased markedly in Finland over the last 25 years. With current therapy, the prognosis of CS appears better than generally considered, but patients presenting with heart failure still have poor long-term outcome.Background— This study was designed to assess the epidemiology, characteristics, and outcome of cardiac sarcoidosis (CS) in Finland. Methods and Results— We identified in retrospect all adult (>18 years of age) patients diagnosed with histologically confirmed CS in Finland between 1988 and 2012. A total of 110 patients (71 women) 51±9 years of age (mean±SD) were found and followed up for outcome events to the end of 2013. The annual detection rate of CS increased >20-fold during the 25-year period, reaching 0.31 in 1×105 adults between 2008 and 2012. The 2012 prevalence of CS was 2.2 in 1×105. Nearly two thirds of patients had clinically isolated CS. Altogether, 102 of the 110 patients received immunosuppressive therapy, and 56 received an intracardiac defibrillator. Left ventricular function was impaired (ejection fraction <50%) in 65 patients (59%) at diagnosis and showed no overall change over 12 months of steroid therapy. During follow-up (median, 6.6 years), 10 patients died of a cardiac cause, 11 patients underwent transplantation, and another 11 patients suffered an aborted sudden cardiac death. The Kaplan–Meier estimates for 1-, 5-, and 10-year transplantation-free cardiac survival were 97%, 90%, and 83%, respectively. Heart failure at presentation predicted poor outcome (log-rank P =0.0001) with a 10-year transplantation-free cardiac survival of only 53%. Conclusions— The detection rate of CS has increased markedly in Finland over the last 25 years. With current therapy, the prognosis of CS appears better than generally considered, but patients presenting with heart failure still have poor long-term outcome. # CLINICAL PERSPECTIVE {#article-title-42}

Coronary angioplasty in drug eluting stent era for the treatment of unprotected left main stenosis compared to coronary artery bypass grafting

Background. Improved outcomes of percutaneous coronary interventions (PCI) with drug-eluting stents (DES) have resulted in their expanded use for left main coronary artery (LMCA) stenosis. Aim. We compared outcomes of patients undergoing PCI for unprotected LMCA stenosis and patients treated by coronary artery bypass grafting (CABG). Method. Between January 2005 and January 2007, 6705 patients were studied with coronary angiography in northern Finland. All subjects treated with revascularization of LMCA stenosis (n=287) were included and followed up for a mean of 12±6 months. Results. From 287 patients, 238 underwent CABG, and 49 had PCI with DES. The incidence of 1-year mortality was 4% among the PCI-treated and 11% among CABG-treated patients (P=0.136). After the first month, mortality among PCI- or CABG-treated patients did not differ statistically significantly (2% versus 7%, P=0.133). The most significant independent predictor of mortality was reduced left ventricular systolic function (hazard ratio 14.9, 95% CI 5.5–40.0, P<0.001). Conclusions. PCI with DES for selected LMCA disease patients results in short- and midterm outcomes comparable to results of CABG in general. PCI is a viable therapeutic option in selected patients with LMCA stenosis.

Normothermic retrograde blood cardioplegia with or without preceding ischemic preconditioning.

BACKGROUND Preconditioning has been suggested as the most powerful mechanism of myocardial protection against prolonged ischemia. However, whether preconditioning offers additional benefits over cardioplegia during coronary artery bypass grafting is not known. METHODS Thirty patients undergoing coronary artery bypass grafting were randomized into two groups. After aortic cross-clamping, group 1 received antegrade blood and blood cardioplegia followed by normothermic retrograde blood cardioplegia (controls), whereas group 2 patients were subjected to 5 minutes of global ischemia followed by reperfusion with antegrade and retrograde blood cardioplegia (preconditioned). The transcardiac differences in oxygen saturation, pH, and lactate were measured during cardiopulmonary bypass. Myocardial biopsy specimens were taken from half of the patients for adenosine triphosphate determination. The extent of myocardial injury was estimated by monitoring the postoperative leakage of creatine kinase-MB and troponin T. Immediate hemodynamic recovery and postoperative complications were also observed. RESULTS The 5-minute preconditioning induced marked lactate and acid production, and myocardial adenosine triphosphate levels tended to decrease. The heart continued to produce lactate and acid during retrograde cardioplegia, but the transcardiac pH and lactate differences were similar in both groups. Adenosine triphosphate level measured at the end of the cross-clamp period was decreased to a half and one third of the preclamp values in the control and preconditioned groups, respectively. The postoperative creatine kinase-MB and troponin T effluxes tended to be more elevated in the preconditioned group, yet hemodynamic recovery and the number of postoperative complications were similar in both groups. CONCLUSIONS The results show that a 5-minute preconditioning ischemia does not offer any additional benefits over normothermic retrograde blood cardioplegia during coronary artery bypass grafting.

Ventricular tachyarrhythmia as a primary presentation of sarcoidosis

AIMS Sarcoidosis is a multisystem, granulomatous disease with occasional cardiac manifestations. The clinical course of patients with ventricular tachyarrhythmias as a primary presentation of sarcoidosis is mostly unknown. METHODS AND RESULTS We describe nine patients (four males and five females) in whom sarcoidosis manifested as ventricular tachycardia (VT). The age of the patients was 53 +/- 10 years (range 33-68). The disease was diagnosed by endomyocardial biopsy in eight patients and by lymph node biopsy in one patient. The presenting arrhythmia varied from non-sustained VT to incessant VT and ventricular fibrillation. All patients received implantable cardioverter defibrillator (ICD) and anti-arrhythmic medication. High-dose steroid treatment was used in eight cases. During the follow-up (50 +/- 34 months), five patients underwent appropriate ICD therapies and non-sustained VT episodes were detected in four patients. Two patients developed incessant VT, which was treated by catheter ablation. One patient was referred for heart transplantation. CONCLUSION Our data indicate that sarcoidosis can manifest as VT without any detectable systemic findings. This makes sarcoidosis an important diagnostic consideration in patients with VT of unknown origin. Arrhythmia control in cardiac sarcoidosis is difficult, and all modern treatments including high-dose steroids, anti-arrhythmic drugs, ICD, and catheter ablation are needed to suppress the arrhythmias.

Utility of plasma apelin and other indices of cardiac dysfunction in the clinical assessment of patients with dilated cardiomyopathy.

Apelin is a recently discovered peptide ligand reported to be involved in the regulation of cardiovascular homeostasis. The exact role of apelin in the pathophysiology of congestive heart failure has remained obscure, and the reported circulating levels of apelin in patients with heart failure have been contradictory. To establish the role of apelin in the assessment of cardiac dysfunction we measured plasma apelin levels in 65 patients with congestive heart failure caused by idiopathic dilated cardiomyopathy (IDC) and 14 healthy volunteers by specific radioimmunoassay. IDC patients were carefully examined including echocardiography, both-sided cardiac catheterization and cardiopulmonary exercise test. In addition, plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), N-terminal pro-atrial natriuretic peptide (NT-proANP), interleukin (IL)-6, tumor necrosis factor alpha (TNF-alpha), epinephrine and norepinephrine were determined. Plasma apelin levels were similar in IDC patients (median 26.5 pg/ml, range<3.40-97.6 pg/ml) and in control subjects (median 24.1 pg/ml, range 19.0-28.7 pg/ml; p=NS). Unlike the levels of NT-proBNP, IL-6, TNF-alpha, and norepinephrine, plasma apelin levels did not reflect the severity of heart failure. Our study demonstrates that although disturbed apelin-APJ signalling in heart may play a role in the pathophysiology of heart failure, circulating apelin levels cannot be applied in the clinical assessment of patients with chronic left ventricular dysfunction.

Determinants of Functional Recovery after Myocardial Infarction of Patients Treated with Bone Marrow Derived Stem Cells after Thrombolytic Therapy

Objective To assess the determinants of functional recovery in patients with ST-elevation myocardial infarction (STEMI) treated initially with thrombolysis, followed by percutaneous coronary intervention and intracoronary injection of bone marrow-derived stem cells (BMC). Design A randomised, placebo-controlled, double-blind study (substudy of FINCELL). Setting Two tertiary cardiac centres. Participants 78 patients with STEMI randomly assigned to receive either intracoronary BMC (n=39) or placebo (n=39) into the infarct-related artery. Interventions Thrombolysis a few hours after symptom onset, percutaneous coronary intervention and intracoronary injection of BMC 2–6 days later. Main outcome measures Efficacy of the BMC treatment was assessed by measurement of the change of global left ventricular ejection fraction (LVEF) from baseline to 6 months after STEMI. Various predefined variables (eg, the levels of certain natriuretic peptides and inflammatory cytokines) were analysed as determinants of improvement of LVEF. Results In the BMC group, the most powerful determinant of the change in LVEF was the baseline LVEF (r=−0.58, p<0.001). Patients with baseline LVEF at or below the median (≤62.5%) experienced a more marked improvement in LVEF (+12.7±12.5 %units, p<0.001) than those above the median (−0.8±6.3 %units, p=0.10). Elevated N-terminal probrain natriuretic peptide (p<0.001) and N-terminal proatrial natriuretic peptide (p=0.052) levels were also associated with improvement in LVEF in the BMC group but not in the placebo group. Conclusions The global LVEF recovers most significantly after intracoronary infusion of BMC in patients with the most severe impairment of LVEF on admission. The baseline levels of natriuretic peptides seem also to be associated with LVEF recovery after BMC treatment. Trial registration ClinicalTrials.gov number, NCT00363324.

Reversible ischemic inhibition of F1F0-ATPase in rat and human myocardium

The physiological role of F(1)F(0)-ATPase inhibition in ischemia may be to retard ATP depletion although views of the significance of IF(1) are at variance. We corroborate here a method for measuring the ex vivo activity of F(1)F(0)-ATPase in perfused rat heart and show that observation of ischemic F(1)F(0)-ATPase inhibition in rat heart is critically dependent on the sample preparation and assay conditions, and that the methods can be applied to assay the ischemic and reperfused human heart during coronary by-pass surgery. A 5-min period of ischemia inhibited F(1)F(0)-ATPase by 20% in both rat and human myocardium. After a 15-min reperfusion a subsequent 5-min period of ischemia doubled the inhibition in the rat heart but this potentiation was lost after 120 min of reperfusion. Experiments with isolated rat heart mitochondria showed that ATP hydrolysis is required for effective inhibition by uncoupling. The concentration of oligomycin for 50% inhibition (I(50)) for oxygen consumption was five times higher than its I(50) for F(1)F(0)-ATPase. Because of the different control strengths of F(1)F(0)-ATPase in oxidative phosphorylation and ATP hydrolysis an inhibition of the F(1)F(0)-ATPase activity in ischemia with the resultant ATP-sparing has an advantage even in an ischemia/reperfusion situation.