Michael Bonios

Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery.

OBJECTIVES The aim of this study was to quantify acute myocardial retention of cardiac-derived stem cells (CDCs) and evaluate different delivery methods with positron emission tomography (PET). BACKGROUND Success of stem cell transplantation for cardiac regeneration is partially limited by low retention/engraftment of the delivered cells. A clinically applicable method for accurate quantification of cell retention would enable optimization of cell delivery. METHODS The CDCs were derived from syngeneic, male Wistar Kyoto (WK) rats labeled with [(18)F]-fluoro-deoxy-glucose ((18)FDG) and injected intramyocardially into the ischemic region of female WK rats after permanent left coronary artery ligation. The effects of fibrin glue (FG), bradycardia (adenosine), and cardiac arrest were examined. Imaging with (18)FDG PET was performed for quantification of cell retention. Quantitative polymerase chain reaction (PCR) for the male-specific SRY gene was performed to validate the PET results. RESULTS Myocardial retention of cells suspended in phosphate-buffered saline 1 h after delivery was 17.6 +/- 11.5% by PCR and 17.8 +/- 7.3% by PET. When CDCs were injected immediately after induction of cardiac arrest, retention was increased to 75.6 +/- 18.6%. Adenosine slowed the ventricular rate and doubled CDC retention (35.4 +/- 5.3%). A similar increase in CDC retention was observed after epicardial application of FG at the injection site (37.5 +/- 8.2%). The PCR revealed a significant increase in 3-week cell engraftment in the FG animals (22.1 +/- 18.6% and 5.3 +/- 3.1%, for FG and phosphate-buffered saline, respectively). CONCLUSIONS In vivo PET permits accurate measurement of CDC retention early after intramyocardial delivery. Sealing injection sites with FG or lowering ventricular rate by adenosine might be clinically translatable methods for improving stem cell engraftment in a beating heart.

Comparison of three different regimens of intermittent inotrope infusions for end stage heart failure

AIMS Inotrope treatment is often necessary in refractory to optimal management end stage heart failure, when signs of end-organ hypoperfusion appear. The effect of specific inotropes on patient outcome remains controversial. The aim of the study was to compare the effect of levosimendan versus dobutamine, alone or in combination with levosimendan, on the outcome of end-stage heart failure patients, requiring inotropic therapy. METHODS AND RESULTS We studied 63 patients in NYHA class IV, refractory to optimal medical therapy, recently hospitalized for cardiac decompensation and stabilized by an intravenous inotrope. They were randomly assigned to intermittent infusions of either a) dobutamine, 10mg/kg/min, versus b) levosimendan, 0.3mg/kg/min, versus c) dobutamine, 10mg/kg/min+levosimendan 0.2 mg/kg/min, each administered weekly, for 6h, over a 6-month period. All patients received amiodarone, 400 mg/day, to suppress the proarrhythmic effects of the inotropes. Baseline characteristics of the 3 groups were similar. At 6 months, survival free from death or urgent left ventricular device implantation was 80% in the levosimendan, 48% in the dobutamine (P=0.037 versus levosimendan), and 43% in the levosimendan+dobutamine (P=0.009 versus levosimendan) group. At 3months, NYHA class improved significantly in all 3 groups, whereas pulmonary capillary wedge pressure decreased (27 ± 4 to 19 ± 8 mmHg, P=0.008) and cardiac index increased (1.5 ± 0.3 to 2.1 ± 0.3 l/min/m(2), P=0.002) significantly only in patients assigned to levosimendan. CONCLUSIONS In patients with refractory end-stage heart failure, intermittent administration of levosimendan conferred survival and hemodynamic benefits in comparison to a regimen of intermittent infusions of dobutamine, alone or in combination with levosimendan.

Mechanical Assistance by Intra-Aortic Balloon Pump Counterpulsation During Reperfusion Increases Coronary Blood Flow and Mitigates the No-Reflow Phenomenon: An Experimental Study

The effects of the intra-aortic balloon pump (IABP) counterpulsation on the extent of myocardial infarction (MI), the no-reflow phenomenon (NRP), and coronary blood flow (CBF) during reperfusion in an ischemia-reperfusion experimental model have not been clarified. Eleven pigs underwent occlusion of the mid left anterior descending coronary artery for 1 h, followed by reperfusion for 2 h. CBF, distal to the occlusion site, was measured. In six experiments, IABP support began 10 min before, and continued throughout reperfusion (IABP Group). Five pigs without IABP support served as controls. At the end of each experiment, the myocardial area at risk (MAR) of infarction and the extent of MI and NRP were measured. Hemodynamic measurements at baseline and during coronary occlusion were similar in both groups. During reperfusion, systolic aortic blood pressure was significantly lower in the IABP Group than in controls. In the IABP Group, CBF reached a peak at 5 min of reperfusion, gradually decreased, but remained higher than at baseline, and significantly higher than in controls throughout the 2 h of reperfusion. In controls, CBF increased significantly above baseline immediately after the onset of reperfusion, then returned to baseline within 90 min. The extent of NRP (37 ± 25% vs. 68 ± 17%, P = 0.047) and MI (39 ± 23% vs. 67 ± 13%, P = 0.036), both expressed as percentage of MAR, was significantly less in the IABP group than in controls. After prolonged myocardial ischemia, IABP assistance started just 10 min before and throughout reperfusion increased CBF and limited infarct size and extent of NRP.

Intermittent inotropic infusions combined with prophylactic oral amiodarone for patients with decompensated end-stage heart failure.

Background: Concern has been raised regarding the mortality and ethics related to the treatment of patients with end-stage chronic heart failure with chronic intermittent intravenous inotropic agents. We examined whether intermittent inotropic agents combined with oral amiodarone to prevent the proarrhythmic effect of inotropic agents results in better outcomes. Methods: The study included 162 patients with decompensated end-stage chronic heart failure, who could be weaned from an initial 72-hour infusion of intravenous inotropes. Group 1 included 140 patients, who entered a 6-month program of weekly intermittent intravenous inotropic agents plus oral amiodarone, 200 mg twice a day. Group 2 included 22 patients, who were treated with optimal conventional therapy and were hospitalized for administration of intravenous medications as needed. Results: The baseline characteristics of groups 1 versus 2, including New York Heart Association functional class (IV in both groups), admission systolic arterial blood pressure (99 ± 14 vs. 97 ± 13 mm Hg), right atrial pressure (13 ± 6 vs. 14 ± 6 mm Hg), pulmonary capillary wedge pressure (28 ± 7 vs. 31 ± 10 mm Hg), serum sodium (136 ± 7 vs. 139 ± 6 mEq/L) and serum creatinine (1.7 ± 0.8 vs. 1.8 ± 1.8 mg/dL), were similar. The 6-month (51% vs. 18%) and 1-year (36% vs. 9%) survival rates were significantly higher (P = 0.001 for both) in group 1 than in group 2. In addition, patients treated with intermittent intravenous inotropic agents improved their functional and hemodynamic status. Conclusions: Intermittent intravenous inotropic agents combined with prophylactic oral amiodarone seem to improve the outcomes of patients with end-stage chronic heart failure. Further research is warranted to elucidate whether this treatment strategy should be considered as a standard therapy in patients with refractory end-stage heart failure.

Increase in coronary blood flow by intra-aortic balloon counterpulsation in a porcine model of myocardial reperfusion

BACKGROUND Studies of the IABP have reported variable effects on coronary blood flow (CBF). The purpose of the present study was to measure the changes in coronary blood flow induced by intra-aortic balloon pump (IABP) counterpulsation in normal and reperfused porcine myocardium. METHODS A 30-ml IABP was placed in the descending aorta of 6 open-chest pigs. Each pig underwent occlusion of the mid-left anterior descending (LAD) coronary artery for 1 h, followed by reperfusion for 2 h. The effects of IABP support on systolic aortic pressure (SAP) and aortic end-diastolic pressure were recorded. The mean CBF, distal to the LAD occlusion site was measured at baseline and during reperfusion, with and without IABP counterpulsation. RESULTS The IABP decreased SAP and aortic end-diastolic pressure in normal and reperfused myocardium, and maintained a peak aortic diastolic augmentation at the level of SAP. In normal myocardium, the IABP decreased mean CBF by 8.4+/-2.2% (p<0.001). At 2, 15, 30, 60, 90 and 120 min of reperfusion, the IABP increased mean CBF by 11.5+/-6.8%, 8.0+/-7.0%, 11.2+/-6.9%, 12.4+/-12.9%, 23.5+/-9.9% and 8.9+/-6.9%, of the corresponding value without the assistance of the IABP (all p<0.05). CONCLUSIONS In the normal heart, IABP counterpulsation decreased CBF, probably because of a decrease in myocardial oxygen demand from a decreased afterload. During reperfusion the IABP increased CBF, suggesting that it might effectively mitigate the no-reflow phenomenon.

Long-Term Survival and Outcomes After Hospitalization for Acute Myocardial Infarction Complicated by Cardiogenic Shock

Cardiogenic shock is the leading cause of death during hospitalization for acute myocardial infarction (MI). However, little data exist regarding the long‐term outcomes of patients who survived the acute phase of MI and were discharged from the hospital.

The Role of Amiodarone in Recent-Onset Atrial Fibrillation after Ibutilide Has Failed to Restore Sinus Rhythm

Background: Ibutilide is a class III antiarrhythmic drug that is used for the cardioversion of atrial arrhythmias, but it can cause torsades de pointes. Amiodarone is also used for the cardioversion of atrial fibrillation and prolongs the QT interval but rarely causes torsades de pointes. Methods and Results: The study included 51 consecutive patients with recent onset atrial fibrillation in whom the administration of ibutilide failed to restore sinus rhythm. In those patients we decided to proceed to intravenous administration of amiodarone. The QT intervals were measured on 12-lead ECG. After 11 ± 5 h of the administration of the amiodarone, 42 patients (82%) were on sinus rhythm. There was no episode of non-sustained torsades de pointes or hypotension that followed the administration of the two antiarrhythmic agents. Conclusions: The administration of amiodarone in the case of ibutilide failure may be a useful adjunct to current cardioversion protocols for recent onset atrial fibrillation.

A combined cellular and surgical ventricular reconstruction therapeutic approach produces attenuation of remodeling in infarcted rats.

BACKGROUND Left ventricular reconstruction (LVR) has been shown to provide transient benefits to the LV structure and function of infarcted hearts; however, long-term results have been disappointing as LVR-induced benefits are typically not sustained. We hypothesized that administration of cardiosphere-derived cells (CDCs), which promote myocardial repair and regeneration, may result in long-term preservation of the beneficial effects of LVR in ischemic cardiomyopathy. METHODS Wistar Kyoto rats underwent myocardial infarction (MI) and two weeks later were randomized into 3 groups: in Group 1 (n=9), LVR was performed by plication of the infarcted apex and CDCs were injected in the infarct border zone (IBZ); group 2 animals (n=9) underwent LVR and received vehicle solution in the IBZ; and Group 3 animals (n=10) were injected with vehicle solution in the IBZ without undergoing LVR. Echocardiograms were performed at baseline, 4 days post-apex plication, and at 3 months post-MI. RESULTS At baseline, all animal groups had a comparable LVEF, LV end-diastolic volume (EDV) and LV end-systolic volume (ESV). Four days post-LV apex plication, Group 1 and Group 2 animals exhibited comparable significant improvement in EF and comparable significant reduction in LVEDV and LVESV. Three months post-MI, Group 1 animals had a decreased LVEDV, decreased LVESV, less impaired CS, increased peak systolic torsion and increased EF compared to animals in Groups 2 and 3. CONCLUSION In infarcted rat hearts, intramyocardial delivery of CDCs in conjunction with LVR resulted in significant and sustained amelioration of LV remodeling and improvement in LV function compared to LVR alone.

Afterload-induced left ventricular diastolic dysfunction during myocardial ischaemia and reperfusion.

What is the central question of this study? While the load dependence of the diastolic function is established for the normal heart, little is known about the response of the acutely ischaemic and reperfused myocardium to alterations in afterload. What is the main finding and its importance? Using a model that simulates the clinical scenario of acute ischaemia–reperfusion, we show that increased afterload aggravates diastolic dysfunction during both acute ischaemia and reperfusion. In addition, increased afterload induces diastolic dyssynchrony, which might be the underlying mechanism of the diastolic dysfunction of the ischaemic myocardium. These findings provide us with new information regarding how better to manage patients who undergo revascularization therapy after acute myocardial infarction.

Effects of l-NAME on coronary blood flow, infarct size and the extent of the no-reflow phenomenon

BACKGROUND NOS inhibitors are a potential treatment for patients with cardiogenic shock during acute myocardial infarction. Despite hemodynamic efficacy, their effects on the extent of myocardial infarction (MI) and the no-reflow phenomenon (NRP) have not been clarified. METHODS Sixteen pigs underwent occlusion of the mid left anterior descending coronary artery for 1h followed by reperfusion for 2h. Coronary blood flow (CBF), distal to the occlusion site, was measured. In eight experiments, L-NAME (non selective NO synthetase inhibitor) administration began 10 min before the onset of reperfusion and continued for 2h (loading dose 1mg/kg, perfusion rate: 1mg/kg/h) (L-NAME group). Eight pigs received similarly normal saline (controls). At the end of each experiment, the myocardial area at risk (MAR) and extent of MI and NRP were measured. RESULTS Hemodynamics at baseline and during ischemia were similar in both groups. During reperfusion, the mean aortic blood pressure was significantly higher in the l-NAME group. In both groups, CBF reached a peak at 5 min of reperfusion, (no difference between groups). CBF gradually returned to baseline levels within 60 min of reperfusion in both groups. No statistically significant differences in the extent of the NRP (51.8 ± 19.7 vs 60.9 ± 11.4 p=0.35) and MI (77.9 ± 13.9 vs 77.1 ± 8.8 p=0.92), both expressed as a percentage of MAR, were observed between the L-NAME group and the control group. CONCLUSIONS L-NAME administration started immediately before and maintained throughout reperfusion has no effect on NRP and MI size. L-NAME might stabilize patients with post-MI cardiogenic shock without adverse effects on infarct size.