Samuel Unzek

Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy

BACKGROUNDnMyocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy.nnnMETHODSnWe studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography.nnnFINDINGSnStem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, p<0.02) resulting in greater left-ventricular mass (1.24 [0.29] vs 1.57 [0.27] g) and better cardiac function (shortening fraction 9.2 [4.9] vs 17.2 [4.2]%, n=8 per group, p<0.05).nnnINTERPRETATIONnThese findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.

Myeloperoxidase-Generated Oxidants Modulate Left Ventricular Remodeling but Not Infarct Size After Myocardial Infarction

Background— Inflammation after myocardial infarction (MI) heralds worse left ventricular (LV) function and clinical outcomes. However, whether inflammation affects LV function by extending myonecrosis and/or altering LV remodeling remains unknown. We hypothesized that cytotoxic aldehydes generated during oxidative stress may adversely affect remodeling and infarct size. One theoretical source of reactive aldehydes is oxidation of common &agr;-amino acids by myeloperoxidase (MPO) released by leukocytes. However, a role for MPO in formation of aldehydes in vivo and the functional consequences of MPO-generated oxidants in ischemia/reperfusion models of MI have not been established. Methods and Results— In studies with cell types found in vascular tissue, MPO-oxidation products of glycine (formaldehyde) and threonine (acrolein) were the most cytotoxic. Mass spectrometry studies of myocardial tissue from murine models of acute MI (both chronic left anterior descending coronary artery ligation and ischemia/reperfusion injury) confirmed that MPO serves as a major enzymatic source in the generation of these cytotoxic aldehydes. Interestingly, although MPO-null mice experienced 35.1% (P<0.001) less LV dilation and a 52.2% (P<0.0001) improvement in LV function compared with wild-type mice 24 days after ischemia/reperfusion injury, no difference in infarct size between wild-type and MPO-null mice was noted. Conclusions— The present data separate inflammatory effects on infarct size and LV remodeling and demonstrate that MPO-generated oxidants do not significantly affect tissue necrosis after MI but rather have a profound adverse effect on LV remodeling and function.

SDF-1 recruits cardiac stem cell-like cells that depolarize in vivo.

Prolongation or reestablishment of stem cell homing through the expression of SDF-1 in the myocardium has been shown to lead to homing of endothelial progenitor cells to the infarct zone with a subsequent increase in vascular density and cardiac function. While the increase in vascular density is important, there could clearly be other mechanisms involved. In a recent study we demonstrated that the infusion of mesenchymal stem cells (MSC) and MSC that were engineered to overexpress SDF-1 led to significant decreases in cardiac myocyte apoptosis and increases in vascular density and cardiac function compared to control. In that study there was no evidence of cardiac regeneration from either endogenous stem cells or the infused mesenchymal stem cells. In this study we performed further detailed immunohistochemistry on these tissues and demonstrate that the overexpression of SDF-1 in the newly infracted myocardium led to recruitment of small cardiac myosin-expressing cells that had proliferated within 2 weeks of acute MI. These cells did not differentiate into mature cardiac myocytes, at least by 5 weeks after acute MI. However, based on optical mapping studies, these cells appear capable of depolarizing. We observed greater optical action potential amplitude in the infarct border in those animals that received SDF-1 overexpressing MSC than observed in noninfarcted animals and those that received control MSC. Further immunohistochemistry revealed that these proliferated cardiac myosin-positive cells did not express connexin 43, but did express connexin 45. In summary, our study suggests that the prolongation of SDF-1 expression at the time of acute MI leads to the recruitment of endogenous cardiac myosin stem cells that may represent cardiac stem cells. These cells are capable of depolarizing and thus may contribute to increased contractile function even in the absence of maturation into a mature cardiac myocyte.

Effect of Recommendations on Interobserver Consistency of Diastolic Function Evaluation

OBJECTIVESnWe sought the impact of recent recommendations on observer concordance on interpretation of diastolic stage and assessment of filling pressure.nnnBACKGROUNDnWorsening stages of diastolic dysfunction are associated with worsening outcome. However, the echocardiographic classification of diastolic function is complex, and parameters may be discordant. The interobserver agreement of diastolic assessment is undefined.nnnMETHODSnA complete diastolic evaluation (transmitral flow, left atrial volume, tissue Doppler, pulmonary venous flow, mitral flow propagation, and left ventricular images) was obtained in 20 patients and interpreted by 14 experts in 8 countries (280 case reads). Each investigator was asked to interpret diastolic class and left ventricular filling pressure. Brain natriuretic peptide level was drawn on the same day of the echocardiogram to corroborate filling pressures obtained by the echocardiogram. Concordance was assessed as kappa, and accuracy was compared with specific application of the recommendations by 2 investigators.nnnRESULTSnFor recognition of raised filling pressure, the sensitivity and specificity of readers for raised filling pressure defined by the reference read were 66 ± 37% and 88 ± 26%, respectively. Complete agreement among all readers was obtained in 10 of 20 cases. Diagnosis of normal and categories of abnormal filling was correct in 71% to 95%, with the lowest values obtained for normal and pseudonormal filling. There was no difference between U.S. and international readers. Not all patients in each diastolic stage showed all of the changes that are typical of that stage, and variations appeared to be attributable to differences in weighting of conflicting observations. Overall, kappa values for filling pressure and diastolic class were 0.71 (range 0.60 to 0.80) and 0.68 (range 0.54 to 0.86).nnnCONCLUSIONSnCorrect results for estimation of filling pressure were obtained by a high proportion of readers. Classification of diastolic stages continues to be variable and might be addressed by provision of a uniform hierarchy of observations.

Drug-eluting stent fracture and acute coronary syndrome ☆ ☆☆

BACKGROUNDnCoronary stent fracture is an underrecognized entity but has been reported more frequently in the drug-eluting stent (DES) era. Nevertheless, the clinical implications of coronary stent fracture remain unclear.nnnMETHODS AND MATERIALSnA literature search for reports of DES fracture was conducted via MEDLINE, and the US Food and Drug Administration Manufacturer and User facility Device Experience (MAUDE) database was accessed via the internet and interrogated for reports of stent fracture between January 1, 2003, and April 30, 2008. Each report was reviewed, and clinical information was extracted for analysis.nnnRESULTSnThe MEDLINE search identified 202 cases of coronary DES fracture, with 95% of cases involving Cypher sirolimus-eluting stents. Clinical information regarding patient presentation was available in 96 cases. Patients presented with ST-elevation myocardial infarction (STEMI) or stent thrombosis in six cases (6%) and with unstable angina or non-STEMI (NSTEMI) in 40 cases (42%). The MAUDE database search identified 337 stent fracture reports, with 97% of cases involving Cypher stents. Clinical information regarding patient presentation was available 193 cases. Patients presented with STEMI or stent thrombosis in 24 cases (12%) and with unstable angina or NSTEMI in 36 cases (19%).nnnCONCLUSIONSnMost reports of drug-eluting stent fracture involve Cypher stents. DES fracture can be associated with stent thrombosis, myocardial infarction and angina. However, whether the incidence of such events reported in the literature and in the MAUDE database is representative of all patients experiencing stent fracture remains unclear.

Recurrent Stent Fracture in the Right Coronary Artery

An 83-year-old female presented in 2007 with an inferiorST-elevation myocardial infarction (STEMI), acceleratedjunctional rhythm, and cardiogenic shock. She hadundergone percutaneous coronary intervention (PCI) tothe ostium of the right coronary artery (RCA) in 2000,with deployment of a 4.0/15mm NIRoyal bare-metal stent(BMS;BostonScientificScimed,Inc.,Natick,MA), withoutcomplication (Figure1). The patient was asymptomaticuntil 2004, when she began to have angina. At thattime, coronary angiography revealed a fracture of theRCA stent and 90% stenosis at the ostium of the RCA.Percutaneous coronary intervention was performed with a3.5/18mmTaxuspaclitaxel-elutingstent(BostonScientificScimed, Inc., Natick, MA) deployed across the priorfractured stent. The procedure was uncomplicated andimmediatepostprocedureangiographyrevealednoresidualappearanceof stentfracture(Figure2).On presentation to our institution in 2007 with inferiorSTEMI, the patient underwent emergent coronary angiog-raphy, which revealedocclusionof the proximalRCA, withvisible thrombus and stent fracture of the prior RCA stent(Figure3A). The stenosis in the RCA was crossed witha guide wire with difficulty and the lesion was dilatedwith serial balloon inflations. Intravascular ultrasound wasperformed, which confirmed an area of stent separationand revealed significantresidual stenosis in the previouslystented segment (Figure3B). Therefore, the lesion wasstented with a 3.5/23mm Multi-link Vision BMS (AbbottVascular, Abbott Park, IL) spanning the 2 previously frac-turedstents.Thefinalangiogramdemonstrated0%residualstenosis and thrombolysis in myocardial infarction (TIMI)grade3 flow (Figure3C).The patient was transferred to the coronary intensivecare unit for further managementand discharged home infavorablecondition16days later. She has had no recurrentangina over 18 months of follow-up. Lifelong clopidogreltherapyis planned.

Management of heart failure: a brief review and selected update.

Despite innovative medications and devices, heart failure (HF) continues to be the leading cause for admission to hospitals in the United States in patients older than 65 years. Many trials have succeeded in improving survival and many have failed. In this article, the authors briefly review the past, describe the present, and speculate about future HF trials.

Bone Marrow and Angioblast Transplantation

Clinical trials using autologous hematopoietic or whole bone marrow preparations in patients in the peri-infarct period are ongoing. These trials are attempting to improve myocardial function. Although it has been demonstrated in animal models that these stem cells do not differentiate into cardiac myocytes, there is now clear evidence in animal models and clinical human trials that their use is likely beneficial when delivered soon after acute myocardial infarction. It should be noted that all of these trials have been performed in days to less than 2 weeks from myocardial injury. The end product of myocardial injury translates into heart failure, an entity that may be minimized by this type of therapy. One comes to the conclusion that the data are promising, but there are still many questions to be answered, for example: What type of cell(s) should be transplanted, and what should be their mode of delivery, optimal time of transplant, etc.