How to Image and Manage Prosthesis-Related Complications After Transcatheter Aortic Valve Replacement.

PURPOSE OF REVIEW: In this review, we provide an overview of potential prosthesis - related complications after transcatheter aortic valve replacement, their incidences, the imaging modalities best suited for detection, and possible strategies to manage these complications. RECENT FINDINGS: Therapy for severe aortic valve stenosis requiring intervention has increasingly evolved toward transcatheter aortic valve replacement over the past decade, and the number of procedures performed has increased steadily in recent years. As more and more centers favor a minimalistic approach and largely dispense with general anesthesia and intra-procedural imaging by transesophageal echocardiography, post-procedural imaging is becoming increasingly important to promptly detect dysfunction of the transcatheter valve and potential complications. Complications after transcatheter aortic valve replacement must be detected immediately in order to initiate adequate therapeutic measures, which require a profound knowledge of possible complications that may occur after transcatheter aortic valve replacement, the imaging modalities best suited for detection, and available treatment options.

Acute kidney injury after in-hospital cardiac arrest in a predominant internal medicine and cardiology patient population: incidence, risk factors, and impact on survival.

INTRODUCTION: Prognosis of survivors from cardiac arrest is generally poor. Acute kidney injury (AKI) is a common finding in these patients. In general, AKI is well characterized as a marker of adverse outcome. In-hospital cardiac arrest (IHCA) represents a special subset of cardiac arrest scenarios with differential predisposing factors and courses after the event, compared to out-of-hospital resuscitations. Data about AKI in survivors after in-hospital cardiac arrest are scarce. METHODS: In this study, we retrospectively analyzed patients after IHCA for incidence and risk factors of AKI and its prognostic impact on mortality. For inclusion in the analysis, patients had to survive at least 48 h after IHCA. RESULTS: A total of 238 IHCA events with successful resuscitation and survival beyond 48 h after the initial event were recorded. Of those, 89.9% were patients of internal medicine, and 10.1% of patients from surgery, neurology or other departments. In 120/238 patients (50.4%), AKI was diagnosed. In 28 patients (23.3%), transient or permanent renal replacement therapy had to be initiated. Male gender, preexisting chronic kidney disease and a non-shockable first ECG rhythm during resuscitation were significantly associated with a higher incidence of AKI in IHCA-survivors. In-hospital mortality in survivors from IHCA without AKI was 29.7%, and 60.8% in patients after IHCA who developed AKI (p < 0.01 between groups).By multivariate analysis, AKI after IHCA persisted as an independent predictor of in-hospital mortality (HR 3.7 (95% CI 2.14-6.33, p ≤ 0.01)). CONCLUSION: In this cohort of survivors from IHCA, AKI is a frequent finding, with adverse impact on outcome. Therefore, therapeutic strategies to prevent AKI in post-IHCA patients are warranted.

Why Follow-up Examinations After Left Atrial Appendage Closure Are Important: Detection of Complications During Follow-up and How to Deal with Them.

PURPOSE OF REVIEW: Device-related thrombus (DRT) formation and incomplete left atrial appendage closure (LAAC) are the two major complications that can occur after LAAC and can potentially limit the success of such a procedure. This review discusses the incidence, clinical and/or prognostic significance, detection methods, treatment options, and potential strategies to prevent these complications. RECENT FINDINGS: It has recently been proven that the presence of a DRT represents an independent predictor for ischemic stroke after LAAC. Continued need for anticoagulation due to incomplete LAAC is clinically relevant to the patient. The appearances of a DRT or an incompletely closed LAA after a LAAC procedure are not rare complications. Due to the clinical and/or prognostic significance of these complications, it is important to detect them in a timely manner during follow-up by using the appropriate diagnostic imaging techniques. Since a DRT is associated with an increased risk of stroke, the therapy should be aggressive. In the case of incomplete LAA closure, an additional closure device may be used to complete occlusion and avoid lifelong anticoagulation therapy.

Incidence, risk factors and prognostic impact of acute kidney injury after coronary angiography and intervention in kidney transplant recipients: a single-center retrospective analysis.

INTRODUCTION: Kidney transplant recipients (KTR) represent a high-risk population for cardiovascular disease. Coronary artery disease (CAD) is the most common cause of morbidity and mortality in this population. In KTR, coronary angiography and intervention (CI) can be associated with the risk of acute kidney injury (AKI). AIM: Data about the incidence and impact of AKI after CI in this population are rare. The aim of the present study is to describe the incidence and risk factors of AKI, periprocedural bleeding and the prognostic impact on 1-year mortality in KTR undergoing CI. MATERIAL AND METHODS: This retrospective single-center study includes all KTR undergoing CI at University Hospital Frankfurt between 2005 and 2015. RESULTS: A total of 135 CIs in KTR were analyzed. AKI occurred in 31 of 135 CIs (23%, AKI group). Patients of the AKI group were older; other baseline characteristics did not show significant differences. The amount of contrast dye used was higher in the AKI group (p = NS). Periprocedural bleeding defined by BARC criteria occurred more often in the AKI group (23% vs. 5%, p < 0.01) and persisted as a risk factor of AKI in multivariate analysis (odds ratio = 6.43, 95% CI: 1.78-23.20, p = 0.01). In-hospital mortality was 3% in the AKI group; no patient of the non-AKI group died during hospitalization (p = 0.2). One-year-survival was significantly higher in the non-AKI group (94% vs. 81%, p = 0.02). CONCLUSIONS: AKI is an important prognostic determinant in KTR undergoing coronary angiography and percutaneous coronary intervention (PCI). Periprocedural bleeding events were associated with AKI. Well-known risk factors for AKI such as contrast agent and diabetes were of minor impact.

Bone marrow and plasma FGF-23 in heart failure patients: novel insights into the heart-bone axis.

AIMS: Fibroblast growth factor 23 (FGF-23) is known to be elevated in patients with congestive heart failure (CHF). As FGF-23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF-23 in CHF remains unclear. It is also unclear if FGF-23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF-23 levels measured in bone marrow plasma (FGF-23-BM) and in peripheral blood (FGF-23-P) in CHF patients to gain further insights into the heart-bone axis of FGF-23 expression. We also investigated possible associations between FGF-23-BM as well as FGF-23-P and outcome in CHF patients. METHODS AND RESULTS: We determined FGF-23-P and FGF-23-BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF-23-BM and FGF-23-P with all-cause mortality in CHF patients, 32 events, median follow-up 1673 days, interquartile range [923, 1828]. FGF-23-P (median 60.3 vs. 22.0 RU/mL, P < 0.001) and FGF-23-BM (median 130.7 vs. 93.1 RU/mL, P < 0.001) levels were higher in CHF patients compared with healthy controls. FGF-23-BM levels were significantly higher than FGF-23-P levels in both CHF patients and in healthy controls (P < 0.001). FGF-23-P and FGF-23-BM correlated significantly with LVEF (r = -0.37 and r = -0.33, respectively), N terminal pro brain natriuretic peptide levels (r = 0.57 and r = 0.6, respectively), New York Heart Association status (r = 0.28 and r = 0.25, respectively), and estimated glomerular filtration rate (r = -0.43 and r = -0.41, respectively) (P for all <0.001) and were independently associated with all-cause mortality in CHF patients after adjustment for LVEF, estimated glomerular filtration rate, New York Heart Association status, and N terminal pro brain natriuretic peptide, hazard ratio 2.71 [confidence interval: 1.18-6.20], P = 0.018, and hazard ratio 2.80 [confidence interval: 1.19-6.57], P = 0.018, respectively. CONCLUSIONS: In CHF patients, FGF-23 is elevated in bone marrow plasma and is independently associated with heart failure severity and all-cause mortality. The failing heart seems to interact via FGF-23 within a heart-bone axis.

Takotsubo Cardiomyopathy Triggered by Venous Air Embolism During Craniotomy in the Sitting Position.

BACKGROUND: We present a case of stress-induced cardiomyopathy (Takotsubo cardiomyopathy) caused by a venous air embolism during a craniotomy performed in the sitting position. CASE DESCRIPTION: A 69-year-old woman was admitted to the neurosurgical department and scheduled for elective resection of a cerebellar metastasis in the sitting position. After craniotomy and opening of the posterior fossa, a venous air embolism was detected via transesophageal echocardiography. The patient immediately presented with cardiac decompensation with signs of takotsubo or stress-induced cardiomyopathy. CONCLUSIONS: Intensivists and anesthesiologists in the operating room and in intensive care units need to be aware of stress-induced cardiomyopathy as a probably underdiagnosed disease entity, especially as management differs significantly from other forms of cardiogenic shock. Diagnosis can be accomplished quickly by bedside echocardiography, emphasizing the need for availability of this tool and the integration of stress-induced cardiomyopathy in diagnostic algorithms in the intensive care unit.

ß-Blockers and ivabradine differentially affect cardiopulmonary function and left ventricular filling index.

OBJECTIVE: Patients with left ventricular (LV) diastolic dysfunction are characterized by exertional dyspnoea. Heart rate (HR) reduction by ß-blockers can improve exercise tolerance by prolonging LV filling, but their negative inotropic and lusitropic properties can be detrimental in this disease. We tested the effects of administering ivabradine, a HR-lowering drug without impact on cardiac kinetics that may favorably affect diastolic function. METHODS: Twenty-four patients with coronary artery disease (CAD) and normal LV ejection fraction on chronic ß-blocker therapy were included. NT-proBNP serum levels were determined prior to and after cardiopulmonary exercise. ß-Blockers were then replaced by ivabradine and patients were re-tested after 6 weeks. Patients were initially classified as having a low (E/e' ≤ 8; n = 11) or high (E/e' > 8; n = 13) LV filling index. RESULTS: E/e' significantly decreased during ivabradine therapy in patients with high E/e' (10.7 ± 2.9 vs. 8.9 ± 1.7; p < 0.01), whereas no difference occurred in patients with low E/e' (6.4 ± 0.7 vs. 6.5 ± 1.1; p = ns). With ivabradine, patients with high E/e' had an increased oxygen uptake at the anaerobic threshold (from 10.8 ± 1.4 to 11.8 ± 1.9 ml/min/kg; p < 0.05) and a steeper slope of the initial oxygen pulse curve (from 293 ± 109 to 359 ± 117 µl/beat/kg/W; p < 0.05). Moreover, patients with high E/e' had lower NT-proBNP serum levels at rest (169 ± 207 vs. 126 ± 146 pg/ml; p < 0.05) and after exercise (190 ± 256 vs. 136 ± 162 pg/ml; p < 0.05) during ivabradine therapy. CONCLUSIONS: In patients with CAD and elevated E/e', switching therapy from ß-blockers to ivabradine may cause a reduction in LV filling pressures and an improved stroke volume response to exercise.

Ivabradine therapy to unmask heart rate-independent effects of ß-blockers on pulse wave reflections.

BACKGROUND: Prior studies suggest that ß-blockers lead to increased pulse wave reflections, thereby negating the blood pressure lowering effects on cardiovascular mortality. Parts of these effects may be induced by the heart rate reduction under ß-blockade. The aim of this study was to unmask heart rate-independent effects of ß-blockade on pulse wave reflections by switching therapy from ß-blockers to ivabradine, an I f channel inhibitor without impact on systemic hemodynamics. METHODS: 14 male patients (age 61 ± 3 years, LVEF 62 ± 1 %) with arterial hypertension and coronary artery disease (CAD) under chronic ß-blocker therapy at moderate dosage and additional renin-angiotensin system-blocking therapy were included. We determined radial augmentation index (rAI) by radial applanation tonometry in patients under ß-blockade both at rest and during early recovery after exercise. ß-Blockers were then replaced by ivabradine. Six weeks later, patients were re-tested at rest and after exercise under ivabradine therapy. RESULTS: Mean heart rate (68 ± 3 vs. 63 ± 3 bpm; p = ns) and resting mean arterial pressure (98 ± 2 vs. 98 ± 2 mmHg; p = ns) were not different between ß-blocker or ivabradine therapy, respectively. The rAI remained unchanged after switching therapy from ß-blocker to ivabradine (86 ± 2 vs. 84 ± 4 %; p = ns). Post exercise, the rAI revealed an identical decrease in both groups (-7.2 ± 2.4 vs. -5.4 ± 2.5 %, p = ns). The increase in heart rate between resting conditions and early recovery post exercise was inversely correlated with the decrease of rAI under ß-blockade (r = -0.70; p < 0.01) and showed a trend towards correlation under ivabradine (r = -0.52; p = 0.07). CONCLUSION: In men at the age of 60 years and CAD, ß-blockade does not exert heart rate-independent, pleiotropic effects on peripheral pulse wave reflections, both at rest or after exercise. Our results fit well within recent studies, demonstrating the fundamental influence of heart rate on rAI.

Procedural safety and predictors of acute outcome of intracoronary administration of progenitor cells in 775 consecutive procedures performed for acute myocardial infarction or chronic heart failure.

BACKGROUND: Cell-based therapies are a promising option in patients with acute myocardial infarction or chronic heart failure (CHF). However, administration of cells requires intracoronary or intracardiac instrumentation, which is potentially associated with periprocedural risks. Therefore, we analyzed periprocedural complications and 30-day outcome in 775 consecutive procedures of intracoronary administration of progenitor cells using the stop-flow technique. METHODS AND RESULTS: Indications for cell administration were acute myocardial infarction (n=126) and CHF of ischemic (n=562) or nonischemic (n=87) etiology. Vessel injury was observed in a total of 9 procedures (1.2%) and could be promptly managed by additional progenitor cell injection (PCI) in all but 1 case. No procedural deaths were observed. A periprocedural increase in troponin T was observed in 3.2% of the CHF procedures, in which no concomitant PCI was performed and troponin levels were not elevated before the procedure. Independent significant predictors of troponin T increase were higher New York Heart Association (NYHA) class (NYHA I versus NYHA IV; P=0.01; NYHA I versus III; P=0.19; NYHA I versus II; P=0.55), concomitant revascularization (P<0.01), presence of elevated troponin T before the procedure (P<0.01), and peripheral occlusive disease (P=0.04). At 30 days, there were 4 deaths (0.5%), 1 stroke (0.13%), 8 acute myocardial infarctions (1%), and 5 hospitalizations for exacerbation of heart failure (0.64%). CONCLUSIONS: Intracoronary infusion of progenitor cells can be performed with adequate safety in patients with acute myocardial infarction or CHF, because the safety profile was similar to what is usually expected from a coronary angiogram in the present cohort. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00962364, NCT00284713, and NCT00289822.

Elevated levels of the mediator of catabolic bone remodeling RANKL in the bone marrow environment link chronic heart failure with osteoporosis.

BACKGROUND: Chronic heart failure (CHF) is associated with a 4-fold increased risk for osteoporotic fractures. Therefore, we sought to identify the pathophysiological link between chronic heart failure and catabolic bone remodeling. METHODS AND RESULTS: In a total cohort of 153 subjects (123 patients with CHF, 30 patients with coronary artery disease and preserved cardiac function) as well as mice with heart failure, bone marrow (BM) plasma levels of the catabolic receptor activator of NF-κB ligand (RANKL), and its antagonist, osteoprotegerin were measured. The osteoclast inducing activity of BM plasma was tested in cell culture. BM plasma levels of RANKL and of the ratio RANKL/osteoprotegerin were significantly elevated in patients with CHF. On multivariate regression analysis, parameters of severity and duration of heart failure were independent determinants of elevated BM plasma RANKL levels. BM plasma levels of RANKL were directly correlated with the systemic marker of bone turnover C-telopeptide of type 1 collagen (r=0.6; P<0.001). Alterations in BM plasma levels of RANKL/osteoprotegerin were confirmed in a mouse model of postinfarction heart failure. Stimulation of human mesenchymal cells with BM plasma obtained from CHF patients increased the formation of osteoclasts, and this effect was blocked by the RANKL inhibition. CONCLUSIONS: CHF is associated with a profound and selective elevation of the bone resorption stimulating RANKL within the BM microenvironment. These data for the first time disclose a direct pathophysiological pathway linking CHF with catabolic bone remodeling associated with an increased osteoporotic fracture risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT 00289822, NCT 00284713, NCT 00326989, NCT 00962364.

Microvascular dysfunction and pulse wave reflection characterize different vascular pathologies in patients at cardiovascular risk.

BACKGROUND: Endothelial function and arterial pulse wave reflections play a crucial role in the pathogenesis of atherosclerosis. While the endothelium-dependent reactive hyperemia index (RHI) of the digital arteries is considered as a marker of microvascular function, an increased augmentation index (AI) may indicate beginning macrovascular damage. In this study we assessed the interrelationships among these noninvasive measures of vascular function. PATIENTS AND METHODS: In 178 all-comer patients with documented cardiovascular risk factors (22 % female; 65 % coronary artery disease, CAD), we measured radial AI (rAI) by radial applanation tonometry and digital AI (dAI) as well as RHI by using fingertip peripheral arterial tonometry. A modified SMART risk score was calculated in all participants based on cardiovascular risk factors and preexisting vascular disease. RESULTS: dAI and rAI demonstrated a significant and robust overall correlation (Pearson rank coefficient r = 0.63, p < 0.01), which was not affected by age, sex, diabetes mellitus and CAD. In contrast, both parameters demonstrated at most a weak correlation (dAI: r = 0.26, p < 0.01 and rAI: r = 0.12, p = 0.10) with microvascular function (RHI). While dAI and rAI were significantly correlated to female sex, age, low body height, low heart rate and the presence of CAD, RHI was associated with the presence of diabetes mellitus and nicotine use. Finally, only microvascular function was associated with the modified SMART risk score, but not augmentation indices. CONCLUSIONS: RHI and increased pulse wave reflection appear to represent two distinct vascular pathologies in patients with cardiovascular risk. In contrast, RHI might be useful to identify patients at highest cardiovascular risk once atherosclerotic disease has been diagnosed.

Early remodeling processes as predictors of diastolic function 5 years after reperfused acute myocardial infarction and intracoronary progenitor cell application.

AIMS: Ischemia-induced left ventricular (LV) diastolic dysfunction (DD) is increasingly recognized as a therapeutic challenge. While DD during acute myocardial infarction (AMI) determines patients' prognosis, it is unknown how LV remodeling after AMI affects the development of DD. Therefore, we aimed to identify AMI characteristics, which determine diastolic function after 5 years. METHODS AND RESULTS: 41 patients with reperfused AMI and intracoronary infusion of progenitor cells were included into the present analysis of the TOPCARE-AMI trial. At 5-year follow-up, we determined LV diastolic function including LV-filling index (E/E') by echocardiography. Diastolic function was normal in 21 patients (DD class 0), impaired in 14 patients (DD class 1) and pseudonormal in 6 patients (DD class 2). E/E' increased from DD class 0 to 2 (6.6 ± 1.3 vs. 9.0 ± 2.4 vs. 12.1 ± 6.2; p < 0.01). E/E' correlated with the maximal creatine kinase activity during AMI (CKMB(max) r = 0.73, p < 0.01), the change in end-diastolic or end-systolic LV volumes between AMI and 4 months (∆LVEDV r = 0.67, p < 0.01; ∆LVESV r = 0.58, p < 0.01), ejection fraction at 5 years (r = -0.47, p < 0.01) and NT-proBNP serum levels at 5 years (r = 0.37, p < 0.05). Multivariate analysis revealed CKMB(max) (ß = 0.56, p < 0.01) and ∆LVEDV (ß = 0.38, p < 0.01) as independent predictors for E/E' 5 years after AMI. CONCLUSION: Adverse early remodeling processes (reflected by LV dilatation between infarction and 4 months) determine long-term diastolic function in patients after reperfused AMI and progenitor cell therapy.

Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI): final 5-year results suggest long-term safety and efficacy.

BACKGROUND: Limited data is available for investigating the long-term safety and effects of intracoronary progenitor cell therapy in patients with acute myocardial infarction (AMI). OBJECTIVE: To assess the clinical course, NT-proBNP and MRI data as objective markers of cardiac function of the TOPCARE-AMI patients at 5-year follow-up. DESIGN: The TOPCARE-AMI trial was the first randomized study investigating the effects of intracoronary infusion of circulating (CPC) or bone marrow-derived progenitor cells (BMC) in 59 patients with successfully reperfused AMI. RESULTS: Five-year follow-up data were completed in 55 patients, 3 patients were lost to follow-up. None of the patients showed any signs of intramyocardial calcification or tumors at 5 years. One patient died during the initial hospitalization, no patient was rehospitalized for heart failure and 16 patients underwent target vessel revascularization (TVR). Only two TVRs occurred later than 1 year after cell administration making it very unlikely that the infused cells accelerate atherosclerotic disease progression. Serum levels of NT-proBNP remained significantly reduced at the 5-year follow-up indicating the absence of heart failure. MRI subgroup analysis in 31 patients documented a persistent improvement of LV ejection fraction (from 46 ± 10% at baseline to 57 ± 10% at 5 years, p < 0.001)). Simultaneously, there was a reduction (p < 0.001) in functional infarct size measured as late enhancement volume normalized to LV mass. However, whereas LV end-systolic volume remained stable, LV end-diastolic volume increased significantly. CONCLUSIONS: The 5-year follow-up of the TOPCARE-AMI trial provides reassurance with respect to the long-term safety of intracoronary cell therapy and suggests favorable effects on LV function.

A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy.

BACKGROUND: Intracoronary administration of bone marrow-derived progenitor cells (BMC) was shown to improve coronary microvascular function in ischemic heart disease. Because coronary microvascular dysfunction is implicated in the pathogenesis and prognosis of nonischemic dilated cardiomyopathy (DCM), we investigated the effects of intracoronary BMC administration in patients with DCM. METHODS AND RESULTS: Intracoronary infusion of BMC was performed in 33 patients with DCM by using an over-the-wire balloon catheter. Left ventricular contractility at baseline and after 3 months was assessed by analysis of left ventricular angiograms. Coronary hemodynamics were determined by intracoronary Doppler wire measurements. After 3 months, regional wall motion of the target area (contractility from -1.08 + or - 0.39 to -0.97 + or - 0.47 SD/chord, P=0.029) and global left ventricular ejection fraction (from 30.2 + or - 10.9 to 33.4 + or - 11.5%, P<0.001) were improved. Increase of regional contractile function was directly related to the functionality of the infused cells as measured by their colony-forming capacity. Minimal vascular resistance index was significantly reduced in the BMC-treated vessel after 3 months (from 1.53 + or - 0.63 to 1.32 + or -0.61 mm Hg x s/cm; P=0.002, n=24), whereas no changes were observed in the reference vessel (from 1.60 + or - 0.45 to 1.49 + or - 0.45 mm Hg x s/cm; P=0.133, n=13). Twelve months after BMC infusion, N-terminal prohormone brain natriuretic peptide (NT-proBNP) serum levels were decreased, suggesting a beneficial effect on left ventricular remodeling processes (from 1610 + or - 993 to 1473 + or - 1147 pg/mL; P=0.038 for logNT-proBNP, n=26). CONCLUSIONS: Intracoronary administration of BMC seems to be associated with improvements in cardiac contractile and microvascular function in patients with DCM. Thus, randomized blinded studies are warranted to evaluate potential clinical benefits of intracoronary BMC administration in patients with DCM.

Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure.

OBJECTIVES: This study investigated whether reduced levels of circulating endothelial progenitors cells (EPCs) in chronic heart failure (CHF) are secondary to an exhaustion of hematopoietic stem cells (HSCs) in the bone marrow or to reduced mobilization. BACKGROUND: Circulating EPCs presumably originate from bone marrow-derived HSC. Persistent mobilization of EPCs was shown to be associated with favorable left ventricular infarct remodeling processes. METHODS: We assessed the number and functional capacity of EPCs in 17 healthy controls, 25 patients with ischemic cardiomyopathy (ICM), and 20 patients with dilated cardiomyopathy (DCM). To document an impairment of HSC function in the bone marrow, the colony-forming unit capacity of bone marrow-derived mononuclear cells and the number of CD34+ HSCs were examined in 6 healthy volunteers, 94 ICM patients, and 25 DCM patients. RESULTS: The number of EPCs was reduced in CHF, irrespective of its etiology. In contrast, the migratory capacity was selectively impaired in EPCs of ICM patients (4.8 +/- 4.0 migrated cells; DCM 9.7 +/- 5.8; p = 0.02). On multivariate analysis, ICM, advanced New York Heart Association functional class, and CHF were independent predictors of functional EPC impairment. The number of bone marrow-derived CD34+ cells did not differ between the CHF populations. However, colony-forming units (CFUs) were selectively reduced in ICM patients (54.4 +/- 24.6; DCM 68.1 +/- 26.9; p < 0.02). Ischemic cardiomyopathy was the only independent predictor of impaired CFU capacity. Impaired CFU capacity was associated with reduced matrix metalloproteinase-9 activity in the bone marrow plasma. CONCLUSIONS: Ischemic cardiomyopathy is associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood, which may contribute to an unfavorable left ventricular (LV) remodeling process.

Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD Registry.

Although intracoronary administration of bone marrow-derived mononuclear progenitor cells (BMCs) may be associated with improved cardiac function in patients with chronic postinfarction heart failure, the impact on prognosis and clinical outcome of these patients is unknown. To identify potential predictors for a favorable clinical outcome, we assessed natriuretic peptide serum levels as objective markers of heart failure and the occurrence of cardiac death in relation to functional capacity of the infused cells in a consecutive series of 121 patients with chronic ischemic heart disease treated with intracoronary infusion of BMCs. Our analyses show that both N-terminal pro-brain natriuretic peptide (NT-proBNP) and N-terminal pro-atrial natriuretic peptide (NT-proANP) serum levels were significantly reduced in patients with established postinfarction heart failure 3 months after transcoronary progenitor cell administration. NT-proBNP serum levels greater than or equal to median (735 pg/mL) at baseline and a high number of infused progenitor cells with colony-forming capacity were the only independent predictors of a favorable response 3 months after intracoronary administration of BMCs. During extended clinical follow-up (577+/-442 days), a total of 14 deaths occurred in the overall patient population. Kaplan-Meier curves for both all cause and cardiac mortality showed that patients receiving a higher number of colony-forming cells were significantly less likely to die than those patients receiving low numbers of colony-forming cells (P=0.01). Most importantly, infusion of a high number of cells with colony-forming capacity was associated with a complete abrogation of increased mortality in patients with elevated NT-proBNP serum levels (> or =735 pg/mL; median) at baseline (P<0.001). Taken together, our results show that patients with objective evidence of postinfarction heart failure demonstrate a significant reduction of both NT-proBNP and NT-proANP serum levels within 3 months following intracoronary infusion of BMCs. Importantly, infusion of progenitor cells with a high functional capacity is associated with a significantly lower mortality during further follow-up.

Intracoronary infusion of progenitor cells is not associated with aggravated restenosis development or atherosclerotic disease progression in patients with acute myocardial infarction.

AIMS: Experimental and clinical pilot studies suggest that intracoronary progenitor cell infusion can improve left ventricular function and remodelling after acute myocardial infarction (AMI). Since progenitor cells are also known to be involved in restenosis development and atherosclerosis progression, an increased restenosis rate may be a risk of intracoronary cell therapy. METHODS: We performed a retrospective study to compare quantitative angiographic measurements of the infarct target vessel in 83 patients with AMI treated with bare metal stent PCI (matched control) and in 83 patients receiving additional intracoronary progenitor cell infusion at a mean of 5 days post-AMI stent PCI and after 4 months. RESULTS: The late loss as a measure of neointima formation was similar between the control and the cell-treated group at follow-up (0.9+/-0.8 vs. 0.9+/-0.7 mm, P=0.9). Moreover, restenosis rate was comparable in both groups (35% control vs. 27% cell-treated group, P=0.2). Multivariable analysis excluded cell therapy as an independent significant predictor of increased late loss (P=0.4), whereas acute gain (P=0.012) and diabetes mellitus (P=0.002) were independent predictors of late loss. Finally, in the cell-treated group, target vessel revascularization rate remained at 28.9% during a median of >3 years of follow-up, thus excluding an effect on atherosclerotic disease progression. CONCLUSION: In patients with AMI successfully treated with bare metal stent PCI, additional intracoronary progenitor cell infusion does not lead to an increased neointima formation within the implanted stent within 4 months or aggravation of atherosclerotic disease progression.

Transcoronary transplantation of progenitor cells after myocardial infarction.

BACKGROUND: Pilot studies suggest that intracoronary transplantation of progenitor cells derived from bone marrow (BMC) or circulating blood (CPC) may improve left ventricular function after acute myocardial infarction. The effects of cell transplantation in patients with healed myocardial infarction are unknown. METHODS: After an initial pilot trial involving 17 patients, we randomly assigned, in a controlled crossover study, 75 patients with stable ischemic heart disease who had had a myocardial infarction at least 3 months previously to receive either no cell infusion (23 patients) or infusion of CPC (24 patients) or BMC (28 patients) into the patent coronary artery supplying the most dyskinetic left ventricular area. The patients in the control group were subsequently randomly assigned to receive CPC or BMC, and the patients who initially received BMC or CPC crossed over to receive CPC or BMC, respectively, at 3 months' follow-up. RESULTS: The absolute change in left ventricular ejection fraction was significantly greater among patients receiving BMC (+2.9 percentage points) than among those receiving CPC (-0.4 percentage point, P=0.003) or no infusion (-1.2 percentage points, P<0.001). The increase in global cardiac function was related to significantly enhanced regional contractility in the area targeted by intracoronary infusion of BMC. The crossover phase of the study revealed that intracoronary infusion of BMC was associated with a significant increase in global and regional left ventricular function, regardless of whether patients crossed over from control to BMC or from CPC to BMC. CONCLUSIONS: Intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction. Transplantation of BMC is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months.

Impaired CXCR4 signaling contributes to the reduced neovascularization capacity of endothelial progenitor cells from patients with coronary artery disease.

Transplantation of bone marrow cells as well as circulating endothelial progenitor cells (EPC) enhances neovascularization after ischemia. The chemokine receptor CXCR4 is essential for migration and homing of hematopoietic stem cells. Therefore, we investigated the role of CXCR4 and its downstream signaling cascade for the angiogenic capacity of cultured human EPC. Ex vivo, differentiated EPC derived from peripheral blood abundantly expressed CXCR4. Incubation of EPC from healthy volunteers with neutralizing antibodies against CXCR4 profoundly inhibited vascular endothelial growth factor- and stromal-derived factor-1-induced migration as well as EPC-induced angiogenesis in an ex vivo assay. Preincubation of transplanted EPC with CXCR4 antibody reduced EPC incorporation and impaired blood-flow recovery in ischemic hindlimbs of nude mice (57+/-4% of normal perfusion versus untreated EPC: 80+/-11%, P<0.001). Bone marrow mononuclear cells (BM-MNC) or EPC of heterozygous CXCR4(+/-) mice displayed reduced CXCR4 expression and disclosed impaired in vivo capacity to enhance recovery of ischemic blood flow in nude mice (blood flow 27+/-11% versus 66+/-25% using wild-type cells, P<0.01). Importantly, impaired blood flow in ischemic CXCR4(+/-) mice was rescued by injection of wild-type BM-MNC. Next, we investigated the role of CXCR4 for functional capacities of EPC from patients with coronary artery disease (CAD). Surface expression of CXCR4 was similar in EPC from patients with CAD compared with healthy controls. However, basal Janus kinase (JAK)-2 phosphorylation was significantly reduced and less responsive to stromal-derived factor-1 in EPC from patients with CAD compared with healthy volunteers, indicating that CXCR4-mediated JAK-2 signaling is dysregulated in EPC from patients with CAD. The CXCR4 receptor signaling profoundly modulates the angiogenic activity and homing capacity of cultured human EPC. Disturbance of CXCR4 signaling, as demonstrated by reduced JAK-2 phosphorylation, may contribute to functional impairment of EPC from patients with CAD. Stimulating CXCR4 signaling might improve functional properties of EPC and may rescue impaired neovascularization capacity of EPC derived from patients with CAD.