End-stage Ischemic Heart Disease Research Articles

Abstract We027: Gut Microbiota Modulation by Immunosuppression and Cardiac Cell Therapy in a Nonhuman Primate Ischemia/Reperfusion Model of Cardiac Regeneration

End-stage ischemic heart disease necessitates heart transplantation, and emerging cell therapy presents a promising solution to address donor scarcity. Disruption of gut microbiota significantly influences various diseases and treatments, including transplantation. However, the impact of immunosuppression and cardiac cell therapy on gut microbiota remains largely unexplored. To elucidate this relationship, we investigated gut microbiota dynamics in response to immunosuppression and cell therapy in a nonhuman primate (NHP) cardiac ischemia/reperfusion (IR) model, with controlled genetic, dietary, and environmental factors. Immunosuppression enriched anaerobes (Faecalibacterium, Streptococcus, Anaerovibrio, Dialister), increasing gut microbiota diversity. These changes correlated with metabolic shifts towards amino acid metabolism and nucleosides/nucleotides biosynthesis. Combined treatment of human induced pluripotent stem cell (iPSC)-derived endothelial cells (EC) and cardiomyocytes (CM) also increased gut microbiota diversity, with specific genera alterations. The EC/CM co-treatment group displayed gut microbiota resembling the pre-injury group, with host metabolism shifting towards amino acid and fatty acid/lipid biosynthesis post-cell therapy. These observed microbiota changes and metabolic shifts could serve as biomarkers for monitoring cell therapy and immunosuppression outcomes, offering potential therapeutic targets to enhance efficacy.

Abdominal Aortic Aneurysm in Heart Transplant Recipients: New Insights from a 30-year Experience at a Single Center

The improvement in survival rates for heart transplant recipients (HTRs) has increased their risk of developing extracardiac diseases such as abdominal aortic aneurysms (AAAs). The purposes of this study were to evaluate the prevalence and to describe the clinical features and natural history of AAA in HTRs. A retrospective review of all patients (375) who underwent heart transplantation (HT) at our center over a 32-year period (1983-2015) was carried out. We identified 20 patients (5.3%) with AAA. All but one patient were male (95%), and most of them (80%) had a history of ischemic heart disease (IHD) prior to transplantation. The mean age of the patients with AAA at transplant was 57.2±7.3years (range: 42-62years). Seven of the 20 patients with AAA already had an AAA (30-55mm) prior to transplantation. The average aneurysm size at the time of diagnosis was 40.9±9.6mm, and the average patient age at the time of diagnosis was 62.2±8.3years. The mean linear expansion rate was 10.6±2.12mm/y, and the exponential expansion rate was 0.220±0.040year-1, respectively. The median follow-up time was 5.4years (range 0.1-27.4years). The median survival was 143months (95% confidence interval (CI) 65 to 180months) for the 20 HTRs with AAA and 68.8months (95% CI 46 to 88months) for the other HTRs. The natural history of AAA in HTR is characterized by an increased expansion rate. Male HTR with end-stage IHD are particularly at risk and should be closely followed-up after HT.

P746Protective role of the longevity associated variant of BPIFB4 in chronic ischemia

Abstract Background A rare Longevity Associated Variant (LAV) of the gene BPIFB4, whose protein product can be secreted, is recessively associated with extreme longevity, positively impacting the cardiovascular system and promoting therapeutic angiogenesis in an hindlimb ischemia model. Aim Aim of this work is to verify if LAV-BPIFB4 may temper the phenotype of chronic ischemia in humans, thus suggesting its therapeutic potential. Methods and results 39 hearts explanted from patients affected by end-stage ischemic heart disease were studied. Of these, 7 were homozygous for BPIFB4-LAV. Homozygous and non-homozygous patients did not differ in sex, age and in the prevalence of comorbidities or risk factors. However, the time elapsed from myocardial infarction to transplantation was significantly longer for LAV homozygous with respect to LAV heterozygous patients (159±95 vs 58±27 months, p=0.045). Histologically, while BPIFB4 levels did not differ in accordance with the genotype, the fraction of Tunel+and 53BP1+apoptotic and senescent myocytes was significantly lower in homozygous patients (1.2±0.4% vs 23.8±21.7%, p=0.026 and 31.5±6.7% vs 44.4±6.1%, p=0.031, respectively). Significantly lower levels of lipoperoxides and higher levels of Parkin were observed in homozygous hearts too. Next, we directly tested the role of BPIFB4 on PDGFRb+ NG2+Tbx18+cardiac pericytes/mural cells (PM) cultured from normal atria (PMnorm, n=10) and from ischemic failing hearts (PMfail, n=7). BPIFB4 gene transcript was significantly more expressed in PMnorm than PMfail. Silencing BPIFB4 expression in PMnorm significantly increased the proportion of senescent gH2AX+Ki67-cells (3.6±2.9% vs 13.6±9.5%, p=0.049). Conversely, addition of recombinant LAV BPIFB4 protein to PMfail cultures significantly reduced the rate of senescent cells (21.1±9.4% vs 6.0±4.8%, p=0.03), an effect that was not observed with the administration of WT BPIFB4. PMfail cultures exposed to LAV BPIFB4 significantly reversed alterations observed with pathology, such as the accumulation of both lipofuscins and of very elongated and interconnected mitochondria in the cell cytoplasm, as well as elevated mitochondrial superoxide anion levels. Finally, a larger fraction of PMnorm cells showed, with respect to PMfail, the nuclear translocation of vitamin D receptor (74.6±6.1% vs 50.1±14.4, p=0.04), coupled with a significant upregulation of its, longevity associated, target gene Klotho. Importantly, LAV BPIFB4 significantly increased the fraction of PMfail with vitamin D receptor nuclear localization (55.8±17.6% vs 85.1±8.2%, p=0.005). Conclusion LAV BPIFB4 could attenuate the progression of ischemic heart disease to heart failure. Part of its protective effect may be due to its ability to reduce mitochondrial oxidative stress and to revert the senescent phenotype of cardiac derived cells. Acknowledgement/Funding CARIPLO foundation

A Serious Complication in a Patient With a Ventricular Assist Device

We report the case of a 47-year-old man with end-stage ischemic heart disease who underwent implantation of a Berlin Heart EXCOR biventricular assist device (VAD) as a bridge to transplantation (Figure 1). He received oral anticoagulation and dual antiplatelet therapy with acetylsalicylic acid and clopidogrel, according to the standard protocol until, 1 month later, he had a hemorrhagic stroke that left no sequelae. Therefore, the decision was made to discontinue the antiplatelet therapy and to treat the patient with acenocoumarol alone. Three months later, he came to the emergency service because of a warning from the VAD that indicated low flow in the system. He had an international normalized ratio (INR) of 2.6. Inspection of the left VAD (Figures 2A and 2B and video clip [supplementary material]) revealed a moving shadow (s) associated with a thrombus that grew rapidly (e) within the blood chamber, in addition to an abnormal expansion of the outer membrane during systole (Figure 2C). As we suspected rupture of 1 of the membranes that separate the 2 chambers (blood and air) and because of the risk of systemic embolization of the thrombus, the left VAD cannulas were rapidly clamped and the flow in the right VAD was reduced to prevent acute pulmonary edema. The malfunctioning VAD was replaced, (Figure 3) and rupture of the inner membrane (*) of the explanted device and the presence of a large associated thrombus (d) were confirmed. The outcome of this replacement was favorable and the patient received a transplant several weeks later. Thrombotic complications associated with VAD are relatively frequent and potentially fatal events. In this case, early identification of the problem and urgent intervention allowed successful replacement of the device and subsequent transplantation.

Initial Clinical Experience With the HeartWare Left Ventricular Assist System: A Single-Center Report

The HeartWare ventricular assist device (HVAD) system (HeartWare International Inc, Framingham, MA) is a new centrifugal continuous-flow ventricular assist device. The aim of the present study is to review our institutional experience with this novel device. We reviewed the files of 50 patients (39 men, 11 women) with a mean age of 50.6 ± 11.8 years (range, 19 to 70 years) who underwent HVAD implantation between July 2009 and November 2011. Two patients underwent HeartWare BIVAD implantation. The underlying heart diseases were end-stage ischemic heart disease (n = 12), acute myocardial infarction (n = 9), dilated cardiomyopathy (n = 27) and acute myocarditis (n = 2). Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles were level 1 (n = 11), 2 (n = 5), 3 (n = 10), and 4 (n = 24). After a cumulative support duration of 11,086 days, Kaplan-Meier analysis revealed a survival of 82.0%, 77.9%, 75.5%, at 1, 12, and 24 months, respectively. Causes of early death were right heart failure (n = 4), multiorgan failure (n = 2), septic shock (n = 2), and major neurologic complications (n = 4). One late death occurred due to a right heart failure. Comparison between patients operated on in cardiogenic shock (INTERMACS 1 and 2) and patients who underwent elective HVAD implantation (INTERMACS 3 and 4) revealed a survival of 61.5% and 44.1% for the INTERMACS 1 and 2 group and 90.3% and 87.1% for the INTERMACS 3 and 4 group at 1 and 12 months, respectively (odds ratio, 4.67; p = 0.003). One patient was weaned from the system after 2 years. Eleven patients (22%) were successfully bridged to transplantation. Mean time to transplantation was 209 days (range, 72 to 427 days). Posttransplant survival at the 1-year follow-up was 90.9% (11 patients). Our experience with HVAD shows satisfying results with an excellent posttransplantation survival. Moreover, the stratified survival based on the level of preoperative stability shows better outcomes in patients undergoing elective HVAD implantation.

Very Late Mycotic Pseudoaneurysm Associated With Drug-Eluting Stent Fracture

A 72-year-old woman with diabetes mellitus and end-stage ischemic heart disease was admitted to the hospital because of an episode of unstable angina. She had undergone coronary artery bypass graft surgery 4 years earlier with sequential left internal mammary artery to left anterior descending and diagonal artery, and saphenous vein graft to left marginal artery. Seven months after surgery, because of disease progression, she underwent a percutaneous coronary intervention with rotational atherectomy and a 3.5×32 mm paclitaxel-eluting stent implantation at the right coronary artery. During the following years, the patient had several admissions for unstable angina. A new angiography showed a diffusely diseased native vessel, an occluded saphenous graft to the marginal, a patent sequential left internal mammary artery graft to left anterior descending and diagonal artery, and persistence of the good result of the stent implanted in the right coronary artery. Because of the extension and severity of the coronary artery disease, she had been considered a no-option patient. During the present admission (1-year after the last angiography) she experienced fever and superficial phlebitis secondary to peripheral venous catheter that was treated with cloxacillin for 10 days. Five weeks later she was readmitted for persistent …

Successful Re-Use of the Transplanted Heart

The case of re-use of a previously transplanted heart after brain death of the first recipient is reported. The second recipient was a 60-year-old man who suffered end-stage ischemic heart disease. The operative and postoperative course was uneventful, with the exception of secondary diabetes. The patient is post-transplantation by more than 10 months and is now in New York Heart Association functional class I. This case confirms the possibility of using this procedure, particularly in the situation when there is a shortage of organ donors.

Symptoms of fatigue and depression in ischemic heart disease are driven by personality characteristics rather than disease stage: a comparison of CAD and CHF patients

Symptoms of fatigue and depression are prevalent across stages of ischemic heart disease (IHD). We examined (i) the effect of both the IHD stage and type-D personality on fatigue and depressive symptoms at 12-month follow-up, and (ii) whether the effect of type-D personality on these symptoms is moderated by IHD stage. Two different samples of patients were included to represent IHD stage: 401 percutaneous coronary intervention patients (early-stage IHD) and 105 ischemic chronic heart failure patients (end-stage IHD) completed the DS14 Type-D Scale at baseline. Logistic regression analysis was used to examine the impact of IHD stage and type-D personality on fatigue and depression at follow-up. Disease stage was neither associated with symptoms of fatigue (P=0.99) nor depression (P=0.29) at 12 months. In contrast, type-D personality was shown to predict both symptoms of fatigue [odds ratio (OR)=2.96; 95% confidence interval (CI): 1.92-4.58, P<0.001] and depression (OR=4.91; 95% CI: 3.16-7.65, P<0.001) at follow-up; the effect of type-D personality on these symptoms was not moderated by disease stage. In multivariable analysis, type-D remained a significant predictor of symptoms of fatigue (OR=3.14; 95% CI: 1.98-4.99, P<0.001) and depression (OR=5.90; 95% CI: 3.60-9.67, P<0.001), also after controlling for symptom levels at baseline. Type-D personality but not disease stage predicted symptoms of fatigue and depression at 12-month follow-up.

Mid-term changes of left ventricular geometry and function after Dor, SAVE, and Overlapping procedures

The aim of this study was to investigate the mid-term changes of left ventricular (LV) geometry and function after Dor, septal anterior ventricular exclusion (SAVE), and Overlapping ventricular remodeling procedures. Forty-three patients who underwent LV reconstruction for end-stage ischemic heart disease, were divided into three groups, undergoing Dor (n=15), SAVE (n=12), and Overlapping procedures (n=16). Coronary artery bypass grafting and mitral annuloplasty were performed concomitantly when indicated. Left ventricular diastolic and systolic dimensions (LVDd and LVDs), LV end-diastolic and end-systolic volume indexes (LVEDVI and LVESVI), LV ejection fraction (LVEF), deceleration time (DcT), sphericity index (SI), and grade of mitral regurgitation were measured on preoperative and postoperative (immediately and at intermediate-term) echocardiography. In the Dor group, the LVEDVI and LVESVI were significantly reduced immediately after the operation, and increased again at intermediate follow-up. The SI was significantly increased immediately after the operation and increased thereafter in a linear fashion. In the SAVE group, the DcT was significantly reduced immediately after the operation and was not improved in the later stage. In the Overlapping group, the LVEDVI and LVESVI were significantly reduced, and remained as such at intermediate follow-up. The SI was not increased and remained almost unchanged after the operation. Progression in LV sphericity after the Dor procedure and persistent reduction of the DcT after the SAVE procedure seem to be procedure-related problems. The Overlapping procedure provided significant LV volume reduction, maintaining the most elliptical LV shape with acceptable early and late mortality.

From the laboratory bench to the patient's bedside: An update on clinical trials with mesenchymal stem cells

Mesenchymal Stem Cells (MSCs) are non-hematopoietic multi-potent stem-like cells that are capable of differentiating into both mesenchymal and non-mesenchymal lineages. In fact, in addition to bone, cartilage, fat, and myoblasts, it has been demonstrated that MSCs are capable of differentiating into neurons and astrocytes in vitro and in vivo. MSCs are of interest because they are isolated from a small aspirate of bone marrow and can be easily expanded in vitro. As such, these cells are currently being tested for their potential use in cell and gene therapy for a number of human diseases. Nevertheless, there are still some open questions about origin, multipotentiality, and anatomical localization of MSCs. In this review, we discuss clinical trials based on the use of MSCs in cardiovascular diseases, such as treatment of acute myocardial infarction, endstage ischemic heart disease, or prevention of vascular restenosis through stem cell-mediated injury repair. We analyze data from clinical trials for treatment of osteogenesis imperfecta (OI), which is a genetic disease characterized by production of defective type I collagen. We describe progress for neurological disease treatment with MSC transplants. We discuss data on amyotrophic lateral sclerosis (ALS) and on lysosomal storage diseases (Hurler syndrome and metachromatic leukodystrophy). A section of review is dedicated to ongoing clinical trials, involving MSCs in treatment of steroid refractory Graft Versus Host Disease (GVHD); periodontitis, which is a chronic disease affecting periodontium and causing destruction of attachment apparatus, heart failure, and bone fractures. Finally, we will provide information about biotech companies developing MSC therapy.

MR imaging in assessing cardiovascular interventions and myocardial injury

Performing an MR-guided endovascular intervention requires (1) real-time tracking and guidance of catheters/guide wires to the target, (2) high-resolution images of the target and its surroundings in order to define the extent of the target, (3) performing a therapeutic procedure (delivery of stent or injection of gene or cells) and (4) evaluating the outcome of the therapeutic procedure. The combination of X-ray and MR imaging (XMR) in a single suite was designed for new interventional procedures. MR contrast media can be used to delineate myocardial infarcts and microvascular obstruction, thereby defining the target for local delivery of therapeutic agents under MR-guidance. Iron particles, or gadolinium- or dysprosium-chelates are mixed with the soluble injectates or stem cells in order to track intramyocardial delivery and distribution. Preliminary results show that genes encoded for vascular endothelial and fibroblast growth factor and cells are effective in promoting angiogenesis, arteriogenesis, perfusion and LV function. Angiogenic growth factors, genes and cells administered under MR-guided minimally invasive catheter-based procedures will open up new avenues in treating end-stage ischemic heart disease. The optimum dose of the therapeutic agents, delivery devices and real-time imaging techniques to guide the delivery are currently the subject of ongoing research. The aim of this review is to (1) provide an updated review of experiences using MR imaging to guide transcatheter therapy, (2) address the potential of cardiovascular magnetic resonance (MR) imaging and MR contrast media in assessing myocardial injury at a molecular level and labeling cells and (3) illustrate the applicability of the non-invasive MR imaging in the field of angiogenic therapies through recent clinical and experimental publications.

Intramyocardial Injection of CD133+ Bone Marrow-Derived Stem Cells Improves Cardiac Function Long-Term in the Majority of Selected Patients with End-Stage Ischemic Heart Disease.

To improve tissue regeneration of ischemic myocardium, autologous bone marrow-derived stem cells have been injected intramyocardially in 10 patients with end-stage ischemic heart disease. Approx. 60 – 380 ml of bone marrow were harvested from the posterior iliac crest and processed in the operating room under GMP conditions using the automated cell selection device CliniMACS. By using the Duesseldorf protocol, the intraoperative isolation of CD133+-stem cells (1.9−10.0 x 106 cells; purity up to 97%) was achieved in less than 3 hours. Following isolation, autologous CD133+-stem cells were injected in a predefined pattern into the myocardium. Cardiac function was assessed by cardiac MRI and echocardiography three, six, and nine months postoperatively. A significant improvement of cardiac function could be documented in 7 out of 10 patients: ejection fraction (EF) before treatment: 10–22% - after 3 months: 18–30% - after 6 months: 19–30%, after 9 months: 21–31%; left ventricular enddiastolic volume (LVEDV) before treatment: 210 ± 123 ml, after 3 months: 169 ± 80 ml, after 6 months: 162 ± 82 ml, after 9 months: 175 ± 70 ml; left ventricular enddiastolic diameter (LVEDD) before treatment: 79.2 ± 7 mm, after 3 months: 57.4 ± 3 mm, after 6 months: 59.4 ± 4 mm, after 9 months: 56.2 ± 5 mm, respectively. In two patients cardiac function improved only temporarily over the first three months, 1 patient died one month after surgery due to a non-cardiac cause. In conclusion, the sole intramyocardial injection of autologous CD133+-cells proved to be safe and led to a significant gain in heart function in 7 of 10 patients, thereby avoiding or postponing (“bridging”) alternative therapies such as heart transplantaton. The benefial effects of intramyocardially injected bone marrow-derived stem cells might be explained by direcct cellular effects including neovascularization and indirect effects including the formation of growth factors promoting tissue repair.

Transendocardial Autologous Bone Marrow Mononuclear Cell Injection in Ischemic Heart Failure

Cell-based therapies for treatment of ischemic heart disease are currently under investigation. We previously reported the results of a phase I trial of transendocardial injection of autologous bone marrow mononuclear (ABMM) cells in patients with end-stage ischemic heart disease. The current report focuses on postmortem cardiac findings from one of the treated patients, who died 11 months after cell therapy. Anatomicopathologic, morphometric, and immunocytochemical findings from the anterolateral ventricular wall (with cell therapy) were compared with findings from the interventricular septum (normal perfusion and no cell therapy) and from the inferoposterior ventricular wall (extensive scar tissue and no cell therapy). No signs of adverse events were found in the cell-injected areas. Capillary density was significantly higher (P<0.001) in the anterolateral wall than in the previously infarcted tissue in the posterior wall. The prominent vasculature of the anterolateral wall was associated with hyperplasia of pericytes, mural cells, and adventitia. Some of these cells had acquired cytoskeletal elements and contractile proteins (troponin, sarcomeric alpha-actinin, actinin), as well as the morphology of cardiomyocytes, and appeared to have migrated toward adjacent bundles of cardiomyocytes. Eleven months after treatment, morphological and immunocytochemical analysis of the sites of ABMM cell injection showed no abnormal cell growth or tissue lesions and suggested that an active process of angiogenesis was present in both the fibrotic cicatricial tissue and the adjacent cardiac muscle. Some of the pericytes had acquired the morphology of cardiomyocytes, suggesting long-term sequential regeneration of the cardiac vascular tree and muscle.

First Clinical Experience With the Incor Left Ventricular Assist Device

The Incor (Berlin Heart AG, Germany) is a small (200 g), implantable, magnetically accentuated axial flow pump (non-pulsatile flow) designed to support the left ventricle for extended periods of time. We report on the first single-center clinical experience with this device. The Incor was studied in 15 consecutive patients (10 men, 5 women), 24 to 59 years of age. Underlying heart disease was end-stage ischemic heart disease (n = 5), acute myocardial infarction (n = 4), dilated cardiomyopathy (n = 3), acute myocarditis (n = 2) and Chagas disease (n = 1). All patients were in New York Heart Association (NYHA) Class IV heart failure. Four patients had prior open heart surgery. Implantation via cannulation of the left ventricular apex and the ascending aorta was elective in 6 patients and on an emergency basis in 9. No early bleeding complications were seen, but late bleeding occurred in 4 patients. Minor cerebral thromboembolic events with transient neurologic symptoms occurred in 3 patients; severe stroke had to be treated in 1 patient. Systemic emboli were seen in 2 patients. Thrombus-related pump dysfunction was suspected in 3 patients, and managed by intensifying anti-coagulation. Five patients were successfully transplanted after a support interval of 90 to 156 days; 1 patient could be weaned from the system after 171 days. Six patients died during support, 9 to 63 days after device implantation. The remaining 3 patients are still under support, with excellent quality of life. The Incor is a left ventricular assist device (LVAD) with transplant and adverse event rates comparable to those of other modern ventricular support devices. Its advantages include the small pump chamber, the virtual absence of device-related infections, and the extraordinary convenience during implantation and explantation.

Preserved benefit of enhanced external counterpulsation in end stage ischemic heart disease

Preserved benefit of enhanced external counterpulsation in end stage ischemic heart disease

Connexin40 mRNA and protein expression is elevated in end-stage human ischemic heart disease

Connexin40 mRNA and protein expression is elevated in end-stage human ischemic heart disease

Subclass Specificity of Autoantibodies against Myosin in Patients with Idiopathic Dilated Cardiomyopathy: Pro-inflammatory Antibodies in DCM Patients

Detection of antimyosin antibodies in non-inflammatory cardiac disease undermines their disease specificity as a sensitive marker of damage in dilated cardiomyopathy (DCM) patients. Antibody subclass specificity could provide a more sensitive marker of disease and possibly discriminate the humoral autoimmune responses in different cardiac diseases. Frequency and reactivity of autoantibodies against α- and β-isoforms of myosin heavy chain (mhc) were evaluated by ELISA for IgG, IgM, and subclasses IgG1, IgG2, and IgG3 in patients with DCM (NYHA III/IV, n = 82), end stage ischemic heart disease (E-IHD: NYHA III/IV, n = 62), mild ischemic heart disease (NYHA I/II, n = 27), and controls (n = 54). Autoantibodies against atrial and ventricular myosin were raised in heartfailure patients compared to mild-IHD and controls but with different antigen affinities. Reactivity in E-IHD was significantly raised against (ventricular) β-mhc compared with only mild-IHD patients, suggesting a relative increase in ventricular specific antibodies in IHD patients with a higher NYHA class. IgG subclass analysis for IgG1, IgG2, and IgG3 against α- and β-mhc showed statistically raised levels of IgG3 only in DCM patients and a significantly higher reactivity of IgG2 in heartfailure patients versus controls. The results demonstrate immunological heterogeneity of antimyosin antibodies developed in different clinical entities. Pro-inflammatory characteristics of IgG3 antibodies in a select group of patients with DCM may contribute to autoimmune mechanisms of injury in these patients.

Neovascularization in the human heart is associated with expression of VEGF-A and its receptors Flt-1 (VEGFR-1) and KDR (VEGFR-2). Results from cardiomyopexy in ischemic cardiomyopathy.

Cardiomyopexy is a novel means of revascularization in end-stage ischemic heart disease leading to neovascularization and increased perfusion of the damaged heart. So far, the mediators of this process have not yet been identified. However, among others, vascular endothelial growth factor-A (VEGF-A) is a strong candidate for inducing this process. We have performed cardiomyopexy in humans by transplanting a flap of the musculus latissimus dorsi onto the epicardium. One of the patients died 7 weeks after cardiomyopexy due to a septic process unrelated to the underlying cardiac disease. Tissue specimen from the transplanted muscle flap, from the myocardium and from the native musculus latissimus dorsi were analysed by histological and immunohistochemical methods. The transplanted muscle appeared severely degenerated and showed no immunoreactivity for von Willebrandt factor (vWF) and for VEGF-A nor for its receptors KDR and Flt-1. However, a granulation zone had developed next to the transplanted muscle enriched with monocytes and macrophages which is characterized by a network of capillaries reaching into the ischemic myocardium and providing evidence for strong induction of angiogenesis. This process is accompanied by the abundance of VEGF-A expression in the endothelial layer of vessels. In parallel, VEGF-receptor KDR is present in capillaries passing into the subepicardial region supporting the idea of VEGF-A-induced angiogenesis. The spatial expression pattern of VEGF-A and KDR suggests VEGF-A to be a promotor of angiogenesis leading to indirect myocardial revascularization.

Myocyte proliferation in end-stage cardiac failure in humans

Introduced several decades ago, the dogma persists that cardiac myocytes are terminally differentiated cells and that division of muscle cells is impossible in the adult heart. More recently, nuclear mitotic divisions in myocytes occasionally were seen, but those observations were challenged on the assumption that the rate of cell proliferation was inconsequential for actual tissue regeneration. Moreover, mitoses were never detected in normal myocardium. However, the analysis of routine histologic preparations constituted the basis for the belief that myocytes were unable to reenter the cell cycle and divide, ignoring the limitations of these techniques. We report here by confocal microscopy that 14 myocytes per million were in mitosis in control human hearts. A nearly 10-fold increase in this parameter was measured in end-stage ischemic heart disease (152 myocytes per million) and in idiopathic dilated cardiomyopathy (131 myocytes per million). Because the left ventricle contains 5.8 x 10(9) myocytes, these mitotic indices imply that 81.2 x 10(3), 882 x 10(3), and 760 x 10(3) myocytes were in mitosis in the entire ventricular myocardium of control hearts and hearts affected by ischemic and idiopathic dilated cardiomyopathy, respectively. Additionally, mitosis lasts less than 1 hr, suggesting that large numbers of myocytes can be formed in the nonpathologic and pathologic heart with time. Evidence of cytokinesis in myocytes was obtained, providing unequivocal proof of myocyte proliferation.

Cardiac Pseudopyogenic Granuloma: A Type of Vascular Hyperplasia in the Transplanted Heart Mimicking Pyogenic Granuloma

We present a unique case of cardiac pseudopyogenic granuloma in a 61-year-old man that underwent orthotopic heart transplantation for end-stage ischemic heart disease. The lesion was an incidental pathological finding in the allograft removed for chronic graft vascular disease. This lesion is attributed to the minor trauma of the biopsy in the right side of the heart following cardiac transplantation. The cardiac right side can be considered the venous side of the heart; therefore, we consider the lesion a mimicker of an intravenous pyogenic granuloma. Pseudopyogenic granuloma may represent organization of a mural thrombus which formed secondary to biopsy procedure(s). The lesion must be distinguished from bacillary angiomatosis, Karposi sarcoma, and other neoplasms that may present an intravascular type of growth.