Cardiac allograft vasculopathy: diagnosis,therapy, and prognosis

Development of cardiac allograft vasculopathy represents the major determinant of long-term survival in patients after heart transplantation. Due to graft denervation, these patients seldom present with classic symptoms of angina pectoris, and the first clinical presentations are progressive heart failure or sudden cardiac death. Although coronary angiography remains the routine technique for coronary artery disease detection, it is not sensitive enough for screening purposes. This is especially the case in the first year after transplantation when diffuse and concentric vascular changes can be easily detected only by intravascular ultrasound. The treatment of the established vasculopathy is disappointing, so the primary effort should be directed toward early prevention and diagnosis. Due to diffuse vascular changes, revascularization procedures are restricted only to a relatively small proportion of patients with favorable coronary anatomy. Percutaneous coronary intervention is preferred over surgical revascularization since it leads to better acute results and patient survival. Although there is no proven long-term advantage of drug-eluting stents for the treatment of in-stent restenosis, they are preferred over bare-metal stents. Severe vasculopathy has a poor prognosis and the only definitive treatment is retransplantation. This article reviews the present knowledge on the pathogenesis, diagnosis, treatment, and prognosis of cardiac allograft vasculopathy.The leading causes of death during the first three years after heart transplantation are nonspecific graft failure and infections. Nonspecific graft failure may be caused by chronic graft rejection, while acute graft rejection accounts for no more than 11% of mortality. The major determinants of patient survival after three years are malignancy and cardiac allograft vasculopathy (CAV), also known as transplant coronary artery disease or cardiac transplant vasculopathy. It is detected by coronary angiography in 8% of patients by year 1, 30% by year 5, and 50% by year 10 after transplantation (1). Due to graft denervation, CAV typically develops without the warning symptoms of angina pectoris and manifests with symptoms of graft failure, arrhythmias, or even sudden cardiac death. Patients may present with atypical symptoms such as exertional dyspnea, gastrointestinal distress, diaphoresis, or syncope. It is not unusual that CAV is diagnosed after an incidental finding of Q-waves on ECG or loss of contractile function on a routine echocardiographic exam (2). The vasculopathic lesions in the proximal coronary segments are more focal and eccentric, while the mid and distal coronary segments are affected in a more diffuse and concentric pattern, with typical vessel pruning (Figure 1) (3). Proximal disease is donor-inherited and atherosclerotic in nature, while the mid- and distal disease is more immune-mediated and recipient-acquired. CAV is characterized by diffuse concentric intimal hyperplasia, ie, thickening of the epicardial arteries and concentric medial disease in the coronary microcirculation with the constriction of the external elastic membrane area and lumen loss (4). Unnoticed by coronary angiography, the most of the intimal thickening occurs during the first post-transplant year (5). The disease progression is often complicated by intracoronary thrombosis and subsequent, often silent, acute myocardial infarction (Figure 2) (6). Early mural thrombi primarily contain platelets, while succeeding thrombi are more organized, usually occlusive and primarily consist of fibrin (7). Development and progression of CAV in transplant patients is strongly associated with enhanced platelet activation, although no evidence supports the benefit from aspirin therapy in these patients (8,9).Open in a separate windowFigure 1Diffuse stenosis of the left anterior descending artery and distal pruning of left circumflex artery in a patient 6 years after heart transplantation.Open in a separate windowFigure 2Acute thrombotic occlusion of the right coronary artery manifested as ventricular fibrillation and cardiac arrest in a patient 2 years after heart transplantation.To create uniform definition and enable staging of transplant vasculopathy, the International Society of Heart and Lung Transplantation (ISHLT) proposed a grading system based on the combination of angiographic finding and graft function defined either by ultrasound or invasive hemodynamic measurement (10): CAV₀ (no detectable angiographic lesions) = no vasculopathy; CAV₁ (mild disease) = left main stenosis <50% or primary vessel stenosis <70% (including right coronary artery – RCA) or any branch stenosis <70%, without graft dysfunction; CAV₂ (moderate disease) = left main stenosis <50% or single primary vessel stenosis >70% or isolated branch stenosis >70% in 2 systems, without graft dysfunction; CAV₃ (severe disease) = left main stenosis ≥50% or stenosis >70% in two or more primary vessels or isolated branch stenosis >70% in three systems; or ISHLT CAV₁ or ISHLT CAV₂ with signs of graft dysfunction. Allograft dysfunction is defined as left ventricular ejection fraction ≤45% or evidence of significant restrictive pathology either on echocardiographic exam (E/A ratio >2, isovolumetric relaxation time <60 ms, deceleration time <150 ms) or right heart catheterization (right atrial pressure >12 mm Hg, pulmonary capillary wedge pressure >25 mm Hg, cardiac index <2 L/min/m²). In this nomenclature, primary vessels stand for the proximal and middle thirds of the left anterior descending artery, the left circumflex, the ramus intermedius, and the dominant or co-dominant RCA. Branch vessels denote distal thirds of the primary vessels or large septal, diagonal, and obtuse marginal branch or any portion of a non-dominant RCA (10). CAV is present in 44% of our patients at 5 years after transplantation with the proportion of CAV₁, CAV_2, and CAV₃ of 50%, 32%, and 18%, respectively.     

PCL/Si-Doped Multi-Phase Calcium Phosphate Scaffolds Derived from Cuttlefish Bone

Increasing attention is focused on developing biomaterials as temporary scaffolds that provide a specific environment and microstructure for bone tissue regeneration. The aim of the present work was to synthesize silicon-doped biomimetic multi-phase composite scaffolds based on bioactive inorganic phases and biocompatible polymers (poly(ε-caprolactone), PCL) using simple and inexpensive methods. Porous multi-phase composite scaffolds from cuttlefish bone were synthesized using a hydrothermal method and were further impregnated with (3-aminopropyl)triethoxysilane 1–4 times, heat-treated (1000 °C) and coated with PCL. The effect of silicon doping and the PCL coating on the microstructure and mechanical and biological properties of the scaffolds has been investigated. Multi-phase scaffolds based on calcium phosphate (hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate) and calcium silicate (wollastonite, larnite, dicalcium silicate) phases were obtained. Elemental mapping revealed homogeneously dispersed silicon throughout the scaffolds, whereas silicon doping increased bovine serum albumin protein adsorption. The highly porous structure of cuttlefish bone was preserved with a composite scaffold porosity of ~78%. A compressive strength of ~1.4 MPa makes the obtained composite scaffolds appropriate for non-load-bearing applications. Cytocompatibility assessment by an MTT assay of human mesenchymal stem cells revealed the non-cytotoxicity of the obtained scaffolds.     

Association of epilepsy and headache from the patient perspective

Headache occurs more frequently in patients with epilepsy as compared to the general population. Current studies in patients with epilepsy and migraine show that this increased frequency is independent of the seizure type, etiology or age at onset. People with epilepsy are 2.4 times more likely to be diagnosed with migraine. In our study, we evaluated patients' attitudes toward comorbidity of epilepsy and all headache types. Study results showed a significant number of patients to have experienced headaches after being diagnosed with epilepsy, and some of them assumed it was a side effect of their antiepileptic drug. Based on these data, we propose a more detailed assessment of the history of epilepsy including questions on headache, and offer the epilepsy patient a newer antiepileptic drug. In this way, we can significantly decrease the comorbidity of these two neurologic disorders and improve the quality of life in epilepsy patients.     

Functional Impressions in Complete Denture and Overdenture Treatment

Tooth loss can cause loss of occlusal, masticatory, esthetic, physiognomic, phonetic and psychosocial function of patients. The most frequently used treatment method of completely edentulous patients and patients with a small number of remaining teeth are complete dentures or overdentures. One of the most important clinical and laboratory procedures in their fabrication is functional impression taking. The aim of this paper was to present procedures of taking functional impressions in fabrication of complete dentures and overdentures, using standardized techniques and materials. An accurate functional impression together with other correctly performed clinical and laboratory procedures ensure good retention and stability of dentures, which is a precondition for restoring patients’ lost functions.Key words: complete denture, overdenture, functional impression     

Epidemiology of cardiomyopathies in children and adolescents: a retrospective study over the last 10 years

We conducted a retrospective study at the Department of Paediatric Cardiology of the University Hospital Centre Rebro, Zagreb, over the period from 1988 to 1998, so as to assess the epidemiology of childhood cardiomyopathies. The patients were categorized according to the guidelines of the Task Force on Cardiomyopathies of the World Health Organization and the International Society and Federation of Cardiology. We identified 121 infants, children and adolescents as having cardiomyopathy, giving an average occurrence for all cardiomyopathies of 38.81 for each 10,000 patients examined in our outpatient clinics for paediatric cardiology. Of the patients, 50 were female (41.3%) and 71 were male (58.7%). The cardiomyopathy was of the dilated variant in 52 patients (42.9%), with 43 patients (35.5%) having hypertrophic cardiomyopathy, and 6 patients (4.8%) identified with restrictive cardiomyopathy. We encountered no patients with arrhythmogenic right ventricular cardiomyopathy. In nine patients (7.4%), it proved impossible to classify the cardiomyopathy. We placed 11 patients (9.0%) in the group of specific cardiomyopathies. Most of those with dilated cardiomyopathy had been diagnosed prior to the age of 3 years (RR 1.9, 95% CI 1.4-2.47). There were no statistically significant differences in the incidences of dilated as compared to hypertrophic cardiomyopathy (Z 0.923, p = 0.1779), but we encountered a significantly lower occurrence of restrictive cardiomyopathy (Z 6.044, p < 0.001). Of those with hypertrophic cardiomyopathy, 15 patients (34.8%) had the asymmetric variant, while 28 patients (65.2%) exhibited the concentric form. During the period of follow-up, 10 patients died, 4 with dilated cardiomyopathy, 4 with hypertrophic cardiomyopathy, 1 with restrictive cardiomyopathy, and 1 with a specific cardiomyopathy. We encountered 12 (9.9%) patients who, besides cardiomyopathies, also suffered from neuromuscular disorders. Most of these had dilated cardiomyopathy. Mitochondrial disorders, in contrast, were more frequently found in patients with hypertrophic cardiomyopathy.     

Impact of admission anemia,C-reactive protein and mean platelet volume on short term mortality in patients with acute ST-elevation myocardial infarction treated with primary angioplasty

ObjectivesTo investigate admission anemia, C-reactive protein (CRP) and mean platelet volume (MPV) together as prognostic markers in ST-elevation myocardial infarction (STEMI).Design and methodsBaseline hemoglobin, CRP and MPV were determined in 543 patients with acute STEMI to whom primary angioplasty was performed and evaluated for short term mortality (30 days).ResultsAfter multivariate analysis anemia (odds ratio 2.69, 95% confidence interval 1.24–5.86) and CRP (odds ratio 3.40, 95% confidence interval 1.13–10.22) remained significant independent predictors of short-term mortality. Addition of anemia and CRP to PAMI risk score improved prediction of short-term outcome; area under ROC curve rose from 0.76 to 0.87 (p < 0.001).ConclusionBetter ability to determine 30-day mortality was obtained when anemia and CRP were incorporated into the PAMI risk score.     

Expression of<Emphasis Type="Italic"> p53</Emphasis>,<Emphasis Type="Italic"> bcl-2</Emphasis> and growth hormone receptor in actinic keratosis,hypertrophic type

According to novel investigations, actinic keratosis (AK) is not a premalignant lesion but is a malignant lesion in the evolution to invasive squamous cell carcinoma (SCC). Thus, we analyzed p53, bcl-2 and growth hormone receptor (GHR) expression in hypertrophic-type AK (HAK) to determine the relative importance of these protooncogenes in the biological behavior of HAK. Expression of p53, bcl-2 and GHR was determined by immunohistochemistry in 33 HAK specimens and surrounding perilesional normal skin (PNS). The relative proportions of immunoreactive cells were determined. Of the 33 HAK specimens, 30 (91%) showed immunopositive staining for p53, 33 (100%) for bcl-2, and 12 (36%) for GHR. Highly positive p53 expression in HAK lesions could indicate that p53 mutation is an early and crucial event in lesion development. The detected pattern of the p53/ bcl-2 ratio in HAK suggests an important role for another gene: the proapoptotic gene bax. Our findings indicate that GHR expression could be a biological marker of progression of HAK to SCC.     

The role of HE4 for prediction of recurrence in epithelial ovarian cancer patients—results from the OVCAD study

Tumor Biology - Patients with epithelial ovarian cancer (EOC) are at high risk of tumor recurrence. Human epididymis protein 4 (HE4) has been shown to be overexpressed in EOC. The primary aim of...     

Subtenonial application of triamcinolone in neovascular form of senile macular degeneration

The aim of this prospective study was to investigate the effectiveness of sub-tenon application of triamcinolone for neovascular age-related macular degeneration. The study included 38 eyes (26 patients; 14 women and 12 men, aged 63 to 82 years) with newly diagnosed subfoveal neovascular age-related macular degeneration. Each eye received sub-tenon injection of 0.5 mL suspension of triamcinolone-acetonide (20 mg of active substance). Follow up period was 12 months. After initial application, the injections were repeated on individual case, none to five times. Elevated intraocular pressure occurred in five patients (seven eyes) and was treated with topical antiglaucomatous therapy. Transient ptosis of upper eyelid occurred in one case and completely recovered in two days. The mean visual acuity was 0.13 +/- 0.17 on the beginning of the study and 0.22 +/- 0.22 at the end of the study. Visual acuity improved in 15/38 (39%) eyes, remained unchanged in 10/38 (26%) eyes, and worsened in 13/38 (35%) eyes. Improvement by three or more lines on Snellen optotype occurred in two cases. Comparing our results to those from other authors, sub-tenon application of triamcinolone did not prove as effective as when applied intravitreally, but is substantially less expensive and easier to perform.