Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS).

BACKGROUND: TRACS sought to describe the clinical outcomes and disease progression of transthyretin (TTR) cardiac amyloidosis (ATTR) in an observational study. Clinical course is largely determined by disease type with ATTR categorized as wild-type (ATTRwt) or genetic-variant protein (ATTRm). Prospective data are lacking in the most common TTR mutation, V122I, present in approximately 3.5% of African Americans. METHODS: Patients with ATTRwt (n = 18) and V122I ATTRm (n = 11) were longitudinally assessed every 6 months for up to 2 years by functional class assessments, biochemical markers, and echocardiography. RESULTS: At baseline, no differences in clinical characteristics, biomarkers, or echocardiographic parameters were noted between patients with ATTRwt and patients with ATTRm. After 15.5 ± 8 months, there were 11 deaths and 1 cardiac transplant, with higher mortality (73% vs 22%, P = .03) and cardiovascular hospitalization (64% vs 28%, P = .02) among patients with ATTRm. The median survival from diagnosis was 25.6 months for ATTRm vs 43.0 months for ATTRwt (P = .04). Univariate predictors of mortality included disease duration, heart rate ≥ 70 beats/min, baseline stroke volume, left ventricular ejection fraction <50%, and ATTRm status. For each 6-month increment, the mean 6-minute walk distance declined by 25.8 m, N-terminal pro b-type natriuretic peptide increased by 1,816 pg/mL, and left ventricular ejection fraction fell by 3.2%, for the entire cohort. CONCLUSIONS: In this prospective study, disease progression, morbidity, and mortality were observed in ATTR cardiomyopathy, particularly due to V122I, over a short duration. Given the prevalence of this mutation, further study of V122I in at-risk African American patients is warranted.

NOX4-Dependent Hydrogen Peroxide Overproduction in Human Atrial Fibrillation and HL-1 Atrial Cells: Relationship to Hypertension.

BACKGROUND/OBJECTIVES: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia with patients dying frequently of stroke. In view of the unclear etiologies of AF and a potential role of oxidative stress, the present study examined cardiac reactive oxygen species production and NADPH oxidase (NOX) expression in AF patients. METHODS AND RESULTS: Patients with AF were older than those without (58.8 ± 11.7 vs. 47.8 ± 19.2, p = 0.047). Whereas total [Formula: see text] production (determined by electron spin resonance) was similar in patients with and without AF, H(2)O(2) production was more than doubled in AF patients (149.8 ± 26.28 vs. 66.9 ± 7.14 pmol/mg/min, p = 0.0055), which correlated well with a doubling in NOX isoform 4 (NOX4) expression. AF patients with co-existing hypertension had three-fold higher H(2)O(2) production compared to those without (239.0 ± 125.1 vs. 83.6 ± 51.3 pmol/mg/min, p = 0.003). Treatment of HL-1 atrial cells with angiotensin II, a known modulator of atrial structural remodeling, resulted in upregulation of NOX4 and H(2)O(2) production, further implicating a potential role of NOX4 in atrial remodeling. CONCLUSION: Our data represent the first implication that NOX4-derived H(2)O(2) may play an important role in the etiologies of AF.

Increased rejection rates in cardiac transplant associated with dexamethasone.

BACKGROUND: Peri-operative immunosuppression in cardiac transplantation includes the use of intravenous methylprednisolone. During a national shortage, intravenous dexamethasone was substituted for methylprednisolone at standard equivalencies. Methylprednisolone and dexamethasone are used interchangeably in many clinical settings; however, their equivalency has not been demonstrated. METHODS: Forty-two consecutive cardiac transplant patients were studied retrospectively. All patients received standard triple immunosuppression. Eighteen patients received dexamethasone and 24 methylprednisolone. Twelve patients were included for comparison after the methylprednisolone shortage resolved. Endomyocardial biopsy (EMB) results graded as > or =1B (ISHLT classification) were considered positive for acute cellular rejection. RESULTS: More patients who received dexamethasone as induction had cellular rejection (12/17; (70%) vs. 14/33; (42%); p=0.05). Four patients were excluded because of deaths unrelated to cardiac function. The increased rate of rejection seen during dexamethasone substitution declined after reinstitution of methylprednisolone (p=0.05). CONCLUSIONS: Peri-operative high-dose dexamethasone in cardiac transplants was associated with higher rates of acute cellular rejection. The equivalencies of dexamethasone and methylprednisolone differ from accepted standards when used in pulse doses. Peri-operative use of glucocorticoids may rely on mechanisms that are different from those considered in the standard equivalency measures. Pulse doses of dexamethasone and methylprednisolone in transplantation may not be interchangeable at standard equivalencies.

The presence of a CD21+ follicular dendritic cell network distinguishes invasive Quilty lesions from cardiac acute cellular rejection.

BACKGROUND: Quilty lesions are a significant source of interobserver variability and overdiagnosis of rejection. These lesions, characterized by a central aggregate of B-cells with a rim of T-cells admixed with capillary-sized blood vessels, exhibit an organization similar to lymphoid tissue. We postulated that this organization is dependent on a follicular dendritic cell (FDC) network and that the presence of such a network would be useful in distinguishing invasive Quilty lesions from acute cellular rejection. METHODS: Thirty-nine lesions of acute cellular rejection [International Society for Heart and Lung Transplantation (ISHLT) grade 1A/1B, n = 7; grade 2, n = 13; grade 3A/3B, n = 18; grade 4, n = 1] and 32 invasive Quilty lesions were collected from our pathology archives. Immunohistochemical staining for CD21 was used to determine the presence of a FDC network. RESULTS: A compact CD21 FDC network was present in 24 of 32 invasive Quilty lesions, and, more significantly, in 23 of 24 invasive Quilty lesions measuring larger than 0.3 mm in greatest dimension. When present, the FDCs were in the center of the lesion and the number of positive cells was proportional to the size of the lesion. A FDC network was completely absent in all but one of the 39 lesions of acute cellular rejection. Review of the H&E material from this single case showed features more consistent with a diagnosis of an invasive Quilty lesion. CONCLUSIONS: The presence of a CD21 FDC network is a reliable diagnostic tool to differentiate invasive Quilty lesions from acute cellular rejection, especially in those lesions (> 0.3 mm) that are most likely to be overdiagnosed as moderate or severe acute cellular rejection (sensitivity 96%, specificity 100%, positive predictive value 100%).

Ethical issues in heart failure: overview of an emerging need.

Modern therapies in cardiovascular medicine aim at preventing death and improving patients' quality of life. However, cardiologists often focus on what can be done rather than what should be done, and the latter consideration may be neglected in the midst of therapeutic optimism. The life-saving success of cardiovascular treatments, combined with an aging population, has created an epidemic of heart failure, a disease that portends considerable morbidity and mortality and raises important questions about what should be done. This and the following essays in this section address the emerging need for ethical analysis of issues raised by patients with heart failure. In this overview, we discuss end-of-life care in end-stage heart failure, new therapies for heart failure, and heart failure research.

Wall tension is a potent negative regulator of in vivo thrombomodulin expression.

Thrombomodulin (TM), a key component of the anticoagulant protein C pathway, is a major contributor to vascular thromboresistance. We previously found that TM protein expression is dramatically reduced in autologous vein grafts during the first two weeks after implantation, coincident to a local inflammatory response, and remains suppressed for at least 6 weeks. To determine the proximate cause of TM loss, in vivo gene expression was quantified by real-time PCR. TM gene expression in vein grafts declined >85% during the first postoperative week and remained suppressed >55% at 6 weeks, accounting for the observed changes in protein expression. The effects of vein graft inflammation were evaluated in animals rendered leukopenic with vinblastine before graft implantation. Abrogating the local inflammatory response affected neither TM protein nor gene expression. To determine how hemodynamic forces might modulate TM expression, the surgical protocol was modified to alter blood flow and pressure-induced vessel distension. TM protein and gene expression did not correlate to changes in shear stress but highly correlated to changes in wall tension, both acutely and over time. We conclude that the primary stimulus for altered TM expression in vein grafts is the exposure to arterial pressure. Furthermore, these data identify strain as a novel and important pathway for in vivo TM gene regulation.

cDNA cloning of rabbit thrombomodulin and characterization of gene expression in cardiovascular tissue.

Thrombomodulin (TM), a component of the protein C anticoagulant pathway, is critical for the maintenance of vascular thromboresistance. To facilitate the study of in vivo TM regulation, we cloned and sequenced the cDNA encoding full-length rabbit TM. Translation of the open reading frame predicts a 580 amino acid protein that contains a 19 amino acid signal peptide, one lectin-like and six EGF-like extracellular domains, a 23 amino acid transmembrane domain and a 36 amino acid cytoplasmic domain. In addition, there are three potential N-linked and six O-linked glycosylation sites. Comparison of the predicted rabbit TM protein with those of human, mouse and rat reveals 67-72% primary sequence conservation with identical domain homology. TM gene expression was quantified in rabbit cardiovascular tissue by real-time PCR using primers and probe based on the derived cDNA sequence and found to correlate with protein expression as determined by Western blot analysis.

Early loss of thrombomodulin expression impairs vein graft thromboresistance: implications for vein graft failure.

Thrombosis is the major cause of early vein graft failure. Our aim was to determine whether alterations in the expression of the anticoagulant proteins, thrombomodulin (TM) and the endothelial cell protein C receptor (EPCR), impair endothelial thromboresistance that may contribute to vein graft failure. Immunohistochemical staining of autologous rabbit vein graft sections revealed that the expression of TM, but not EPCR, was reduced significantly early after graft implantation. Western blot analysis revealed that TM expression was reduced by >95% during the first 2 weeks after implantation, with gradual but incomplete recovery by 42 days. This resulted in up to a 95% reduction in the capacity of the grafts to activate protein C and was associated with an increase in bound thrombin activity, which peaked on day 7 at 28.7 +/- 3.8 mU/cm(2) and remained elevated for more than 14 days. Restoration of TM expression using adenovirus vector-mediated gene transfer significantly enhanced the capacity of grafts to activate protein C and reduced bound thrombin activity on day 7 to levels comparable to that of normal veins (5.7 +/- 0.4 versus 5.2 +/- 1.1 mU/cm(2), respectively, P=0.74). Surprisingly, neointima formation was not affected by this inhibition of local thrombin activity. These data suggest that the early loss of TM expression significantly impairs vein graft thromboresistance and results in enhanced local thrombin generation. Although enhanced local thrombin generation may predispose to early vein graft failure due to thrombosis, it does not seem to contribute significantly to late vein graft failure due to neointimal hyperplasia.