Volkmar Lange

Impact of Myocardial Fibrosis in Patients With Symptomatic Severe Aortic Stenosis

Background— In this prospective follow-up study, the effect of myocardial fibrosis on myocardial performance in symptomatic severe aortic stenosis was investigated, and the impact of fibrosis on clinical outcome after aortic valve replacement (AVR) was estimated. Methods and Results— Fifty-eight consecutive patients with isolated symptomatic severe aortic stenosis underwent extensive baseline characterization before AVR. Standard and tissue Doppler echocardiography and cardiac magnetic resonance imaging (late-enhancement imaging for replacement fibrosis) were performed at baseline and 9 months after AVR. Endomyocardial biopsies were obtained intraoperatively to determine the degree of myocardial fibrosis. Patients were analyzed according to the severity of interstitial fibrosis in cardiac biopsies (severe, n=21; mild, n=15; none, n=22). The extent of histologically determined cardiac fibrosis at baseline correlated closely with New York Heart Association functional class and markers of longitudinal systolic function (all P<0.001) but not global ejection fraction or aortic valve area. Nine months after AVR, the degree of late enhancement remained unchanged, implying that AVR failed to reduce the degree of replacement fibrosis. Patients with no fibrosis experienced a marked improvement in New York Heart Association class from 2.8±0.4 to 1.4±0.5 (P<0.001). Only parameters of longitudinal systolic function predicted this functional improvement. Four patients with severe fibrosis died during follow-up, but no patient from the other groups died. Conclusions— Myocardial fibrosis is an important morphological substrate of postoperative clinical outcome in patients with severe aortic stenosis and was not reversible after AVR over the 9 months of follow-up examined in this study. Because markers of longitudinal systolic function appear to indicate sensitively both the severity of myocardial fibrosis and the clinical outcome, they may prove valuable for preoperative risk assessment in patients with aortic stenosis.

Low-Gradient Aortic Valve Stenosis: Myocardial Fibrosis and Its Influence on Function and Outcome

OBJECTIVES This prospective cohort study in patients with aortic stenosis (AS) aimed to identify surrogates of myocardial fibrosis that are easy to derive in clinical practice, allow the differentiation of low-gradient severe AS from moderate AS, and have an impact on clinical outcome. BACKGROUND In patients with symptomatic aortic AS, a characteristic subgroup (i.e., up to one-third) exhibits severe AS with a concomitant low mean valve gradient either with preserved or reduced ejection fraction (EF). It is hypothesized that these patients tend to have an advanced stage of myocardial fibrosis and poor clinical outcome. METHODS Eighty-six patients with moderate or severe AS were examined by echocardiography including conventional aortic valve assessment, mitral ring displacement, and strain-rate imaging. Replacement fibrosis was quantified by late-enhancement magnetic resonance imaging. Biopsy samples were taken from patients with severe AS (n = 69) at aortic valve replacement. All patients were followed for 9 months. RESULTS Patients were divided into 4 groups according to aortic valve area (<1.0 cm(2)), mean valve gradient ≥40 mm Hg, and EF (<50%): group 1, moderate AS (n = 17); group 2, severe AS/high gradient (n = 49); group 3, severe AS/low gradient/preserved EF (n = 11); and group 4, severe AS/low gradient/decreased EF (n = 9). At baseline, a significant decrease in mitral ring displacement and systolic strain rate was detected in patients with low-gradient AS. In low-gradient groups, a higher degree of interstitial fibrosis in biopsy samples and more late-enhancement magnetic resonance imaging segments were observed. A close inverse correlation was found between interstitial fibrosis and mitral ring displacement (r = -0.79, p < 0.0001). Clinical outcome was best for patients in group 1, whereas mortality risk increased substantially in groups 2 through 4. CONCLUSIONS In severe AS, a low gradient is associated with a higher degree of fibrosis, decreased longitudinal function, and poorer clinical outcome despite preserved EF. Mitral ring displacement differentiates between moderate AS and low-gradient/severe AS with preserved EF.

Stimulation of L-type Ca2+ current in human atrial myocytes by insulin

OBJECTIVE The L-type calcium current (ICa,L) in isolated human atrial myocytes was investigated as a possible target of insulin in the regulation of cardiac function. METHODS Atrial myocytes were obtained from patients undergoing cardiac surgery. Using the whole-cell configuration of the patch-clamp technique, we investigated the stimulation of ICa,L by insulin in single human atrial myocytes. RESULTS We found a dose-dependent stimulation of ICa,L by insulin at concentrations of 100 nM, 1 microM and 10 microM. Maximum stimulation of ICa,L over basal ICa,L was 140 +/- 12% (n = 11) at 10 microM insulin. The maximum conductance of ICa,L was increased by 10 microM insulin from 4.0 +/- 0.3 nS to 8.3 +/- 1.0 nS (n = 6). The stimulation of ICa,L by insulin was dose-dependent and reversible. Isoproterenol (10 nM) that stimulates ICa,L by 271 +/- 48% (n = 10) over basal ICa,L acted faster than insulin. The half-maximum stimulation of ICa,L by isoproterenol and insulin (10 microM) was reached after 31 +/- 2 s and 52 +/- 5 s, respectively. The insulin effect shown was totally reversed by acetylcholine (3 microM) which is known to inhibit adenylyl cyclase activity/cAMP-production via Gi-proteins. Also, the selective insulin receptor tyrosine kinase inhibitor (hydroxy-2-naphthanelyl-methyl)phosphonic acid completely inhibited the insulin induced effect. CONCLUSION Our data show that insulin stimulates the L-type calcium current in isolated human atrial myocytes in a dose-dependent and reversible manner which appears to involve the insulin receptor tyrosine kinase. Insulin regulation of ICa,L in human atrial myocytes may be an interesting system for the analysis of the metabolic syndrome in man.

Donor antigen-specific regulatory T-cell function affects outcome in kidney transplant recipients

Chronic transplant dysfunction, a major impediment to long-term allograft survival, is caused by several factors including an ongoing alloimmune response termed chronic rejection. To define some of these factors further, we selected 107 patients mismatched to their donors from 623 patients transplanted at a single center. Patients were categorized according to their immunosuppressive treatment and further divided into those with stable or chronic allograft dysfunction. Donor human lymphocyte antigen allopeptide-specific T-cell lines were then generated from stable patients and those with biopsy-proven chronic allograft nephropathy. Increased amounts of CD4+CD25+ regulatory T cells (Tregs) and Treg-associated gene expression profiles were found in cell lines derived from the patients with stable compared with those with chronic allograft dysfunction. Furthermore, a higher percentage of Tregs was found in patients with stable graft function on tacrolimus-based compared with cyclosporine-based immunosuppression protocols. Patients with stable graft function had a significantly higher expression of interleukin (IL)-4 and IL-10, whereas the cytokines IL-2, IL-17, and interferon-γ were significantly higher in patients with allograft dysfunction in vitro. Thus, enhancing the operational role of naturally occurring donor-specific Tregs in allograft recipients by adjusting the immunosuppression protocol may be advantageous particularly for patients with ongoing chronic rejection.

Regulatory Allospecific T Cell Clones Abrogate Chronic Allograft Rejection

True alloantigen-specific tolerance is the ultimate goal of solid organ transplantation, eliminating the need for long-term immunosuppression. Recent evidence suggests that Th1-derived cytokines are associated with rejection and Th2-derived cytokines with long-term allograft survival, but the roles of these subsets in rejection and tolerance are incompletely understood. Here, we analyzed the functional and regulatory capacities of T cell clones derived from tolerant and rejecting rats (Wistar rat donors, Lewis rat recipients). We generated and subcloned T cell lines from lymphocytes derived from either acutely rejecting grafts or from the grafts of CTLA4-Ig-treated tolerant rats. Pretransplantation adoptive transfer of T cell clones generated from rejected grafts (Th1 clones) accelerated acute rejection or promoted development of chronic rejection, whereas transfer of T cell clones generated from tolerized grafts (Th2 clones) protected rats from acute rejection and progressive organ dysfunction. When Th1 and Th2 clones were injected simultaneously, Th2 clones specifically regulated activation of Th1 clones. Rats that received injections of Th2 clones accepted long-term donor-specific skin grafts but acutely rejected third-party skin grafts. Tolerant rats treated with Th2 clones demonstrated an increased number of regulatory CD4+CD25+Foxp3+ cells and strong mononuclear cell staining for IL-10 but negligible IFN-gamma, IL-17, and IL-23 compared with untreated rats or those treated with Th1 clones. In summary, these results demonstrate the regulatory functions of Th2 cells in a clinically relevant allogeneic transplant model and provide new insight into the functional role of Th2 cells in preventing the process of chronic rejection.

Cardiac allograft vasculopathy after cardiac transplantation and hormone therapy : Positive effects?

Background. There is a great deal of controversy surrounding the issue of hormone replacement therapy after transplantation. The question whether or not this therapy has effects in cardiac allograft vasculopathy (CAV), the Achilles heel of cardiac transplantation or other unique aspects of allograft function is still unknown. Methods. We investigated the long-term effect of 17β-estradiol as well as phytoestrogen Coumestrol, a synthetically produced phytoestrogen, on the development of CAV and the degree of fibrosis in an ovariectomized female heterotopic chronic allograft model (LEW-F344). Results. We found that, 150 days after transplantation, no significant effect of estrogen application on intimal thickening of coronary arteries was observed. 17β-estradiol and phytoestrogen Coumestrol did significantly reduce the perivascular immune reaction. However, the immune effect had no consequence on the intensity of CAV. Although neither 17β-estradiol nor phytoestrogen Coumestrol revealed a positive effect on CAV, the group of animals treated with 17β-estradiol showed the highest decline in heart function and the most distinct fibrosis. Conclusions. 17β-estradiol does not affect CAV positively, but worsens cardiac allograft function and leads to increased fibrosis. This is the first study showing a negative effect of 17-β-estradiol after heart transplantation in the long term.

Hemodynamic assessment of severe aortic stenosis: MRI evaluation of dynamic changes of vena contracta.

Purpose:Direct magnetic resonance imaging (MRI) planimetry of the maximal systolic aortic valve area does not consider temporal variations of the opening area during the ejection period. We evaluated an MRI-based methodology for the assessment of valvular dynamics in patients with severe aortic stenosis by measuring the systolic variability of the valvular blood stream, that is, the “vena contracta.” Materials and Methods:With institutional review board approval, we examined 22 patients (13 male, 9 female; mean age, 68 ±10 years) with severe aortic stenosis using 1.5 T MRI and a standardized scanning protocol consisting of gradient-echo phase-contrast velocity imaging and steady-state free precession-cine MRI before and after valve replacement therapy. Temporal changes of the aortic valve area, represented by systolic variations of the area of poststenotic turbulent flow at its smallest convergence, that is, the proximal vena contracta, were determined by MRI and quantified by a calculated parameter of temporal valve dynamics (T). T was defined as the period which the aortic valve spent over its maximal opening area (>85%) during systole. MRI was also used to determine left ventricular hypertrophy before (LVMI) and its regression (LVMR) after valve replacement. Findings were compared with transthoracic echocardiography and cardiac catheterization. Results:All patients had an echocardiographic effective orifice area, EOATTE, of <1.0 cm2. The comparison of T to LVMI and LVMR revealed significant correlations (LVMI: r = −0.62; P = 0.002; LVMR: r = 0.62; P = 0.002). Further significant correlations with aortic stenosis severity were observed in the comparison with manual planimetry, invasive measurements, and echocardiographic valve areas, as well as with pressure gradients. Conclusions:MRI can measure systolic variations of the aortic valve area. Quantitative parameters of the hemodynamic relevance of valve dynamics obtained by this method correlate with established parameters of aortic stenosis severity and LVMR.

Cardiac surgery and hematologic malignancies: a retrospective single-center analysis of 56 consecutive patients

OBJECTIVE Patients with a history of hematologic malignancies (HMs) are considered high-risk candidates for cardiac surgery. Increased perioperative rates of infections, thrombo-embolic complications, and bleeding disorders are reported. However, low patient numbers and lack of control groups limit all published studies. METHODS A total of 56 patients with a history of HM underwent cardiac surgery. As many as 29 patients suffered from non-Hodgkin lymphoma, five from Hodgkin disease, and 12 from myeloproliferative disorders, one from acute lymphatic leukemia, and nine from monoclonal gammopathy. Surgery consisted of coronary artery bypass grafting, valvular surgery or combination procedures. HM patients were matched to 142 controls. Matching criteria applied consisted of sex, age, main diagnosis, and co-morbidities. RESULTS In-hospital mortality was elevated in HM patients though not reaching significance (P = 0.7). HM patients demonstrated increased rates of vascular, pulmonary, infectious complications (P > 0.1), and transfusion requirements (P = 0.077). The long-term survival of HM patients was significantly impaired (P = 0.043). A history of irradiation or chemotherapy predisposed to postoperative respiratory insufficiency, acute renal failure, and an impaired long-term survival (P > 0.065). CONCLUSIONS Cardiac surgery in patients with a history of a malignant hematologic disorder might achieve acceptable results. However, a higher complication and mortality rate have to be anticipated. Patients with hematologic disorders and a history of either irradiation or chemotherapy appear to be at an increased risk to develop postoperative end-organ failure.

Cardiac Operations in the Presence of Meningioma

BACKGROUND We investigated the effect of concomitant intracranial meningiomas on perioperative and postoperative complications after cardiac operations. Also studied was the intraoperative and perioperative management and long-term outcome of such patients. METHODS We retrospectively evaluated 16 cardiac surgical patients with intracranial meningiomas between January 1996 and July 2007. Neurologic outcome, incidence of transient neurologic deficits, and long-term follow-up focusing on freedom from any cardiac or neurosurgical intervention were assessed. RESULTS Five men and 11 women with a concomitant diagnosis of intracranial meningioma underwent cardiac operations using extracorporeal circulation. One patient received additional edema prophylaxis by intravenous dexamethasone. All patients were discharged home in good physical condition. Data on long-term survival were available on 14 patients, with 12 alive. Postoperatively, 2 patients died from myocardial infarction at 26.8 months and 2 from metastatic colon cancer at 57.9 months. Perioperative neurologic disorders were observed in 2 patients, comprising one stroke after intervention for aortic dissection and one thromboembolic event 2 weeks after biologic mitral valve replacement due to anticoagulation disorders. No meningioma-related adverse event was observed. CONCLUSIONS The presence of intracranial meningioma does not appear to be a risk factor for patients undergoing cardiac operations. No meningioma-related neurologic sequelae were documented postoperatively. Neurosurgical consultation should be obtained in all patients preoperatively.

Inhibition of nuclear translocation of calcineurin suppresses T-cell activation and prevents acute rejection of donor hearts.

Background. Inhibition of calcineurin (CnA) activity by cyclosporine A (CsA) is the mainstay in immunosuppressive therapy. CsA inhibits the phosphatase activity of the cytosolic phosphatase CnA and, therefore, prevents the dephosphorylation and subsequently nuclear translocation of the transcription factor nuclear factor of activated T cells (NFAT). However, CsA has multiple other targets within the cell and is, therefore, not specific. We developed a new approach to inhibit CnA/NFAT signaling. This synthetic peptide prevented CnA nuclear translocation in vitro. The purpose of this study was to demonstrate that this novel approach could potentially inhibit T-cell function in vitro and in vivo. Methods. T-cell activation (Jurkat T cells, naïve rat T cells, and peripheral human T cells) was assessed by protein synthesis, interleukin (IL)-2 promoter activity, and IL-2 levels after T-cell activation. Immunohistological stainings for CnA were performed to investigate nuclear localization of CnA. The immunosuppressive effects in vivo of the synthetic peptide were investigated in rats with heterotopic transplanted hearts. Results. The nuclear localization signal peptide significantly decreased alloantigen-specific T-lymphocyte proliferation, IL-2 promoter activity, and IL-2 production (338%±27% vs. 149%±11%, n=8, P<0.05) in cultured T cells by inhibition of CnA nuclear translocation. The synthetic peptide also significantly decreased the number of graft infiltrating CD8+ T lymphocytes. Moreover, treatment with the synthetic inhibitory inhibited acute graft rejection (5±0.6 days vs. 12±2 days, n=10, P<0.05). Conclusions. Inhibition of nuclear translocation of CnA is a novel approach to inhibit the activation of the CnA/NFAT signaling cascade. Further studies have to demonstrate the long-term use of this principle in vivo.