Differences in phenotypes, symptoms, and survival in patients with cardiomyopathy-a prospective observational study from the Sahlgrenska CardioMyoPathy Centre.

Introduction: Cardiomyopathy is the fourth most common cause of heart failure. The spectrum of cardiomyopathies may be impacted by changes in environmental factors and the prognosis may be influenced by modern treatment. The aim of this study is to create a prospective clinical cohort, the Sahlgrenska CardioMyoPathy Centre (SCMPC) study, and compare patients with cardiomyopathies in terms of phenotype, symptoms, and survival. Methods: The SCMPC study was founded in 2018 by including patients with all types of suspected cardiomyopathies. This study included data on patient characteristics, background, family history, symptoms, diagnostic examinations, and treatment including heart transplantation and mechanical circulatory support (MCS). Patients were categorized by the type of cardiomyopathy on the basis of the diagnostic criteria laid down by the European Society of Cardiology (ESC) working group on myocardial and pericardial diseases. The primary outcomes were death, heart transplantation, or MCS, analyzed by Kaplan-Meier and Cox proportional regression, adjusted for age, gender, LVEF and QRS width on ECG in milliseconds. Results: In all, 461 patients and 73.1% men with a mean age of 53.6 ± 16 years were included in the study. The most common diagnosis was dilated cardiomyopathy (DCM), followed by cardiac sarcoidosis and myocarditis. Dyspnea was the most common initial symptom in patients with DCM and amyloidosis, while patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) presented with ventricular arrythmias. Patients with ARVC, left-ventricular non-compaction cardiomyopathy (LVNC), hypertrophic cardiomyopathy (HCM), and DCM had the longest time from the debut of symptoms until inclusion in the study. Overall, 86% of the patients survived without heart transplantation or MCS after 2.5 years. The primary outcome differed among the cardiomyopathies, where the worst prognosis was reported for ARVC, LVNC, and cardiac amyloidosis. In a Cox regression analysis, it was found that ARVC and LVNC were independently associated with an increased risk of death, heart transplantation, or MCS compared with DCM. Further, female gender, a lower LVEF, and a wider QRS width were associated with an increased risk of the primary outcome. Conclusions: The SCMPC database offers a unique opportunity to explore the spectrum of cardiomyopathies over time. There is a large difference in characteristics and symptoms at debut and a remarkable difference in outcome, where the worst prognosis was reported for ARVC, LVNC, and cardiac amyloidosis.

Valproic acid selectively increases vascular endothelial tissue-type plasminogen activator production and reduces thrombus formation in the mouse.

Essentials Stimulating endogenous fibrinolysis could be a novel antithrombotic strategy. The effect of valproic acid on endothelial tissue plasminogen activator in mice was investigated. Valproic acid increased tissue plasminogen activator expression in vascular endothelium. Valproic acid reduced fibrin deposition and thrombus formation after vascular injury. SUMMARY: Background The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue-type plasminogen activator (t-PA) production is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t-PA production and an enhanced fibrinolytic capacity in vivo is unknown. Objectives To determine whether the HDAC inhibitor valproic acid (VPA) stimulates production of t-PA in the vasculature of mice, and whether VPA pretreatment affects fibrin deposition and clot formation after mechanical vessel injury. Methods Mice were injected with VPA twice daily for up to 5 days. t-PA mRNA, and antigen expression in the mouse aorta and the circulating levels of t-PA were determined. Fibrin and thrombus dynamics after mechanical vessel injury were monitored with intravital confocal microscopy. Potential effects of VPA on platelets and coagulation were investigated. Results and Conclusions We found that VPA treatment increased vascular t-PA production in vivo and, importantly, that VPA administration was associated with reduced fibrin accumulation and smaller thrombi in response to vascular injury, but still was not associated with an increased risk of bleeding. Furthermore, we observed that higher concentrations of VPA were required to stimulate t-PA production in the brain than in the vasculature. Thus, this study shows that VPA can be dosed to selectively manipulate the fibrinolytic system in the vascular compartment and reduce thrombus formation in vivo.

Effect of shear stress, statins and TNF-α on hemostatic genes in human endothelial cells.

Atherosclerotic plaque formation and progression are dependent on local shear stress patterns and inflammatory cytokines. Statins effectively reduce the progression of atherosclerosis and the incidence of cardiovascular events. However, the benefit of statins cannot be explained by cholesterol reduction alone. This study, investigated the non-lipid lowering effects of simvastatin and rosuvastatin on endothelial anti- and prothrombotic genes under different biomechanical and inflammatory stress conditions. Endothelial cells responded in a similar way to simvastatin and rosuvastatin. However, they were more sensitive to simvastatin. The statins had anti-inflammatory properties counteracting the TNF-α effect on the hemostatic genes studied. There was no observed synergistic effect between shear stress and simvastatin. Simvastatin had a counteracting effect on t-PA and PAI-1 compared to TNF-α and shear stress. Simvastatin blocked the TNF-α suppressive effect on thrombomodulin and eNOS, irrespective of shear stress. The strong inductive effect of TNF-α on VCAM-1 was counteracted by simvastatin and shear stress in an additive dose-response dependent way.

Influence of TNF-alpha and biomechanical stress on endothelial anti- and prothrombotic genes.

Biomechanical stress modulates vascular tone, vascular remodelling and the spatial localisation of atherosclerotic plaques. Inflammatory cytokines, such as TNF-alpha, regulate expression of genes that impair the function of endothelial cells. This study investigates the combinatory effect of different biomechanical stresses and TNF-alpha on the expression of endothelial anti- and prothrombotic genes. Human umbilical vein endothelial cells were exposed to TNF-alpha and different levels of static/pulsatile tensile stress or shear stress. The response in endothelial cells to TNF-alpha was not modulated by tensile stress. However, shear stress was a more potent stimulus. Shear stress counteracted the cytokine-induced expression of VCAM-1, and the cytokine-suppressed expression of thrombomodulin and eNOS. Shear stress and TNF-alpha additively induced PAI-1, whereas shear stress blocked the cytokine effect on t-PA and u-PA. A flow profile characterized by high laminar shear stress seems to render the endothelial cell more resistant to inflammatory stress.

Effects of two complex hemodynamic stimulation profiles on hemostatic genes in a vessel-like environment.

Endothelial cells are the main sensors of changes in the biomechanical flow environment and play a pivotal role in vascular homeostasis. An in vitro perfusion model was developed to study the regulatory effect on gene expression by different flow and pressure profiles. Human umbilical vein endothelial cells were grown to confluence inside capillary microslides or silicone tubes. Thereafter, they were exposed to different levels of shear stress or different levels of static or pulsatile pressure. Genes representing various hemostasis functions of the endothelial cells were analyzed. Shear stress was a more effortful stimulus than static or pulsatile tensile stress. Although shear stress affected mRNA expression of all six studied genes (tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor [PAI]-1, Thrombomodulin [TM], urokinase-type plasminogen activator [u-PA], vascular cell adhesion molecule [VCAM-1], and endothelial nitric oxide synthase [eNOS]), none of the genes was found regulated by pressure. Shear stress down-regulated t-PA and VCAM-1 in a dose response-dependent way, and up-regulated TM. u-PA, eNOS, and PAI-1 were up-regulated by shear stress, but there was no obvious dose-response effect for these genes. These findings suggest that shear stress has a more powerful gene regulatory effect on endothelial gene expression than tensile stress. Low shear stress induced a more proatherogenic endothelial surface but preserved t-PA gene expression levels compared to high shear stress.

Educating educators about alcoholism and drug addiction: the role of employee assistance programmes.

The historical development of employee assistance programmes (EAPs) from occupational alcoholism programmes is outlined. Services for the three prevention levels of a 'broad brush' programme are described. The 'at-risk' characteristics of academia in potentiating alcoholism and addiction are noted, including several intrinsic characteristics of academics which could predispose to substance abuse. Ways in which EAPs enhance organizational goals are noted and several crucial steps in designing an academic EAP are suggested.

Effects of preliminary culture on the membrane microviscosity of lymphocytes from young and old donors. Microviscosity correlates with mitogenic response.

Membrane microviscosity was assessed by a fluorescence polarization technique in fresh and precultured human peripheral blood lymphocytes of young and old subjects. Membrane microviscosity was significantly higher in fresh, non-treated cells of old donors as compared to young adults. Preincubation of cells in culture medium supplemented with pooled human serum diminishes the original microviscosity difference between the age groups. The observed increase in membrane fluidity correlates with the improvement of the mitogen-induced proliferative response due to preculturing cells from aged subjects. The results support the suggestion that membrane microviscosity can affect the proliferative response of lymphocytes, and it may play a role in the decline of the immune responsiveness in the elderly.

The effect of passive immunization on active immunity against Clostridium perfringens type D in lambs.

Lambs in different stages of development of active immunity against Clostridium perfringens type D were treated with partially purified immunoglobulin in an attempt to superimpose a passive immunity on an existing or developing active immunity. Three different studies were undertaken to determine the impact of partial purified immunoglobulins on these vaccinated animals. In 2 of the 3 studies, active immunity was induced by administering the normal routine enterotoxaemia vaccinations and allowing the basic immunity to become established, for a period ranging from 2 weeks for the animals in study 1 and 4 months for those in study 2, before passive immunization with the partially purified immunoglobulins took place. An increase in the epsilon antibody titre occurred in each of the 2 studies after the animals were passively immunized with immunoglobulin, though this increase was not statistically significant (P greater than 0.05). In the 3rd study, when the animals were given the initial vaccination of the Onderstepoort enterotoxaemia oil adjuvant vaccine together with the immunoglobulin, an immediate increase in the epsilon antitoxin titre occurred that was statistically significant (P less than 0.05) 2-14 days after administration. No negative effects were noted on the development of an initial active immunity or an existing active immunity against Clostridium perfringens type D when they were passively immunized with partially purified immunoglobulin.

Diminished heat-shock protein synthesis following mitogen stimulation of lymphocytes from aged donors.

Studies of the diminished mitogen-induced proliferative response of T lymphocytes from older subjects show that aging must result in some defect(s) in the intracellular events required for transition from the G0 or quiescent state through the prereplicative interval and into the first S phase of the cell cycle. This conclusion is supported by observations of diminished inducibility of the lymphokine IL-2 and its receptor during aging. The current study demonstrates that decreased proliferative response to phytohemagglutinin (PHA) is also paralleled by decreased induction during the prereplicative interval of two of the most strongly enhanced proteins in mitogen-activated T cells: HSP90 and P73, which are also members of the heat-shock protein family. Diminished induction of HSP90 and P73 is observed in lymphocytes from older subjects (mean age 75), regardless of differences in health status of the subject populations. These results suggest that in vivo aging of human T cells results in a general defect in the induction of gene products required for transition from quiescence into the S phase of the cell cycle and that diminished T cell proliferation in advanced age is not due to a specific, "intrinsically immunologic" defect in induction of IL-2 and the IL-2 receptor.

Expression of the human T cell antigen receptor complex in advanced age.

Several studies of T cell-associated surface marker expression in older subjects "with no evidence of diseases known to affect immune function" have suggested that diminished expression of the constant portion (CD3) of the human T cell antigen-receptor complex (CD3/Ti) may be associated with aging. To determine if there is a decrease with age in expression of this complex, we determined the percent of cells positive for WT31, an antibody that recognizes a constant epitope on Ti alpha-beta heterodimers, CD3, CD4 and CD8 by immunofluorescence on peripheral blood lymphocytes from young controls (19-31 years), and 2 well characterized populations of older donors (greater than 69 years). The first group of older donors had no history of chronic or recent acute illness and saw a physician only for routine medical care. The second group was selected from patients seen in a geriatrics clinic for diagnoses that included osteoarthritis and cardiopulmonary disorders. There were no significant differences in the percent of cells positive with WT31, or with antibodies to CD4 and CD8 between young adults and the 2 groups of older donors. The clinic subjects showed a consistent decrease in percent of CD3+ lymphocytes in peripheral blood mononuclear cells compared to young adults (5-10% reduction) with less difference between the healthy older subjects and young adults. In the clinic subjects this reduction appears to be due to a decrease in CD3+, WT31-lymphocytes. These cells represent about 5-6% of the total T cell population in the young and healthy older group and are known to express CD3 in combination with Ti gamma-delta dimers. We show here that these cells are about equally distributed in high and low density lymphocytes after Percoll fractionation. We conclude that significant quantitative reduction in expression of the CD3/Ti antigen-receptor complex on human T cells is not a feature of the primary aging process and cannot account for diminished in vitro proliferative response of healthy subjects with age. However, diminished abundance of T cells expressing products of the Ti gamma-chain in less healthy older subjects may predispose to or result from diseases not usually associated with altered immune function.

Occurrence of Clostridium tetani in soil and horses.

The annual incidence of tetanus in the RSA is up to 300 cases with more than 50% of these coming from Natal/KwaZulu. The condition of playing fields and the excretion of Clostridium tetani by horses was therefore investigated. The overall contamination rate of soils in the Durban area is lower than that of published data from other parts of the world, for instance 28% for Durban in comparison with 31-42% for Japan and Quebec. A rugby field in the Transvaal showed 40% contamination and a pasture used for horses for more than 20 years 65%. No case of human or equine tetanus has ever been reported from either the playing field or the pasture. A permanent carrier state in horses could not be established; the organisms were only excreted for 3-4 days. At any one time only 2 out of 27 horses in a stable were excreting C. tetani. Only 7 of 118 faeces samples were positive over a period of 4 months (5-9%).

Lymphocyte proliferative response to PHA and anti-CD3/Ti monoclonal antibodies, T cell surface marker expression, and serum IL-2 receptor levels as biomarkers of age and health.

Alteration of T cell surface marker expression with a decrease of CD3 positive cells relative to the number of CD4 and CD8 positive cells, diminished in vitro proliferative response to mitogenic stimuli like PHA and antibodies to the CD3/Ti complex, and increase in serum IL-2 receptor levels, are among the changes in immunologic parameters that have been associated with advanced age. To distinguish between effects of the primary aging process and diseases of aging not known to be directly related to immune function, we investigated these variables in two well characterized populations of elderly donors (greater than 70 years) and a young adult control group (less than 35 years). The first group of older donors reported no evidence of significant chronic or recent acute illness and saw a physician only for routine medical care. The second group was randomly selected from individuals seen in a geriatric medicine clinic for diagnoses that included osteoarthritis and cardiopulmonary disorders. Altered surface marker expression and increased serum IL-2 receptor levels were seen only in the second group. On the other hand, lymphocyte proliferative responses to PHA, Leu 4 (anti-CD3) and a monoclonal antibody to the beta-chain of the T cell antigen receptor (WT31) were significantly decreased in both populations. Because we would expect primary aging to affect even extremely fit individuals of advanced age, we conclude that decrease in T cell proliferative response may represent a biomarker of primary aging in man. The alteration in surface marker expression and increased IL-2R levels in serum appear to be effects secondary to non-immunologic disease rather than aging.

A review of Legionella pneumophila in horses and some South African serological results.

An examination of the sera of 329 horses for L. pneumophila antibodies revealed a much lower exposure rate than that reported in the United States of America. Further serological investigations of persons closely associated with a sero-positive horse indicated that the horse could not be considered to be a source of infection but that both humans and animals were probably exposed to a common source of infection. The results showed that 192/329 (58.4%) of the sera tested negative, 114/329 (34.7%) had end-point titres of 1/2, 22/329 (6.7%) end-points of 1/16 and one an end point of 1/256 (0.3%). Serological testing of the people closely associated with horses showed that out of 22 people, 3 had a positive end-point titre of 1:64 and only one person showed an end-point titre of 1:256.

Husfeldt hernia repair: indications and results. A follow-up study.

Ninety-seven consecutive patients with hiatal hernia were operated upon with a modified Husfeldt hernia repair during a ten-year period. Thirty-two of the patients had severe reflux complications, such as ulcerative oesophagitis, oesophageal stricture and shortened oesophagus. Ninety patients were carefully followed up postoperatively. The mean duration of follow-up was 5 years. Analysis of the postoperative results in relation to the type of hernia showed no difference between sliding and combined hernia. Recurrence of hernia, unsatisfactory clinical results and gastro-oesophageal reflux were recorded more often in patients with severe reflux complications. The main cause of unsatisfactory results in these patients was found to be a shortened oesophagus. The method proved to be a reliable procedure for surgical treatment of not only uncomplicated hernias, but also cases complicated by oesophageal stricture if the stricture was not associated with shortened oesophagus. It is considered that a shortened oesophagus is a contra-indication for employment of the Husfeldt method.

Hiatal hernia complicated by oesophageal stricture. Surgical treatment and results. A follow-up study.

During a 10-year period, 1967-1976, 57 patients were operated upon for hiatal hernia and gastro-oesophageal reflux complicated by oesophageal stricture. Forty-four patients were managed by various surgical antireflux procedures combined with dilation of the stricture. In 12 patients the stricture was resected and the oesophageal continuity restored by oesophagogastrostomy. The primary mortality was 3.5%. Fifty-two patients were carefully followed up postoperatively by periodic control examiniations. The results of the treatment are presented. The main cause of unsatisfactory postoperative results was gastro-oesophageal reflux uncorrected by the surgical procedure. In the patients subjected to a hernia repair the failure of the antireflux procedure was due mainly to a shortened oesophagus associated with the stricture. It is concluded that most of these strictures can be successfully treated by dilation after establishment of control of the pathological reflux by means of an antireflux surgical procedure. The location, width, length and rigidity of the stricture, as revealed at the preoperative examination, are not decisive for the choice of therapeutic approach.

Hiatal hernia and shortened oesophagus.

The existence of an anatomically shortened oesophagus in patients with hiatal hernia, and its influence on the results of surgical repair of the hernia, is the subject of great controversy. One hundred and forty patients operated upon for hiatal hernia were studied for presence of shortened oesophagus. The method of examination and criteria for evaluation of the oesophageal shortening are described. The oesophagus was found to be anatomically shortened in 52 of these patients. None of the findings obtained at the preoperative examinations employed in the study could be used as a pathognomonic sign for diagnosing a shortened oesophagus. Irreducibility of the cardia below and the diaphragm, as observed radiologically, in association with other severe reflux complications, such as oesophageal stricture and/or ulcerative, makes it presence very likely, however. The incidence of shortened oesophagus in this series was higher in patients with a long history of symptomatic gastro-oesophageal reflux. The influence of the shortened oesophagus on the result of the surgical repairs used in this study, and aimed mainly at restoring the abdominal segment of the oesophagus, was clearly unfavourable.

Tumors of the thymus and thymic region: III. Clinicopathological studies on teratomas and tumors of Germ Cell type.

In a series of 82 patients with tumors of the thymus and thymic region there were 11 with teratomas and germinal tumors. Four of these patients had benign cystic teratomas, 4 had malignant teratomas, 1 had an embryonal carcinoma, and 2 had seminomas. The benign teratomas were removed by simple extirpation without complications. The malignant teratomas were highly invasive, and despite extensive operations and postoperative radiotherapy, 3 of the 4 patients died within 9 months. One patient with predominantly seminomatous differentation of the teratoma was alive and well more than 3 years after the operation. The patient with an embryonal carcinoma died after 4 months. One of the 2 patients with seminoma remained alive 20 years after radical excision and postoperative radiotherapy. The other, who had a huge seminoma, died during operation. The prognosis in patients with seminomas or with predominantly seminomatous structures in teratomas seems to be good after combined radical excision and radiotherapy, although nonradical resection followed by raditherapy may be justified in high-risk patients.

Tumors of the thymus and thymic region: I. Clinicopathological studies on thymomas.

A series of 43 patients with thymoma was reviewed. The patients were classified with respect to some factors of prognostic significance. The tumors were reclassified histologically, and a staging system with three defined stage-groups was applied to the series on the basis of operative findings and histological examination of surgical specimens. Surgical-pathological staging is of high prognostic and therapeutic importance in thymomas. Complete removal of the tumor was possible in the 25 patients with stage I or II disease and in 14 of the 18 patients with stage III tumors. Pleural metastases were observed in half of the patients with stage III disease. Even patients with extensive local spread or pleural metastases were subject to tumor resection. The treatment of choice is radical resection along in stage I; radical extirpation and, if indicated, postoperative radiotherapy in stage II; and radical resection whenever possible, even in cases of pleural spread, in stage III, with postoperative radiotherapy and chemotherapy. Myasthenia gravis is an indication rather than a contraindication to radical treatment of thymoma, although some patients may deterioratte. The importance of total thymectomy is stressed.

Tumors of the thymus and thymic region: II. Clinicopathological studies on Hodgkin's disease of the thymus.

Among 82 patients with a tumor in the thymic region, 17 had a lesion that fulfilled the criteria for Hodgkin's disease of the thymus; the histopathological differentiation of this entity from thymomas is discussed. All patients received surgical treatment and postoperative radiotherapy. After a mean observation time of 10 years there was no local recurrence and no death due to the disease, though 3 deaths were cuased by the treatment. New clinical manifestations occurred in 3 of the 14 long-term survivors: they were treated successfully by operation or irradiation. A very aggressive surgical approach involving extirpation of all tumor tissue, extensive excision of the surrounding tissues and adjacent lymph nodes, and supplementary radiotherapy seems to be the treatment of choice.

Intrapleural streptokinase in the treatment of haemothorax and empyema.

Thirty-eight patients with haemothorax or empyema, in whom conventional drainage treatment had proved ineffective were treated with streptokinase instillations. An increased yield of fluid was noted in all cases, up to 1300 ml after one instillation. Re-expansion of the lung was observed radiologically in 30 cases. No serious complications occurred. The method seems very useful and is recommended.