The genetics of black larva, an autosomal recessive lethal mutation located on chromosome 3 in the mosquito Anopheles albimanus

Lung tissue from 14 normal residents of high altitude regions, 10 patients with chronic bronchitis and emphysema, and 1 patient with Pickwickian syndrome was studied with regard to the occurrence of pulmonary vascular changes. In addition to the well-known pulmonary arterial alterations, lesions in small pulmonary veins were found in the great majority of the cases. These changes, consisting of medial hypertrophy and arterialization and of bundles of smooth muscle cells within the venous intima, have not been described before in man. These findings suggest that alveolar hypoxia acts not only on small pulmonary arteries and arterioles but also on veins of small caliber, probably by inducing venoconstriction.     

Expression of endothelin-1 in the lungs of patients with pulmonary hypertension

BACKGROUND: Pulmonary hypertension is characterized by an increase in vascular tone or an abnormal proliferation of muscle cells in the walls of small pulmonary arteries. Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide with important mitogenic properties. It has therefore been suggested that endothelin-1 may contribute to increases in pulmonary arterial tone or smooth-muscle proliferation in patients with pulmonary hypertension. We studied the sites and magnitude of endothelin-1 production in the lungs of patients with various causes of pulmonary hypertension. METHODS: We studied the distribution of endothelin-1-like immunoreactivity (by immunocytochemical analysis) and endothelin-1 messenger RNA (by in situ hybridization) in lung specimens from 15 control subjects, 11 patients with plexogenic pulmonary arteriopathy (grades 4 through 6), and 17 patients with secondary pulmonary hypertension and pulmonary arteriopathy of grades 1 through 3. RESULTS: In the controls, endothelin-1-like immunoreactivity was rarely seen in vascular endothelial cells. In the patients with pulmonary hypertension, endothelin-1-like immunoreactivity was abundant, predominantly in endothelial cells of pulmonary arteries with medial thickening and intimal fibrosis. Likewise, endothelin-1 messenger RNA was increased in the patients with pulmonary hypertension and was expressed primarily at sites of endothelin-1-like immunoreactivity. There was a strong correlation between the intensity of endothelin-1-like immunoreactivity and pulmonary vascular resistance in the patients with plexogenic pulmonary arteriopathy, but not in those with secondary pulmonary hypertension. CONCLUSIONS: Pulmonary hypertension is associated with the increased expression of endothelin-1 in vascular endothelial cells, suggesting that the local production of endothelin-1 may contribute to the vascular abnormalities associated with this disorder.     

Obstructive lesions of distal mesenteric arteries. A light and electron microscopic study

Two cases of "nonocclusive" intestinal infarction are reported. No thrombosis or significant atherosclerosis was identified and proximal mesenteric arteries were widely patent. However, distal mesenteric arteries were thickened and had pinpoint lumens. Light microscopic findings suggested that this marked luminal narrowing was due to prominent intimal fibromuscular proliferation, medial hypertrophy and mild structural disarray, focal periarterial fibrosis, and transmural elastosis. Electron microscopic findings indicated that the endothelium was normal but the basal lamina was irregularly thickened. The predominant cellular component of the thickened intima consisted of smooth muscle cells, and smooth muscle cells of the media were seen to migrate through an extensively disrupted and degenerated internal elastic lamina. Deposits of young elastic fibers, collagen, and ground substance were also noted, particularly in the intima. The need for careful sectioning and microscopic examination of small distal mesenteric arteries in cases of so-called nonocclusive intestinal infarction is emphasized.     

Quantitative analysis of pulmonary vascular disease in complete transposition of the great arteries

Forty autopsy cases of complete transposition of the great arteries (TGA) and 22 autopsy cases of ventricular septal defect (VSD) were analyzed histologically for evidence of vascular damage due to pulmonary vascular disease (PVD). Positive correlations were generally observed between an index of pulmonary vascular disease (IPVD) and blood pressure of pulmonary circulation. No significant difference in IPVD was found between TGA and VSD in the first five months of life, when cases of each disease were compared at similar blood pressure levels. After that age, however, IPVD was much higher in TGA, and particularly severe PVD in this disease was demonstrated histologically. Morphometrical analysis of the pulmonary artery revealed hypertrophy of the muscular cost in response to elevated blood pressure. However, the progress of medial hypertrophy was retarded in TGA in the first five months, and medial thickness in arteries of cases of TGA older than five months was only 70% of that in VSD at the same blood pressure levels. Suppression of this process of reinforcement of the arterial wall in response to the stress of high pulmonary pressure was regarded as one of the important factors precipitating severe pulmonary vascular disease in transposition of the great arteries.     

Intramural coronary artery dysplasia of the ventricular septum and sudden death

We report four cases of sudden unexpected death in three males and one female aged 12 to 31 years. Death occurred during exercise in three of four cases, and there was no history of sudden death or previous cardiac history in any patient. At autopsy, there was marked intramural coronary artery dysplasia of the ventricular septum, accompanied in three of the four cases by myocardial fibrosis. The arterial dysplasia was characterized by severe medial thickening with smooth muscle cell disorganization and marked luminal narrowing. There was no evidence of myofiber disarray or asymmetric septal hypertrophy to suggest hypertrophic cardiomyopathy. Other than an ostium secundum type atrial septal defect in one case, there were no associated cardiac or extracardiac lesions found at complete autopsy of these individuals. We conclude that small vessel disease of intramural coronary arteries of the ventricular septum may be an isolated finding leading to sudden cardiac death in young adults.     

Chronic thromboembolic pulmonary hypertension

Acute pulmonary hypertension has a high mortality at the onset. Patients surviving the first phase will usually recanalize the pulmonary arteries through intrinsic thrombolytic mechanisms and medical treatment. However, in some cases there is insufficient resolution of the emboli with subsequent thrombotic and fibrotic reorganization, leading to a worsening of the pulmonary obstruction. In the open pulmonary arteries the disease may lead to hypertrophy of the media and intimal proliferation, thus leading to a further increase in the pulmonary vascular resistance. This again leads to hypertrophy of the right ventricle and ultimately to right-sided heart failure. Untreated, chronic thromboembolic pulmonary hypertension has a five-year mortality approaching 100%, but extensive pulmonary thrombendarterectomy using extracorporeal circulation and deep hypothermia has been shown to lower the pulmonary vascular resistance and thereby improve the prognosis significantly. Operative treatment can now be offered in Denmark, and the purpose of this review is to draw attention to the disease, its symptoms, diagnosis and the surgical treatment.     

Functional and structural adaptation of the yak pulmonary circulation to residence at high altitude

The high-altitude (HA) native yak (Bos grunniens) has successfully adapted to chronic hypoxia (CH) despite being in the same genus as domestic cows, which are known for their great hypoxic pulmonary vasoconstrictor responses (HPVRs), muscular pulmonary arteries, and development of severe pulmonary hypertension on exposure to CH. To determine possible mechanisms by which the pulmonary circulation may adapt to CH, yak pulmonary vascular reactivity to both vasoconstrictor and vasodilator stimuli and yak pulmonary artery structure were assessed. Hypoxia caused a small but significant HPVR, and norepinephrine infusion caused a greater rise in pulmonary arterial pressure (Ppa) than did hypoxia. Acetylcholine, an endothelium-dependent vasodilator, had no effect on Ppa but lowered pulmonary resistance (Rp) by causing an increase in cardiac output. Sodium nitroprusside, an endothelium-independent vasodilator, decreased both Ppa and Rp significantly. Yak small pulmonary arteries had a 4.1 +/- 0.1% medial thickness, with vessels < or = 100 microns devoid of smooth muscle. Yak pulmonary artery endothelial cells were much longer, wider, and rounder in appearance than those of domestic cows. Thus the yak has successfully adapted to HA conditions by maintaining both a blunted HPVR and thin-walled pulmonary vessels. Differences in both endothelial cell morphology and response to acetylcholine between the yak and those reported in the domestic cow suggest the adaptation to HA may include changes not only in the amount of pulmonary vascular smooth muscle but in endothelial cell function and structure as well.     

Pediatric lung transplantation. Indications, techniques, and early results

From July 1990 to April 1993, 36 lung transplantations in 33 patients were performed in our pediatric transplant program (0.25 to 23 years, mean age 10.3 years). Eight children had been continuously supported with a ventilator for 3 days to 4.5 years before transplantation and three were supported by extracorporeal membrane oxygenation. Indications for lung transplantation in this pediatric population included the following: cystic fibrosis (n = 13), pulmonary hypertension, and associated congenital heart disease (n = 10), pulmonary atresia, ventricular septal defect and nonconfluent pulmonary arteries (n = 3), pulmonary fibrosis (n = 6), and acute respiratory distress syndrome (n = 1). Three children underwent retransplantation for acute graft failure (n = 2) or chronic rejection (n = 1). Pulmonary fibrosis was related to complications of treatment of acute of myelogenous leukemia with bone marrow transplantation in two children and to bronchiolitis obliterans, bronchopulmonary dysplasia, interstitial pneumonitis, and Langerhans cell histiocytosis in four others. Thirteen children underwent lung transplantation and concomitant cardiac repair. Bilateral lung transplantation, ventricular septal defect closure and pulmonary homograft reconstruction of the right ventricular outflow tract to the transplanted lungs was performed in three children by means of a new technique that avoids the need for combined heart-lung transplantation. Two patients had ventricular septal defect closure and single lung transplant for Eisenmenger's syndrome, two had ligation of a patent ductus arteriosus and transplantation, three additional children underwent atrial septal defect closure and lung transplantation, and two underwent lung transplantation for congenital pulmonary vein stenosis. Eight early deaths and three late deaths occurred (actuarial 1-year survival 62%). Lung transplantation in children has been associated with acceptable early results, although modification of the adult implantation technique has been necessary. Lung transplantation and repair of complex congenital heart defects is possible; heart-lung transplantation may only be required for patients with severe left heart dysfunction and associated pulmonary vascular disease. Bronchiolitis obliterans remains a major concern for long-term graft function in pediatric lung transplant recipients.     

Intramyocardial small-vessel disease in chronic alcoholism

A morphologic study of the small (50 to 200 micron) intramyocardial coronary arteries was performed. The cases chosen for study were selected from a relatively young group of patients without clinical evidence of alcoholic cardiomyopathy or pathologic evidence of large coronary artery disease, in order to evaluate alterations in the small vessels which could possibly be attributed to the chronic alcoholic state. Five basic vascular abnormalities were described. The most common alteration found in all nine cases was vascular wall edema (48 per cent), followed by perivascular fibrosis (42 per cent), vascular sclerosis (36 per cent), subendothelial humps (13 per cent), and vascular wall inflammation (11 per cent). The significance and pathogenesis of these changes were discussed. Primary endothelial cell damage was proposed as a common pathogenic mechanism for all five types of vascular abnormality. It was suggested that following endothelial damage, fluid and macromolecules penetrate into the vessel wall or into the perivascular space where, by incompletely understood processes, they induce vascular wall myocytes to produce collagen, elastin, and basement membrane-like substances. Evidence supporting this mechanism was derived from the common observation of vascular wall edema, from the occasional presence of erythrocytes and leukocytes within the vessel wall, and from experimental data in the literature. Several possible etiologic agents were implicated in the pathogenesis of endothelial and vessel wall injury. These included alcohol itself, acetaldehyde, biogenic amines, and magnesium deficiency. It is probable, however, that there are multiple etiologic factors which affect the small cardiac vessels of the chronic alcoholic. Finally, the proposal was advanced that the nonspecific pathology of the myocardium in chronic alcoholism may be a result of ischemia secondary to disease of the small intramyocardial coronary ateries.     

Morphological observations on the vasculitis in the mucocutaneous lymph node syndrome. A skin biopsy study of 27 patients

Twenty-seven skin biopsies were obtained from the exanthemata of patients in the acute stage of the mucocutaneous lymph node syndrome (MCLS). The three vascular systems of different caliber size--the intrapapillary capillary loops (ICL), the superficial arteriolar or venular plexus (SAP, SVP) and the small subcutaneous vessels--were examined to investigate the characteristics of the vasculitis in MCLS and differentiate it from infantile polyarteritis nodosa (IPN). Significant papillary edema and dilatation of ICL, SAP and SVP were observed on the 4th day after the onset of the illness, and then gradually decreased. In the subcutaneous regions, vasculitis began with endothelial necrosis, and subendothelial edema and degenerative changes in the muscle cells followed. These changes in the small subcutaneous vessels were observed for a longer period than in the ICL, SAP and SVP. Moderate mononuclear cell infiltrations were observed. Both arteries and veins were affected.     

Clinical primary pulmonary hypertension: three pathologic types

Clinically, there is a group of patients with elevated pulmonary arterial pressure in whom the underlying cause is not apparent. The pulmonary arterial wedge pressure is not elevated. For such cases, the designation of primary pulmonary hypertension may be made clinically. From the clinical categorization of primary pulmonary hypertension, three distinct pathologic entities emerge, namely 1) plexogenic pulmonary arteriopathy, 2) recurrent pulmonary thromboembolism, and 3) pulmonary veno-occlusive disease. The plexogenic type is characterized initially by pulmonary arterial vasoconstriction with medial hypertrophy. Secondary proliferative intimal lesions, including the plexiform lesion, develop. Recurrent pulmonary thromboembolism is characterized by the presence of arterial thrombi of varying ages involving the microscopic-sized pulmonary arteries. Thrombi may be embolic in nature or may develop in situ. Pulmonary veno-occlusive disease is characterized by obstructive lesions of pulmonary veins and venules. The clinical presentation of the three pathologic types may be so similar that definitive diagnosis depends upon histologic examination of the lung from tissue obtained either by biopsy or at necropsy.     

Right ventricular pathology in chronic pulmonary hypertension

Right ventricular free wall biopsy specimens in 40 patients undergoing surgery for relief of chronic thromboembolic pulmonary hypertension were normal in 5%, disclosed only myocyte hypertrophy in 80%, mild focal fibrosis in 12.5%, and myocarditis in 2.5%. There was no relation between postsurgical functional or hemodynamic outcomes and the presence of focal fibrosis.     

Determinants of coronary reserve in rats subjected to coronary artery ligation or aortic banding

OBJECTIVE: We investigated whether decreased coronary reserve in hearts after coronary artery ligation or in hearts from rats after aortic banding can be related to remodeling of resistance arteries. METHODS: Maximal coronary flow (absolute flow) and cardiac perfusion (flow corrected for heart weight) were determined in isolated, perfused rat hearts after adenosine or nitroprusside, at 3 and 8 weeks after coronary artery ligation or 4-5 weeks after aortic banding. Perivascular collagen and medial thickness of resistance arteries were determined by morphometry. RESULTS: maximal coronary flow of infarcted hearts had been restored to sham values at 3 weeks. Growth of cardiac muscle mass from 3 to 8 weeks exceeded the increase in maximal coronary flow, leading to a decreased perfusion at 8 weeks. A slight, transient increase in perivascular collagen, but no medial hypertrophy, was found after infarction. After aortic banding perivascular fibrosis and medial hypertrophy led to a decreased maximal coronary flow in both the hypertrophied left and the non-hypertrophied right ventricle. Consequently, perfusion of the left ventricle was most severely reduced. CONCLUSIONS: Reduced maximal perfusion after aortic banding is determined by both cardiac hypertrophy and vascular remodeling. In contrast, during infarction-induced remodeling, reduction of perfusion is not determined by vascular remodeling, but mainly by disproportional cardiac hypertrophy relative to vascular growth.     

Heparin inhibits mesenteric vascular hypertrophy in angiotensin II-infusion hypertension in rats

OBJECTIVE: Chronic infusion with angiotensin II increases blood pressure and activates growth mechanisms to produce hypertrophy of the heart and vessels. In order to better understand mechanisms of angiotensin II induced vascular hypertrophy, this study aimed to determine whether heparin, a potent inhibitor of smooth muscle proliferation mechanisms, was able to inhibit vascular hypertrophy. METHODS: Angiotensin II (100, 200 or 300 ng/min/kg s.c.) or a saline vehicle control were infused into rats for 14 days. A separate group of animals were co-infused with heparin (0.3 mg/h/kg i.v.) and angiotensin II (200 ng/min/kg s.c.) to test whether hypertension or hypertrophy were antagonized. Blood pressure was measured by tail cuff method and vessel media cross sectional area was measured by morphometry in aorta and mesenteric arteries. RESULTS: Blood pressure elevation and cardiovascular hypertrophy produced by angiotensin II were strongly dose-dependent. Hypertrophy responses at 14 days of treatment also appeared to be influenced partly by local factors as medial cross sectional area was increased more in mesenteric arteries than in thoracic aorta, and left ventricle weight was least affected. Heparin treatment did not influence the increase of blood pressure in angiotensin II infused animals, but the mesenteric vascular hypertrophy response due to angiotensin II was inhibited by approximately 50%. Inhibition of a modest cardiac hypertrophy and aortic medial hypertrophy did not reach significance. CONCLUSIONS: Angiotensin II infusion produced vascular medial hypertrophy and increased blood pressure, however the inhibitory effect of heparin on hypertrophy in mesenteric arteries was not mediated through angiotensin II induced vasoconstriction or blood pressure elevation. These data suggest that heparin interferes directly with the hypertrophy mechanism in mesenteric arteries, and that heparin-sensitive growth mechanisms are important in mediating angiotensin induced mesenteric vascular hypertrophy.     

Is angiographic spasm real spasm?

Systematic morphological study of the cerebral arteries was made in six autopsy cases of ruptured aneurysms. The time course of the arterial luminal narrowing was observed by repeated angiograms, and segments of the narrowed arteries were studied histologically. Various histological changes were found consistent with the angiographic findings. We have devided these into three stages according to the duration of the disease. In the acute stage (less than one day) the contraction of the medial smooth muscle cells may be the main cause of the luminal narrowing. In the subacute stage, arteries showed a reduction in lumen size with medial thickening, marked corrugation of the internal elastic lamina, and thrombus formation attached to the endothelial surface. If vasoconstriction remained localized to the same segment for several days, the intimal or medial thickening and thrombus might produce the luminal narrowing consistent with the angiographic narrowing. In the chronic stage (more than two weeks), most cases showed dilatation of the arterial lumen on angiography. These arteries showed frank necrosis of the smooth muscle cells histologically. In a case which demonstrated progressive luminal narrowing on angiograms over 2 weeks, the arterial wall showed luminal narrowing with cellulofibrous thickening of the intima and organization of the thrombus. The presence of these structural changes in the narrowed arteries seen at angiography seems to be very important for proper understanding and treatment of vasospasm.     

Pulmonary tumor emboli and cor pulmonale in primary carcinoma of the lung

Tumor embolization was found at autopsy in the pulmonary arteries of 33 of 331 patients dying with primary carcinoma of the lung (other than oat cell carcinoma). Venous or lymphatic vascular involvement, or both, was greater frequency of tumor embolization htan epidermoid carcinomas (16.5% vs. 5.8%). In 16 of the 33 cases, diffuse, obliterative intimal fibrosis was found in small arteries affected by the tumor embolization. Enlargement of the right cardiac ventricle was present in 26 of the 33 cases. Dyspnea as the initial symptom or as one of the major symptoms, occurred in 21 patients. The average interval between onset of dyspnea and death was 4 weeks. It is concluded that pulmonary arterial embolization is a relatively frequent complication of primary lung carcinoma, particularly adenocarcinoma, which may lead to the developemnt of pulmonary hypertension and cor pulmonale Dyspnea, occurring de novo in patients with primary lung carcinoma is an ominous sign and should alert the clinician to the possibility of arterial pulmonary tumor embolization.     

Striking electrocardiographic changes associated with pheochromocytoma. Masquerading as ischemic heart disease

A patient with pheochromocytoma presented striking electrocardiographic changes mimicking ischemic heart disease at one time and acute pulmonary embolism at other times. Diffuse left ventricular hypokinesia was demonstrated in the presence of normal coronary arteries. Following removal of the pheochromocytoma, the electrocardiographic abnormalities disappeared.     

Collateral ventilation and pulmonary arterial smooth muscle in the coati

Collateral ventilation can participate in ventilation-perfusion regulation by shifting normoxic gas into hypoxic lung regions. In species lacking collateral pathways, such as cattle and swine, ventilation-perfusion balance must rely heavily on hypoxic vasoconstriction, which may explain why their muscular pulmonary arteries are much thicker than those of other animal species. The presence of these unusually muscular vessels in turn may account for the vigorous pressor response to acute hypoxia in these species. The only other species known to lack collateral ventilation is the coati. To determine whether coatis fit the pulmonary circulatory pattern of cattle and swine, we measured pulmonary arterial wall dimensions and pulmonary vascular responsiveness to acute airway hypoxia in 11 adult coatis. Hypoxia caused impressive pulmonary arterial hypertension [normoxia = 17 +/- 1 (SE) Torr, hypoxia = 40 +/- 2 Torr, cardiac output unchanged]. The medial thickness of muscular pulmonary arteries (50-300 microns) was 17.1 +/- 1.8% (SD) of external diameter, a thickness unprecedented in normotensive adult mammals. We conclude that coatis fit the pattern of other species lacking collateral ventilation, since they have thick-walled pulmonary arteries and a vigorous pressor response to hypoxia.     

Dopamine D1/D2 antagonist combinations as antagonists of the discriminative stimulus effects of cocaine

Platelet-derived growth factor (PDGF) exists as a dimer composed of two homologous but distinct peptides termed PDGF-A and -B chains, and may exist as AA, AB, and BB isoforms. The PDGF-B chain has been implicated as a mediator of renal vascular rejection by virtue of up-regulated expression of its receptor, PDGF beta-receptor, in affected arteries. A role for PDGF-A chain in mediating intimal proliferation has been suggested in human atherosclerosis (Rekhter MD, Gordon D: Does platelet-derived growth factor-A chain stimulate proliferation of arterial mesenchymal cells in human atherosclerotic plaques? Circ Res 1994, 75:410), but no studies of this molecule in human renal allograft injury have been reported to date. We used two polyclonal antisera to detect expression of PDGF-A chain and one monoclonal antibody to detect PDGF-B chain by immunohistochemistry in fixed, paraffin-embedded tissue from 1) normal adult kidneys, 2) a series of renal transplant biopsies chosen to emphasize features of vascular rejection, and 3) allograft nephrectomies. Immunohistochemistry was correlated with in situ hybridization on adjacent, formalin fixed tissue sections from nephrectomies utilizing riboprobes made from PDGF-A and -B chain cDNA. PDGF-A chain is widely expressed by medial smooth muscle cells of normal and rejecting renal arterial vessels of all sizes by immunohistochemistry and in situ hybridization. PDGF-A chain is also expressed by a population of smooth muscle cells (shown by double immunolabeling with an antibody to alpha-smooth muscle actin) comprising the intima in chronic vascular rejection. In arteries demonstrating acute rejection, up-regulated expression of PDGF-A chain by endothelial cells was detected by both immunohistochemistry and in situ hybridization. In contrast, PDGF-B chain was identified principally in infiltrating monocytes within the rejecting arteries, similar to its localization in infiltrating monocytes in human atherosclerosis. Although less prominent than the case for PDGF-A chain, PDGF-B chain also was present in medial and intimal smooth muscle cells in both rejecting and nonrejecting renal arteries. PDGF-A and -B chains have now been localized at both the mRNA and protein levels to the intimal proliferative lesions of vascular rejection. These peptides, which are known stimuli for smooth muscle cell migration and proliferation in experimental vascular injury, may have similar stimulatory effects on smooth muscle cells in an autocrine and/or paracrine manner to promote further intimal expansion and lesion progression in this form of human vasculopathy.