Craniofacial pain can be the sole prodromal symptom of an acute myocardial infarction: an interdisciplinary study / El dolor cráneo-facial puede ser el único síntoma prodrómico de un infarto agudo de miocárdio: estudio interdisciplinario

We recently found craniofacial pain to be the sole symptom of anacute myocardial infarction (AMI) in 4% of patients. Wehypothesized that this scenario is also true for symptoms ofprodromal (pre-infarction) angina. We studied 326 consecutivepatients who experienced myocardial ischemia. Intra-individualvariability analyses with respect to ECG findings and paincharacteristics were performed for those 150 patients whoexperienced at least one recurrent ischemic episode. AMI patients(n=113) were categorized into two subgroups: “abrupt onset”(n=81) and “prodromal angina” (n=32). Age, gender and riskfactor comparisons were performed between groups. Craniofacialpain constituted the sole prodromal symptom of an AMI in 5% ofpatients. In those who experienced two ischemic episodes, womenwere more likely than men to experience craniofacial pain in bothepisodes (p<0.01). There was no statistically significant differencebetween episodes regarding either ECG findings or the use of thetwo typical pain quality descriptors “pressure” and “burning”. This study is to our knowledge the first to report that craniofacialpain can be the only symptom of a pre-infarction angina.Craniofacial pain constitutes the sole prodromal AMI symptomin one out of 20 AMI patients. Recognition of this atypicalsymptom presentation is low because research on prodromalAMI symptoms has to date studied only patients with chest pain.To avoid a potentially fatal misdiagnosis, awareness of thisclinical presentation needs to be brought to the attention ofclinicians, researchers and the general public.

En un estudio previo encontramos que un dolor en la región cráneo-facial puede ser el único síntoma de un infarto agudo de miocardio (IAM) en el 4 por ciento de los casos. En el presentetrabajo la hipótesis fue que este escenario es cierto también para la angina pre-infarto o angina prodrómica.En el estudio se incluyeron 326 pacientes consecutivos con isquemia cardiaca sintomática. Se realizó un análisis intraindividual con respecto a características del dolor y hallazgoselectrocardiográficos en los 150 pacientes que presentaron episodios recurrentes de isquemia cardiaca. Los pacientes con infarto agudo se categorizaron en dos grupos: “comienzoabrupto” (n=81) y “angina prodrómica” (n=32). Se realizaron comparaciones entre grupos con respecto a edad, género y factores de riesgo cardiovasculares. El dolor en la región cráneofacial constituyó el único síntoma prodrómico (pre-infarto) de un IAM en el 5 por ciento de los casos. En aquellos pacientes que experimentaron dos episodios isquémicos, las mujeres tuvieron una mayor prevalencia de dolor cráneo-facial en los dos episodios (p<0.01). No se detectaron diferencias estadísticas entre episodios con respecto a hallazgos electrocardiográ ficos o al empleo de los descriptores verbales del dolor de origen cardíaco “opresivo” y “quemante”.Este es el primer estudio de investigación en documentar queel dolor en la región cráneo-facial puede ser el único síntoma de una angina pre-infarto. En efecto, esto ocurre en uno decada 20 casos de IAM. El reconocimiento de esta presentación clínica es baja debido a que históricamente los criterios de inclusión de los estudios de angina pre-infarto incluyeron únicamente pacientes con dolor de pecho. Para evitar el error diagnóstico con consecuencias fatales para el paciente, es importante que esta información llegue tanto a los clínicos como al público en general.

Effects of some modulators on purine nucleoside phosphorylase activity in myocardial tissue.

Purine nucleoside phosphorylase (PNP) in mammalian tissue is an enzyme responsible for formation of purine bases in DNA. It is also believed that PNP is crucial under energy-deprived conditions for the cell to metabolise adenosine during ATP degradation. This work describes a new method for determination of PNP activity in myocardial tissue using a commercially available substrate, 2-amino-6-mercapto-7-methylpurine riboside (MESG). The method involves the photometric assessment of the reaction between PNP (extracted from myocardial tissue) and MESG. Quantification as well as temperature- and pH-dependency for myocardial PNP activity is described. Also, the effect of some modulators has been studied. We have established the presence of PNP activity in pig myocardial tissue. Further, the results indicate a pH tolerance under slightly acid conditions and a calcium ion dependence of the enzyme.

Growth factor PDGF-BB stimulates cultured cardiomyocytes to synthesize the extracellular matrix component hyaluronan.

BACKGROUND: Hyaluronan (HA) is a glycosaminoglycan located in the interstitial space which is essential for both structural and cell regulatory functions in connective tissue. We have previously shown that HA synthesis is up-regulated in a rat model of experimental cardiac hypertrophy and that cardiac tissue utilizes two different HA synthases in the hypertrophic process. Cardiomyocytes and fibroblasts are two major cell types in heart tissue. The fibroblasts are known to produce HA, but it has been unclear if cardiomyocytes share the same feature, and whether or not the different HA synthases are activated in the different cell types. METHODOLOGY/PRINCIPAL FINDINGS: This study shows, for the first time that cardiomyocytes can produce HA. Cardiomyocytes (HL-1) and fibroblasts (NIH 3T3) were cultivated in absence or presence of the growth factors FGF2, PDGF-BB and TGFB2. HA concentration was quantified by ELISA, and the size of HA was estimated using dynamic light scattering. Cardiomyocytes synthesized HA but only when stimulated by PDGF-BB, whereas fibroblasts synthesized HA without addition of growth factors as well as when stimulated by any of the three growth factors. When fibroblasts were stimulated by the growth factors, reverse dose dependence was observed, where the highest dose induced the least amount of HA. With the exception of TGFB2, a trend of reverse dose dependence of HA size was also observed. CONCLUSIONS/SIGNIFICANCE: Co-cultivation of cardiomyocytes and fibroblasts (80%/20%) increased HA concentration far more that can be explained by HA synthesis by the two cell types separately, revealing a crosstalk between cardiomyocytes and fibroblasts that induces HA synthesis. We conclude that dynamic changes of the myocardium, such as in cardiac hypertrophy, do not depend on the cardiomyocyte alone, but are achieved when both cardiomyocytes and fibroblasts are present.

Osteoprotegerin promotes fibrous cap formation in atherosclerotic lesions of ApoE-deficient mice--brief report.

OBJECTIVE: Osteoprotegerin (OPG) is a tumor necrosis factor receptor-related cytokine, initially found to inhibit osteoclastogenesis. In the present study we investigated the effect of OPG treatment on atherosclerosis. METHODS AND RESULTS: Hypercholesterolemic apoe(-/-) mice were treated with recombinant 15 mg/kg OPG or vehicle injections twice a week for 10 consecutive weeks. Mice treated with OPG showed increased amounts of smooth muscle cells and collagen within the atherosclerotic lesions. OPG treatment did not affect atherosclerotic lesion size (8.2% versus 7.6%) or total vessel area but led to a 250% increase in lesion collagen, formation of mature collagen fibers in subendothelial fibrous caps, and upregulated mRNA for lysyl oxidase that promotes collagen crosslinking. In cell culture studies, OPG promoted cell proliferation in rat aortic smooth muscle cells. In contrast, OPG treatment did not affect markers of vascular or systemic inflammation. CONCLUSIONS: OPG treatment promotes smooth muscle accumulation, collagen fiber formation, and development of fibrous caps but does not affect inflammatory properties of atherosclerotic lesions. Its effects may contribute to plaque stabilization.

Suppressed signal transduction in the bronchial epithelium of patients with systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune disorder, which frequently affects the lungs, with manifestations of interstitial lung disease (ILD) with lung fibrosis and of pulmonary hypertension. The pathogenesis remains largely unrecognised. OBJECTIVE: The aim of this study was to elucidate the inflammation in the bronchial mucosa in patients with SSc. SUBJECTS AND METHODS: Twenty-three subjects diagnosed with SSc participated. Twelve of the SSc patients showed signs of ILD, four were smokers and seven were treated with oral corticosteroids. Seventeen non-smoking, age- and sex-matched healthy subjects served as controls. Bronchoscopy was performed to sample endobronchial mucosal biopsies, which were immunohistochemically stained using a panel of antibodies against inflammatory markers. RESULTS: The number of neutrophils was significantly elevated in the submucosa of SSc patients, regardless of ILD, or whether the subject was smoking or using oral corticosteroids. No up-regulation of neutrophil chemoattractants or cytokines was seen in the bronchial epithelium. The signal transduction pathways and adhesion molecule expression tended to be suppressed or unchanged in SSc patients compared with controls. CONCLUSION: It is concluded that SSc is associated with a chronic neutrophilic inflammation in the bronchial mucosal, with signs of suppressed signal transduction, regardless of the presence of interstitial lung disease.

Chlamydia pneumoniae infection results in generalized bone loss in mice.

Osteoporosis is associated with a general bone loss. Whether infections could contribute to osteoporosis is not known. Chlamydia pneumoniae causes chronic infections and produces potentially bone resorptive cytokines. The effect of C. pneumoniae infection was investigated in vivo in 10-week old mice (c57BL/6) and in vitro in the human osteoblast-like cell line hFOB 1.19 (hFOB). Bone mineral density (BMD) was measured before and 16 days after infection. C. pneumoniae-infected mice had decreased (p<0.05) total and subcortical BMD at the distal femur and proximal tibia compared with controls, but no body-weight gain differences. IL-6 (56 vs. 39pg/mL, p=0.02) and IL-1beta (11 vs. 0pg/mL, p=0.003) levels in sera, and CD3(+) T-cells (p=0.04) were higher in infected mice compared with controls. In vitro, hFOB infected with C. pneumoniae was associated with increased IL-6 (p=0.01) and RANKL (p<0.05) mRNA expression; additionally, IL-6 secretion increased in a dose-dependent manner (p<0.05). In summary, mice infected with C. pneumoniae had generalized bone loss associated with increased IL-6 and IL-1. In addition, C. pneumoniae established an infection in an osteoblast cell line in vitro with similar cytokine profiles as those in vivo, supporting a causal linkage.

Parallel up-regulation of FGF-2 and hyaluronan during development of cardiac hypertrophy in rat.

The importance of glycosaminoglycan hyaluronan (HA) and its receptor CD44 in cell proliferation is becoming increasingly evident. Expression of the genes coding for hyaluronan synthase 1 (HAS1), HAS2, HAS3, CD44, fibroblast growth factor-2 (FGF-2), and FGF receptor-1 (FGFR-1) and the histological evidence for increases of HA and CD44 were investigated in an experimental rat model of cardiac hypertrophy. The abdominal aorta was ligated to induce cardiac hypertrophy, and mRNAs prepared from heart tissue were analyzed after 1, 6, and 42 days. The total concentration of HA was quantified, and HA and CD44 were studied histochemically. The expression of HAS1, HAS2, CD44, and FGF-2 was considerably up-regulated at days 1 and 6 and returned to basal levels after 42 days. FGFR-1 was up-regulated at day 1 but at basal levels once more at days 6 and 42. The concentration of HA significantly increased in aorta-ligated rats. Histochemical analysis showed increased expression of CD44 in hypertrophied myocardium mainly in and around the coronary arteries. These results agree well with other studies of tissue growth (malignancies and wound healing). The increase of HA, its synthases, and receptor in parallel with FGF-2 and its receptor illustrates their complicated interplay in the development of cardiac hypertrophy. The up-regulation of both HAS1 and HAS2 indicates the importance of HA production in the hypertrophic process and the possibility that HA is needed for two different purposes for the heart to be able to adapt to the increased afterload caused by aortic ligature.

Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle.

Intracellular parasitism by Chlamydiales is a complex process involving transmission of metabolically inactive particles that differentiate, replicate, and re-differentiate within the host cell. A type three secretion system (T3SS) has been implicated in this process. We have here identified small molecules of a chemical class of acylated hydrazones of salicylaldehydes that specifically blocks the T3SS of Chlamydia. These compounds also affect the developmental cycle showing that the T3SS has a pivotal role in the pathogenesis of Chlamydia. Our results suggest a previously unexplored avenue for development of novel anti-chlamydial drugs.

Myocardial hypertrophy and function are related to age at onset in familial amyloidotic polyneuropathy.

Heart complications are frequently encountered in hereditary transthyretin amyloidosis. Lately, reports of late onset familial amyloid polyneuropathy (FAP) cases presenting with a phenotype similar to that observed in senile systemic amyloidosis have emerged. The aim of the present study was to evaluate morphological and functional features of the heart by echocardiography including myocardial strain measurements, and to compare the outcome for early with those of late onset FAP cases. Eighty-one biopsy and genetically proven FAP, ATTR Val30Met patients were investigated with two-dimensional, M-mode echocardiography and myocardial strain with special attention to inter-ventricular septum (IVS) thickness. IVS thickness was closely related to the age at onset (P < 0.0001), but not to duration of disease. Seventeen percent of the patients had severe left ventricular hypertrophy (IVS > 15 mm). These patients were all late onset cases and represented 39% of all of the late onset cases. Strain measurements were also closely related to IVS thickness and age at onset thereby signifying a decreased function of the heart muscle in late onset cases. From the present investigation it appears that late onset Swedish FAP-cases more readily develop cardiomyopathy with an increased IVS thickness. Different pathways for amyloid formation in the heart may operate in early and late onset cases.

Metabolic manipulation of glioblastoma in vivo by retrograde microdialysis of L-2, 4 diaminobutyric acid (DAB).

OBJECTIVES: To study the metabolic effects in vivo of L-2, 4 diaminobutyric acid (DAB) administered by retrograde microdialysis in glioblastoma and to evaluate the feasibility of the technique. METHODS: In 10 patients with glioblastoma, a stereotactic biopsy was performed followed by implantation of microdialysis catheters. One or two catheters were implanted in tumor tissue and two reference catheters were implanted in normal brain tissue and subcutaneous abdominal tissue, respectively. Tumor catheters were perfused with 80 or 120 mmol/l DAB and reference catheters were perfused with a Ringer solution, all with a flow rate of 2.0 microl/min. Treatment was given for at mean 9.1 (5-19) days. RESULTS: The treatment was well tolerated by the patients with the exception of two patients in whom a transient brain edema appeared. No complications related to the technique were encountered. During treatment, an increase in the extracellular amino acids alanine, glycine, glutamate, aspartate, serine, threonine, and taurine was found demonstrating a significant influence on the intracellular pool of free amino acids induced by DAB. No change in glucose metabolism or glycerol was evident. The metabolism in normal brain was unaffected during treatment. CONCLUSIONS: Retrograde microdialysis is a feasible method for intracerebral administration of drugs to tumor tissue in patients with glioblastoma. We found it possible to deliver DAB to glioblastoma tumors in fully mobilized patients and to assess the metabolic effects induced by the treatment. The changes in extracellular amino acids were in concordance to what was expected from in vitro studies. Elevation of glutamate and taurine may be regarded as markers for an induced cellular toxicity while the unchanged level of glycerol may indicate no direct effects on phospholipase activity and membrane phospholipid composition. The effects were restricted to the tumor compartment. Although an improved survival could possibly be suspected no dramatic effect on outcome could be detected. However, the series was small and, most probably, the time for treatment was too short.

The contribution of Ca+ calmodulin activation of human erythrocyte AMP deaminase (isoform E) to the erythrocyte metabolic dysregulation of familial phosphofructokinase deficiency.

Erythrocyte membrane leakage of Ca2+ in familial phosphofructokinase deficiency results in a compensatory increase of Ca2+-ATPase activity that depletes ATP and leads to diminished erythrocyte deformability and a higher rate of hemolysis. Lowered ATP levels in circulating erythrocytes are accompanied by increased IMP, indicating that activated AMP deaminase plays a role in this metabolic dysregulation. Exposure to a calmodulin antagonist significantly slows IMP accumulation during experimental energy imbalance in patients' cells to levels that are similar to those in untreated controls, implying that Ca2+-calmodulin is involved in erythrocyte AMP deaminase activation in familial phosphofructokinase deficiency. Therapies directed against activated isoform E may be beneficial in this compensated anemia.

Parasympathetic dysfunction in hypertrophic cardiomyopathy assessed by heart rate variability: comparison between short-term and 24-h measurements.

In this study, we evaluate cardiac autonomic function in hypertrophic cardiomyopathy (HCM) by assessing heart rate variability (HRV), comparing a short-term laboratory method with an ambulatory (24-h) method, in patients with and without beta-blockade. Reduced HRV is a risk factor for adverse events in some cardiac diseases, but is not a proven risk indicator in HCM. Analysis of HRV has been based on either short- or long-term electrocardiographic recordings and previous studies in HCM have shown conflicting results. There is no consensus on which method to prefer, and we evaluate, for the first time, both short- and long-term analyses in patients with HCM. Long- and short-term HRV analyses were performed in 43 patients with HCM. They were divided in two groups, 22 patients on beta-blockade and 21 non-treated patients. As controls, 121 healthy subjects were used. Young patients without beta-blockade showed a reduction in HRV parameters reflecting parasympathetic function, both in the short- and long-term registrations, which was attenuated by beta-blockade. Parasympathetic autonomic regulation was found to be impaired in young patients with HCM. This may be of clinical relevance as abnormal autonomic function might be a substrate for malignant dysrhythmias. The impairment was attenuated by beta-blockade, which might indicate a clinically useful effect. We also show that short- and long-term methods yield similar results, suggesting that a short-term registration might be sufficient to assess HRV in patients with HCM.

Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL).

BACKGROUND: Studies in experimental models and preliminary clinical experience suggested a possible therapeutic role for the soluble tumor necrosis factor antagonist etanercept in heart failure. METHODS AND RESULTS: Patients with New York Heart Association class II to IV chronic heart failure and a left ventricular ejection fraction < or =0.30 were enrolled in 2 clinical trials that differed only in the doses of etanercept used. In RECOVER, patients received placebo (n=373) or subcutaneous etanercept in doses of 25 mg every week (n=375) or 25 mg twice per week (n=375). In RENAISSANCE, patients received placebo (n=309), etanercept 25 mg twice per week (n=308), or etanercept 25 mg 3 times per week (n=308). The primary end point of each individual trial was clinical status at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the combined outcome of death or hospitalization due to chronic heart failure from the 2 studies was also planned (RENEWAL). On the basis of prespecified stopping rules, both trials were terminated prematurely owing to lack of benefit. Etanercept had no effect on clinical status in RENAISSANCE (P=0.17) or RECOVER (P=0.34) and had no effect on the death or chronic heart failure hospitalization end point in RENEWAL (etanercept to placebo relative risk=1.1, 95% CI 0.91 to 1.33, P=0.33). CONCLUSIONS: The results of RENEWAL rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.

Unique antitumour effects of L-2,4 diaminobutyric acid on cultured hepatoma cells.

A single hepatoma cell line was grown in vitro and incubated with L-2,4 diaminobutyric acid (DAB), a non-metabolizable amino acid, under various conditions. The tumour cells were irreversibly damaged by incubation for 8 hours with 8 mmol/L of DAB. The tumour cell-destroying effect of DAB was dose- and time-dependent with no effect at a DAB concentration of 1.6 mmol/L. The presence of N-methyl alpha-aminoisobutyric acid (a specific substrate of amino acid transport system A) in the incubation medium abrogated the tumour cell destructive effect of DAB in a dose-dependent fashion. The presence of non-physiological amino acids in the incubation medium per se was not the cause of tumour cell destruction, since inclusion of alpha-amino-isobutyric acid and N-methyl alpha-aminoisobutyric acid in the incubation medium did not influence the viability of hepatoma cells. We conclude that the tumour cell destructive effect of DAB was the result of a huge and unlimited uptake of DAB energized by the Na(+)-gradient and that this uptake was not subjected to the law of saturation kinetics. This was combined with a tumour cell energy crisis in attempts to restore the Na(+)-gradient.

8'-aminoguanosine inclusion results in enhanced efflux of taurine in preconditioned ischemic myocardium.

Attenuated purine levels are characteristic findings of ischemic preconditioning (PC). Lower energy demand in PC myocardium leading to less nucleotide decay is a reasonable explanation. However, experimental data suggest that the activities of the enzymes involved in purine metabolism are increased in PC myocardium. Recently it was suggested that PC favored degradation of exogenous adenosine to inosine successively ending up in enhanced lactate production. This was probably because of the involvement of the hexose monophosphate pathway in the PC ischemic myocardium. This route may therefore be supplementary in energy metabolism as a metabolic flow can be started by adenosine ending up in lactate without initial adenosine 5'-triphosphate (ATP) investment. Purine nucleoside phosphorylase (PNP) is a key enzyme in the proposed metabolic route. In the current study the effect of PNP inhibition (with 8'-aminoguanosine) on myocardial energy metabolism during PC was studied in an open chest porcine heart model using the microdialysis technique. A dose-dependent inhibition of PNP by 8'-aminoguanosine was observed in PC myocardium. This inhibition resulted in an enhanced exodus of taurine reflecting a disturbed energy economy of the cardiomyocytes. Addition of inosine being a true substrate of PNP reversed these changes, which indicated that 8'-aminoguanosine was a competitive inhibitor of PNP. It is concluded that the ischemic PC phenomenon at least partly involves the activated enzyme PNP.