Dual-energy X-ray absorptiometry registers bone mineral in the liver.

OBJECTIVE: To analyse the difference in bone mineral content (BMC) between the left and right trunk generally obtained by dual-energy X-ray absorptiometry (DXA) by creating identical images over the liver region and the contralateral side. PATIENTS AND DESIGN: Fifty-four patients were selected at random from 1,722 subjects examined by DXA because of osteoporosis. Another five patients were selected who had been followed for osteoporosis by repeated DXA two to five times at intervals from 2 to 36 months. One healthy volunteer was followed for one day by means of DXA total body measurements. All protocols were analysed with respect to BMC, fat mass (FM) and lean tissue mass (LTM) of the imaged trunk and liver. RESULTS: BMC of the right trunk exceeded that of the left trunk in 78% of the investigated subjects. The right (liver) image dominated in all 81 investigations calculated from 60 subjects. There were intraindividual short- and longterm variations between repeated DXA examinations. The amounts of FM and LTM were distributed symmetrically between the right and left trunk. CONCLUSIONS: DXA registers BMC in the liver, which explains the general dominance of the right trunk. The absorption over the liver region varies in the same individual in repeated measurements at intervals of hours to months.

Transaortic approach for the Alfieri stitch.

The management of associated mitral regurgitation in patients undergoing cardiac surgery is controversial. A simple, reliable, and fast repair is advantageous, especially in critically ill patients. We describe a simple method of transaortic edge-to-edge repair in patients with associated mitral regurgitation undergoing aortic valve surgery.

Effects of intramyocardial injection of phVEGF-A165 as sole therapy in patients with refractory coronary artery disease--12-month follow-up: angiogenic gene therapy.

OBJECTIVE: To test the safety and bioactivity of phVEGF-A165 after intramyocardial injection during 12-month follow-up. DESIGN: Open-labelled study. SUBJECTS: Inclusion criteria were angina pectoris, Canadian Cardiovascular Society (CCS) class III-IV, unamenable to further revascularization, ejection fraction (EF) >30%, perfusion defects extending over >10% of the anterolateral left ventricle wall detectable with adenosine single photon emission computerized tomography (SPECT) and at least one patent vessel visible by coronary angiography. Seven of 39 patients referred for gene therapy were included. INTERVENTION: Via a mini-thoracotomy under general anaesthesia. phVEGF-A165 was injected directly into the myocardium at four sites in the anterolateral region of the left ventricle. RESULTS: Operative procedures were uneventful. Perioperative release of myocardial markers and electrocardiogram (ECG) changes were detected in two patients. There were no perioperative deaths but one patient died 7 months postoperatively because of myocardial infarction. Plasma vascular endothelial growth factor (VEGF)-A levels increased two to threefold peaking 6 days postoperatively (P < 0.004) and returning to baseline by day 30. A significant reduction in angina pectoris was reported. The CCS class improved from 3.3+/-0.2 to 1.9+/-0.3 (P < 0.01) and nitroglycerine intake decreased from 39+/-15 to 12+/-5 tablets week(-1) (P < 0.001) 2 months after gene transfer. Improvements remained after 12 months when nitroglycerine consumption approached zero. Improved myocardial function in the phVEGF-A165 injection region was documented in all patients (P < 0.016) by tissue velocity imaging (TVI). Reduced reversible ischaemia was detected by adenosine SPECT in four patients. Improved collateralization was detected in four patients with coronary angiography. CONCLUSION: Intramyocardial injection of phVEGF-A165 is safe and may lead to improved myocardial perfusion and function with longstanding symptomatic relief in end-stage angina pectoris. Based on these results this therapeutic potential is being tested in a double-blind placebo controlled multicentre trial.

Simple method for direct cannulation of ascending aortic aneurysms.

A simple method for direct cannulation of aneurysms of the ascending aorta is described. It avoids the need for femoral artery cannulation and offers an easy route for retrograde cerebral perfusion during deep hypothermic circulatory arrest.

Mortality in 497 patients with affective disorders attending a lithium clinic or after having left it.

The impact of lithium prophylaxis on mortality has been studied in 497 patients, 405 bipolars and 92 unipolars, who attended the same out-patient lithium clinic for up to 30 years. In order to avoid preselection, no minimum period of lithium treatment was required in our study. Of a total of 6014 patient-years, 4330 were spent in regular contact with the study clinic. General mortality due to natural causes was not significantly increased; among cardiovascular diseases, only pulmonary embolism showed an excess mortality. No patients died of lithium intoxication or chronic renal insufficiency. Patients were divided into three groups: Group A, 277 patients, attended the study clinic until death or the end of the study, Group B, 86 patients, left the clinic but continued to take lithium, and Group C, 134 patients, both left the clinic and stopped taking lithium. Among bipolars, the suicide rate compared to the general population was in excess in all three groups. Among unipolars, suicides occurred only after the patients had left the study clinic and stopped taking lithium. A special analytical method was used for intergroup comparisons of suicide rates. Bipolars in Group A attending the study clinic regularly had a suicide rate of 3.5 per 1000 patient-years. The rate increased to 6.3 or by 80 % if patients had left the clinic and did not take lithium any longer as in Group C. The suicide rate in Group C increased by 45% compared to Group B, patients who left the clinic but continued to take lithium. Our results support the hypothesis that lithium has a significant antisuicidal effect in bipolars as well as in unipolars. The suicide mortality can be further reduced by regular attendance in a specialised mood disorder clinic.

Myocardial outflow of calcitonin gene-related peptide in relation to metabolic stress during coronary artery bypass grafting without cardiopulmonary bypass.

OBJECTIVE: Because of adverse effects of cardiopulmonary bypass and the prospect of shortening intensive care and hospital stay, coronary artery bypass grafting without cardiopulmonary bypass is gaining increased attention. The impact of the localized myocardial ischemia that is inherent in these procedures has not been thoroughly investigated in human beings. We have investigated metabolic changes, possible myocardial damage, and myocardial outflow of the vasodilator calcitonin gene-related peptide during coronary artery bypass grafting without cardiopulmonary bypass. METHODS: Coronary sinus and arterial blood was sampled before coronary arterial occlusion, after 10 minutes of ischemia, and after 1 and 10 minutes of reperfusion in 9 consecutive patients (mean age 70 +/- 5 years) who had an anastomosis performed to the left anterior descending artery without cardiopulmonary bypass. RESULTS: No perioperative myocardial infarctions occurred. The arteriovenous difference in lactate decreased during ischemia, to reach a minimum after 1 minute of reperfusion (-0.17 +/- 0.25 vs 0.15 +/- 0.25 mmol/L before ischemia; P =.008). Myocardial lactate extraction decreased (from 11.2 +/- 13.6 micromol/min before ischemia to -3.0 +/- 7.0 micromol/min after 1 minute of reperfusion; P =.012), that is, a net production of lactate. The arteriovenous difference in calcitonin gene-related peptide decreased from -0.1 +/- 2.6 pmol/L before ischemia to -30.5 +/- 26.5 pmol/L (P =.008) after 1 minute of reperfusion. CONCLUSIONS: The localized myocardial ischemia associated with these procedures causes metabolic changes in the myocardium, but no myocardial damage. The ischemia-related outflow of calcitonin gene-related peptide indicates that the vasodilating and cardioprotective properties of this peptide that are known from animal studies may be of importance in myocardial ischemia in human beings.

Release and effects of calcitonin gene-related peptide in myocardial ischaemia.

1. Low pH and lactic acid perfusion evoke a reproducible, and concentration-dependent outflow of CGRP from the isolated heart. 2. PGI2 causes outflow of CGRP from the isolated heart. Furthermore, low pH perfusion causes release of PGI2, and cyclo-oxygenase inhibition attenuates not only this release of PGI2, but also the outflow of CGRP that is evoked by low pH perfusion, indicating that a portion of the C-fibre activation exerted by low pH is mediated by PGI2. 3. The outflow of CGRP that is caused by low pH but not that evoked by capsaicin or PGI2 is dependent on the endothelium, whereas the vasodilating effect of CGRP is preserved after removal of the endothelium. 4. TTX attenuates release of CGRP caused by low concentrations of capsaicin, indicating that an axon reflex mechanism in the peripheral endings of C-fibre afferents can augment local outflow of CGRP. 5. Outflow of CGRP evoked by low pH and capsaicin have common features, such as sensitivity to RR and CPZ. N-type calcium channels are involved in release of CGRP by both stimuli. 6. In the coronary vasculature, exogenous CGRP augmented post-occlusive hyperaemia. 7. In the pig in vivo, CGRP causes marked dose-dependent reduction of systemic vascular resistance. This effect of CGRP was partly reduced by CGRP(8-37). 8. Capsaicin pretreatment resulted in lower myocardial levels of CGRP, and ischaemic myocardium had lower content of CGRP than non-ischaemic areas. Capsaicin-treated animals had larger myocardial infarctions, possibly due to depletion of CGRP. When endogenous stores of CGRP were intact, administration of additional CGRP to the ischaemic myocardium had no cardioprotective effect. 9. In patients undergoing CABG without CPB, 10-20 minutes of local ischaemia (as evidenced by a net production of lactate) was associated with increased levels of CGRP in coronary sinus blood. 10. Based on the present findings it may therefore be suggested that local cardiac CGRP-release from capsaicin-sensitive C-fibre afferents during myocardial ischaemia functions as an endogenous physiological protective response. The possibility thus exists that effects of CGRP observed in animal studies may play a role in human myocardial ischaemia.

Hemodynamic performance of cryopreserved aortic homograft valves during midterm follow-up.

OBJECTIVES: The aim of this prospective study of adult patients operated with a cryopreserved aortic homograft was to use serial echocardiographic data to evaluate the postoperative hemodynamic performance of these valves. BACKGROUND: Only limited data on hemodynamic performance of aortic homografts at rest and during exercise are available. Controversy also exists regarding incidence and progression of aortic regurgitation (AR). METHODS: Fifty-nine patients aged 39-86 years who received an aortic homograft (median size 21 mm) implanted with subcoronary technique were studied with serial Doppler-echocardiography (D-E). In 31 of these patients, D-E also was performed during supine exercise. RESULTS: Overall survival was 100% during a median follow-up of 28 months (range 4-54). During follow-up AR grade II or more was detected in 25% of the patients with an increasing time-related risk of developing AR. Maximum and mean pressure differences at 7 months follow-up calculated with the short form of the Bernoulli equation were 11.4 (4.6) and 5.5 (2.1) mm Hg, respectively. During supine exercise that increased cardiac output 72%, maximum pressure difference increased from 11.9 (5.2) to 18.5 (9.5) mm Hg. CONCLUSIONS: The aortic homograft valve shows low pressure differences at rest and during exercise, but AR grade I or II is often seen during follow-up. As AR progresses with time we stress the importance of echocardiographic follow-up of patients with aortic homografts.

Aggravation of myocardial infarction in the porcine heart by capsaicin-induced depletion of calcitonin gene-related peptide (CGRP).

The potent vasodilator calcitonin gene-related peptide (CGRP) is stored in a population of C-fiber afferents that are sensitive to capsaicin. CGRP has been suggested to have a beneficial effect in myocardial ischemia. In this study we used capsaicin pretreatment to deplete cardiac C-fiber peptide stores and tried to evaluate the role of endogenous CGRP in myocardial ischemia. Six pigs were pretreated with capsaicin (50 mg/kg). Forty-eight hours later, they were subjected to 40min occlusion of the left anterior descending coronary artery. After 4 h of reperfusion, the heart was excised, and the extent of myocardial infarction was measured by using triphenyl tetrazolium chloride. Content of CGRP in the ischemic and the nonischemic myocardium was measured by radioimmunoassay. Capsaicin-treated pigs had more extensive myocardial infarction (56+/-6% vs. 26+/-8% of the area at risk; p=0.013) and a lower myocardial content of CGRP (14+/-6 vs. 32+/-5 pmol/g; p=0.039) compared with six untreated control pigs. Furthermore, capsaicin-treated pigs had significantly increased mean arterial blood pressure compared with controls. This study indicates that peptides released from cardiac C fibers have a beneficial effect in myocardial ischemia and reperfusion. In view of its potent effects in cardiovascular regulation, CGRP is a possible candidate for the mediation of the observed cardioprotective effect.

Calcitonin gene-related peptide in myocardial ischaemia and reperfusion in the pig.

OBJECTIVE: In myocardial ischaemia, slow conducting capsaicin-sensitive C-fibres are activated. Apart from the mediation of pain, activation of these fibres causes release of various peptides, such as calcitonin gene-related peptide (CGRP), which is a potent vasodilator. The aim of this study was to investigate the role of CGRP in the context of myocardial ischaemia in vivo. METHODS: The left anterior descending coronary artery (LAD) was occluded during 45 min in 27 anaesthetised open-chest pigs. LAD flow, mean arterial pressure (MAP), heart rate, peak dP/dt, arterial and coronary venous concentration of CGRP was measured prior to ischaemia, and during 4 h of reperfusion. The extent of myocardial infarction was measured using staining with triphenyl tetrazolium chloride. RESULTS: Retroinfusion of CGRP (100 micrograms) into the ischaemic myocardium was associated with a more pronounced hyperaemia, and systemic hypotension, during early reperfusion. The infarct size in relation to the area at risk was not affected by CGRP or the CGRP antagonist CGRP(8-37), and averaged 67 +/- 3%. There were no changes in plasma CGRP levels during ischaemia or reperfusion. CONCLUSION: Exogenously administered CGRP can cause systemic hypotension and augments postischaemic coronary flow. In this model, no cardioprotective effect of CGRP could be proven.

Ion channels involved in the release of calcitonin gene-related peptide by low pH, prostacyclin and capsaicin in the isolated guinea-pig heart.

The aim of this study was to characterise the release of calcitonin gene-related peptide (CGRP) by capsaicin, low pH and prostacyclin in terms of Ca2+ channel dependence, interactions with K(ATP) channels and the role of action potential propagation, in the isolated, perfused guinea-pig heart. The Ca2+ channel blocker omega-conotoxin reduced CGRP release evoked by 10(-7) M capsaicin, as well as CGRP release evoked by pH 7. CGRP release caused by capsaicin at low (10(-7) M) but not high (10(-6) M) concentrations was also attenuated by tetrodotoxin, indicating partial dependence on action potential propagation. CGRP release caused by prostacyclin was not altered by any of the tested drugs. The K(ATP) channel activator cromakalim and the K(ATP) channel blocker glibenclamide had no effect on CGRP release. Previous findings that low pH and capsaicin stimulate capsaicin-sensitive afferents in the isolated heart at least partly through common mechanisms are thus supported. Attenuation of capsaicin-evoked release of CGRP by tetrodotoxin suggests recruitment of additional nerve terminals by a local axon reflex.

Myocardial injury after electrical therapy for cardiac arrhythmias assessed by troponin-T release.

Episodes of ventricular fibrillation with subsequent intracardiac, and to a lesser extent, external defibrillation give rise to a statistically significant increase in S-troponin T, S-CK-MB(mass) and S-myoglobin indicative of a minor myocardial injury or dysfunction. In contrast, no such signs were observed after external direct-current conversion of atrial fibrillation using high energies, or after pace-terminated ventricular tachycardia.

Comparison of standardized initial doses of two antithyroid drugs in the treatment of Graves' disease.

OBJECTIVES: To obtain a simple standard regimen, suitable for general practice, and based upon the addition of antithyroid drug plus thyroxine for attaining euthyroidism in patients with Graves' disease. DESIGN: Prospective, randomized trial of patients with Graves' disease followed for 3 months after the initiation of therapy with an antithyroid drug and combined with the later addition of triiodothyronine to keep the patient euthyroid. The patients were randomized, according to birth date, between methimazole and propylthiouracil. Three dose schemes were tested for each antithyroid drug. SETTING: The study was performed at the thyroid outpatient units of two general hospitals, with the patients having been referred from primary care. SUBJECTS: Ninety-four patients with Graves' disease who were suitable for treatment with antithyroid drugs. INTERVENTIONS: The patients were allocated into six groups. Three groups received methimazole (10 mg every 6th, 8th or 12th h) and three received propylthiouracil (100 mg every 6th, 8th or 12th h). Twenty micrograms of triiodothyronine was added when the patients were euthyroid to avoid hypothyroidism. MAIN OUTCOME MEASURES: The lowest serum free thyroxine level within 3 months of the initiation of the antithyroid treatment. RESULTS: Fourteen per cent of the patients on methimazole 10 mg every 12th h and 29% on propylthiouracil 100 mg every 12th h did not achieve euthyroidism within the 3-month observation period. All but one patient on methimazole 10 mg every 8th h or propylthiouracil 100 mg every 8th h reduced the free serum thyroxine levels to the normal or hypothyroid range within the observation period. All of the patients on methimazole 10 mg every 6th h and 56% on propylthiouracil 100 mg every 6th h reduced the serum T4 values into the hypothyroid range within the period. CONCLUSION: A standard regimen, based upon the addition of methimazole 10 mg every 8th or 6th h or propylthiouracil 100 mg every 8th or 6th h and followed by the addition of thyroxine or triiodothyronine when euthyroid to avoid hypothyroidism, seems to be suitable for attaining euthyroidism within 3 months in patients with Graves' disease. A dose scheme based on methimazole 10 mg every 12th h or propylthiouracil 100 mg every 12th h were found to be unsuitable due to an unacceptably high incidence of failure to attain euthyroidism or hypothyroidism within 3 months.

Attenuation of low pH-, but not capsaicin- or PGI2-evoked CGRP-release by endothelium removal using saponin.

The aim of the present study was to evaluate the role of the endothelium in low pH-, capsaicin-, and prostacyclin (PGI2)-evoked release of calcitonin gene-related peptide (CGRP)-like immunoreactivity (-LI) from C-fibre afferents in the isolated, perfused guinea-pig heart. CGRP-LI release, and formation of the stable PGI2-metabolite 6-keto-PGF1 alpha, in response to moderate acidosis (pH 7, 6, but not 5) were significantly reduced after removal of endothelium using saponin (50 micrograms mL-1) perfusion. In contrast, the release of CGRP-LI evoked by capsaicin (10(-7) M) or PGI2 (10(-5) M) remained unchanged after removal of the endothelium. Saponin treatment did not influence the vasodilator action of CGRP, whereas the vasodilation evoked by substance P (SP) was abolished. It is concluded that CGRP release evoked by low pH, but not that evoked by capsaicin or exogenous PGI2, is partly endothelium dependent. Our data suggest that endothelially produced PGI2 is involved in low pH-evoked release of CGRP from capsaicin sensitive nerves in the heart.

Renal, thyroid and parathyroid function during lithium treatment: laboratory tests in 207 people treated for 1-30 years.

A total of 207 patients (diagnoses revised according to DSM-III-R) attended our outpatient clinic and were treated with lithium for 1-30 years. They were subjected to conventional renal, thyroid and parathyroid function tests. With increasing treatment duration, the renal tests showed only moderate deviations from expected reference values. No patient developed renal insufficiency. Oversubstitution (thyrotropin < or = 0.1 mU/l) was suspected in 25% of the patients on thyroxine. Cross-sectionally unrecognized hypothyroidism was found in 6% of the patients. Elevated ionized serum calcium was found in 25% and elevated serum intact parathyroid hormone in 23% of the patients.

Cyclo-oxygenase products released by low pH have capsaicin-like actions on sensory nerves in the isolated guinea pig heart.

OBJECTIVE: Previous work has shown that ischaemia releases calcitonin gene related peptide (CGRP) from capsaicin sensitive nerve terminals in the perfused heart. Prostacyclin (PGI2) is also released during ischaemia. The aim of this study was to investigate whether the release of CGRP by low pH and lactic acid was associated with PGI2 formation and if PGI2 mediated its effect through capsaicin receptors which could be inhibited by capsazepine. METHODS: The isolated Langendorff perfused guinea pig heart was used with a constant perfusion pressure of 70 cm H2O. Low pH was accomplished by changing the Tyrode solution to buffers with pH 7, 6, and 5, or lactic acid (5 mM with pH 6.9). The outflow of CGRP and the stable PGI2 metabolite 6-keto-PGF1 alpha was measured by radioimmunoassay. RESULTS: Low pH (pH 7, 6, 5) and lactic acid evoked release of CGRP. At moderate acidosis (pH 7 and 6) the CGRP release was dependent on extracellular Ca2+, while at pH 5 approximately half of the peptide release persisted in the absence of extracellular Ca2+. This release was attenuated by diclofenac or indomethacin, two inhibitors of prostaglandin formation, as well as by the capsaicin receptor antagonist capsazepine. Both arachidonic acid and PGI2, the predominant cyclo-oxygenase product formed during myocardial ischaemia, evoked a capsazepine sensitive release of CGRP, while capsazepine did not influence the formation of PGI2 evoked by low pH or arachidonic acid. CONCLUSIONS: In the isolated guinea pig heart, moderate acidosis is associated with CGRP release dependent on influx of extracellular Ca2+ and formation of PGI2, with subsequent stimulation of capsazepine sensitive receptors. With more severe acidosis there is an additional non-PGI2-linked CGRP release. Capsazepine represents a novel pharmacological principle for inhibiting the effects of prostanoids on sensory nerves without influencing their formation.

Myocardial release of troponin T after coronary bypass surgery.

The temporal changes in cardiac S-troponin T, S-creatine kinase-MB(S-CK-MB)mass and S-myoglobin were studied for 5 days after coronary bypass grafting in 70 patients. Perioperative infarction occurred in ten patients (2 Q wave, 8 non-Q wave). All three markers showed significant increase even in patients without signs of perioperative infarction. Within 8-12 hours their levels rose significantly (p < 0.001) more in the infarction than in the non-infarction cases. Troponin T and CK-MBmass both showed early (< 8-12 h) peaks in patients with perioperative infarction. CK-MBmass returned to near normal levels within 48-72 hours, whereas troponin T remained markedly increased throughout the observation. Myoglobin concentrations varied widely among the infarction cases. In the non-infarction group, troponin T and CK-MBmass (but not myoglobin) were related to the aortic cross-clamp time. Troponin T (but not CK-MBmass) remained elevated throughout the study period in patients with longer cross-clamp times. These findings may indicate continuous release from damaged myocardium in cases of perioperative infarction. Troponin T and CK-MBmass can serve as markers of perioperative infarction and troponin T may also be useful as a marker in studies on myocardial protection.

Capsazepine-sensitive release of calcitonin gene-related peptide from C-fibre afferents in the guinea-pig heart by low pH and lactic acid.

The present study aimed to evaluate the possible influence of the selective capsaicin antagonist, capsazepine, on the release of calcitonin gene-related peptide (CGRP)-like immunoreactivity from sensory nerves in the isolated perfused guinea-pig heart. Low-pH buffer (pH 7, 6, 5), capsaicin (10(-7) M), lactic acid (5, 20, 50 mM) and nicotine (10(-4) M) all evoked a clear-cut release of CGRP-like immunoreactivity. Incubation with capsazepine (10(-6) to 10(-5) M) significantly reduced the CGRP-like immunoreactivity release evoked by low pH, capsaicin and lactic acid (5 mM) but not that evoked by nicotine. Furthermore, the capsaicin-evoked stimulation of heart rate was inhibited by incubation with capsazepine. The inorganic dye, ruthenium red, which has previously been shown to attenuate capsaicin-, but not nicotine-induced CGRP release from the heart, also reduced the release of CGRP caused by low pH and lactic acid (5 mM). It is concluded that the CGRP-like immunoreactivity release evoked from the heart by low pH and lactic acid shares several characteristic features with the release evoked by capsaicin. Since tissue pH is low in myocardial ischaemia and this is well known to cause pain, the use of capsazepine to inhibit the function of C-fibre afferents may represent a novel principle to influence autonomic reflex reactions associated with cardiac pathological conditions.