Growth Hormone, Atherosclerosis and Peripheral Arterial Disease: Exploring the Spectrum from Acromegaly to Growth Hormone Deficiency.

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are increasingly recognised for their role in cardiovascular (CV) physiology. The GH-IGF-1 axis plays an essential role in the development of the CV system as well as in the complex molecular network that regulates cardiac and endothelial structure and function. A considerable correlation between GH levels and CV mortality exists even among individuals in the general population without a notable deviation in the GHIGF- 1 axis functioning. In addition, over the last decades, evidence has demonstrated that pathologic conditions involving the GH-IGF-1 axis, as seen in GH excess to GH deficiency, are associated with an increased risk for CV morbidity and mortality. A significant part of that risk can be attributed to several accompanying comorbidities. In both conditions, disease control is associated with a consistent improvement of CV risk factors, reduction of CV mortality, and achievement of standardised mortality ratio similar to that of the general population. Data on the prevalence of peripheral arterial disease in patients with acromegaly or growth hormone deficiency and the effects of GH and IGF-1 levels on the disease progression is limited. In this review, we will consider the pivotal role of the GH-IGF-1 axis on CV system function, as well as the far-reaching consequences that arise when disorders within this axis occur, particularly in relation to the atherosclerosis process.

Endocrine Disorders and Peripheral Arterial Disease - A Series of Reviews Cushing Syndrome-Cortisol Excess.

Cushing syndrome (CS), characterised by endogenous or exogenous glucocorticoid hormone excess, is associated with several systemic complications, including impaired glucose metabolism, which often becomes clinically manifest as diabetes mellitus (DM). In addition, CS can harm the arterial wall because of hyperglycaemia, dyslipidaemia, hepatic steatosis, and central obesity. These metabolic disorders promote atherosclerosis by synthesising adipokines, leptin, and proinflammatory cytokines. Lower limb arterial complications in CS are common and significantly impact morbidity and mortality. Furthermore, CS, in combination with DM, is likely to cause more diffuse vascular disease that predominantly affects distal arterial beds. In conclusion, CS promotes atherosclerosis, including peripheral artery disease, by causing functional and morphological deterioration of the arterial vessel wall and increasing the presence of classical risk factors of atherosclerosis.

Increased fatigability of the gastrocnemius medialis muscle in individuals with intermittent claudication.

BACKGROUND: We attempted to identify possible differences in the contractility of the gastrocnemius medialis (GM) muscle between healthy controls and individuals with peripheral arterial disease (PAD) and intermittent lower-limb claudication. METHODS: The GM muscles of 17 PAD patients and 17 healthy controls were examined with tensiomyography. Single or multiple electrical impulses were used to trigger muscle contractions, and the time and amplitude of contractions were measured. RESULTS: After single-impulse stimulation, the GM muscles of PAD patients showed significantly shorter contraction times (P < 0.001) than the GM muscles of controls. During 1 min of repetitive electrical stimulation, the contraction velocity of the controls' GM muscles typically showed a sustained increase throughout the stimulation period, whereas in PAD patients, a significant decrease in contraction velocity was observed after 30 s. The onset of muscle fatigue was unrelated to the ankle brachial index (ABI) of the examined leg. When the legs of PAD patients with higher and lower ABIs were compared to each other, no significant differences were found regarding the time and amplitude of contraction after single-impulse stimulation. CONCLUSIONS: The GM muscles of individuals with intermittent claudication contract more quickly and fatigue earlier than the GM muscles of healthy controls. Because the contraction time, measured with tensiomyography, reflects the individual's muscle fibre composition, our findings may reflect a shift from type I fibres to type II fibres in the GM muscles of PAD patients. Our data support the idea that calf myopathy is present in claudication-prone patients and, in part, determines the clinical manifestations of PAD.

Cerebrovascular reactivity to l-arginine in the anterior and posterior cerebral circulation in migraine patients.

OBJECTIVE - Cerebral infarction preferentially affects the posterior cerebral artery distribution in migraine patients. The results obtained from the few known studies that have compared the anterior and posterior cerebral endothelial function are contradictory. To the best of our knowledge, cerebrovascular reactivity to L-arginine (CVR), measured by transcranial Doppler sonography (TCD), has not been previously used to determine the posterior cerebral endothelial function in migraine patients with (MwA) and without aura (MwoA). MATERIALS AND METHODS - Forty migraine patients without comorbidities (20 MwA, 20 MwoA) and 20 healthy subjects were included. By employing strict inclusion criteria, we avoided the possible vascular risk factors. Mean arterial velocity in the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) was measured by TCD before and after infusion of L-arginine, and CVR to L-arginine was then calculated. RESULTS - All migraine patients had lower CVR to L-arginine in PCA (P = 0.002) and similar in MCA (P = 0.29) compared to healthy subjects. This difference was also present in MwA and MwoA compared to healthy subjects (P = 0.003). CONCLUSIONS - Lower CVR to L-arginine in PCA in migraine patients could associate migraine and cerebral infarcts that are more common in the posterior cerebral artery distribution.

Prevention of ischemic events in patients with peripheral arterial disease design, baseline characteristics and 2-year results an observational study.

AIM: Peripheral arterial disease (PAD) is associated with frequent cardiovascular ischemic events. We followed the survival of PAD patients and tested whether PAD remains an adverse prognostic indicator in spite of treatment according to the current European guidelines on cardiovascular disease prevention. METHODS: Eight hundred eleven patients with PAD and 778 control subjects, aged 65 (SD 9) years at inclusion, with a male/female ratio of 3/2 were treated according to the European guidelines on cardiovascular disease prevention and evaluated yearly for occurrence of death, non-fatal acute coronary syndrome, stroke or critical limb ischemia (major events) and revascularization procedures (minor events). At baseline, classical risk factors were significantly more prevalent in the PAD group and protective cardiovascular medication was prescribed to patients with PAD more frequently than to control subjects. RESULTS: In the PAD group, the 2-year Kaplan-Meier survival estimate was 96.7% (CI 95.4-97.9) vs. 98.2% (CI 97.2-99.1) in the control group, P=0.059. The groups differed in the 2-year major event-free survival: 93.5% (CI 92.7-95.3) in PAD vs. 97.1% (CI 95.9-98.4) in controls, P<0.017, as well as in event-free survival: 79.9% (CI 77.1-82.9) in PAD vs.96.4% (CI 95.0-97.9) in controls, P<0.001. CONCLUSION: Patients with PAD had a borderline higher risk of all-cause death and a significantly higher risk of major and minor non-fatal cardiovascular events compared to control subjects. However, treatment according to the European guidelines on cardiovascular disease prevention resulted in encouragingly low absolute mortality and morbidity. (ClinicalTrials.gov number NCT00761969.).

The influence of atorvastatin on walking performance in peripheral arterial disease.

BACKGROUND: Recently it has been shown that statins can improve walking distance in patients with peripheral arterial disease. We examined whether statins used in moderate dosages with the aim of reaching the target levels for hypercholesterolemia could improve walking performance in patients with peripheral arterial disease. PATIENTS AND METHODS: 37 patients with hypercholesterolemia (LDL cholesterol = 3.46 +/- 0.13 mmol/l), who had previously not been treated by statins, were randomized in a double-blind study to a group receiving either atorvastatin at 20 mg/day (N = 20) or placebo (N = 17). All patients had stable intermittent claudication (Fontaine class IIa or IIb). At baseline, after one and three months the pain-free walking distance was measured in all patients. RESULTS: After 3 months patients in the treated group had reached target cholesterol values (LDL cholesterol = 2,34 +/- 0.9 mmol/l), whereas no significant change in lipids was observed in the control group. The ankle-brachial pressure index (ABPI) did not change significantly in either group. After 3 months the pain-free walking distance was increased significantly (p < 0.001), but similarly in both groups (at entry: 56 (53-108) m vs 53 (53-106) m; after 3 months: 79 (53-108) m vs 106 (66-159) m, for the treated and placebo group, respectively). Therefore this effect had to be attributed to regular exercise and not to statin use. CONCLUSIONS: Our results show that routine treatment with statin (atorvastatin 20 mg/day), which is effective in reducing the level of cholesterol, does not produce an improvement in walking performance in patients with peripheral arterial disease.

Peroxisome proliferator-activated receptor gamma/Pro12Ala polymorphism and peroxisome proliferator-activated receptor gamma coactivator-1 alpha/Gly482Ser polymorphism in patients with sarcoidosis.

BACKGROUND AND AIM OF THE WORK: Reduced expression and activity of the peroxisome proliferator-activated receptor gamma (PPARG) have been measured in cells of bronchoalveolar lavage fluid in sarcoidosis patients. PPARG, together with its transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), has important modulating effects on immune response and apoptosis. In the present study, we investigated whether the polymorphisms Pro12Ala (rs1805192) in the PPARG gene and Gly482Ser (rs8192678) in the PPARGC1A gene, which affect transcriptional activities, are associated with sarcoidosis. METHODS: We performed an integrative "omic" approach and identified the PPARG gene as a suitable candidate. Polymerase chain reaction was performed followed by restriction fragment length polymorphism to determine PPARG/Pro12Ala and PPARGC1A/Gly482Ser genotypes of 104 sarcoidosis patients and 112 healthy control subjects. RESULTS: A higher frequency of the Ala allele (p=0.0101, OR=1.84, CI 1.18-2.88), as well as a significantly higher frequency of Pro/Ala heterozygotes and Ala/Ala homozygotes at the Pro12Ala/PPARG polymorphism (p=0.0020, OR=2.45, CI 1.42-4.25) were found in patients with sarcoidosis. In addition, a higher frequency of the Ser allele (p=0.013, OR=1.69, CI 1.13-2.53) and Gly/Ser heterozygotes and Ser/Ser homozygotes (p=0.0470, OR=1.80, CI 1.04-3.10) at the Gly482Ser/PPARGC1A polymorphism were found in patients with sarcoidosis as compared to healthy control subjects. CONCLUSION: Our results indicate that the presence of the Ala allele at the PPARG/Pro12Ala polymorphism and the Ser allele at the PPARGC1A/Gly482Ser polymorphism may be a predisposing factor for sarcoidosis.

Endothelial dysfunction in post-myocardial infarction patients with various expressions of risk factors.

It has not been established yet whether patients who suffer myocardial infaction (MI) in the absence of classic risk factors also have endothelial dysfunction (ED), as has been shown for patients with risk factors, and if so, to what extent it is manifested. Young male patients in the stable phase after MI were included in the study. At the time of MI, 20 patients had high and 21 patients low expression of risk factors. The control group consisted of 35 healthy age-matched males. ED was estimated by ultrasound measurement of the endothelium-dependent dilation of the brachial artery, induced by the reactive hyperemia test. Compared to the control group, the level of endothelium-dependent vasodilation was significantly reduced in both groups of patients (controls: 9.1% +/- 5.6%; patients with high risk: 5.5% +/- 5.1%; patients with low risk: 5.6 +/- 3.5 %; ANOVA, p<.01). There was no difference between both groups of patients. These results showed that ED is not associated or due only to classic risk factors. It appears that ED may occur and precede development of atherosclerosis in the absence of classic risk factors. These novel findings can have important clinical implications.

Flow-mediated dilatation and intima-media thickness in patients with lacunar infarctions.

OBJECTIVES: To evaluate systemic endothelial function and atherosclerotic changes in patients with lacunar infarctions (LI) we examined flow-mediated dilatation (FMD) and intima-media thickness (IMT) and compared them to patients with similar risk factors (SR) and healthy controls. METHODS: FMD and IMT were investigated in patients with LI (20 patients, aged 60.9 +/- 7.3 years), 21 age- and gender-matched patients with SR and 21 healthy controls. RESULTS: FMD was more impaired in patients with LI (0.4% +/- 5.0%) compared to patients with SR (3.8% +/- 4.8%) and healthy controls (7.9% +/- 6.0%) (P < or = 0.01), whereas IMT was similarly thickened in both groups of patients. CONCLUSIONS: We found that patients with LI have a diminished FMD, but a similar IMT, compared to patients with SR. Our results reveal that for a given level of atherosclerosis patients with LI have additional endothelial impairment.

Relation of CTG expansion and clinical variables to electrocardiogram conduction abnormalities and sudden death in patients with myotonic dystrophy.

We prospectively followed 63 patients with myotonic dystrophy (DM) after establishing diagnosis of DM for an average 8 years in an attempt to detect conduction disturbances (by electrocardiography and/or Holter monitoring) and sudden cardiac events (sudden death, cardiac syncope) and correlate them to potential predicting factors (CTG repeat expansion in the myotonin protein kinase gene and several clinical variables: clinical type and duration of DM, age and sex). Twenty-six patients developed conduction disturbances, five patients died suddenly, and two patients experienced cardiac syncope necessitating urgent implantation of pacemaker. Analysis showed no significant correlation between conduction disturbances and/or cardiac events and CTG expansion. Furthermore, no correlation was found with type of DM, whereas conduction disturbances and sudden cardiac events correlated with patients' age, duration of disease and male sex. Results on our cohort of DM patients show that CTG expansion has no role in predicting neither conduction abnormalities nor sudden death. It seems that risk of sudden death increases with duration of disease and age, and that risk is higher in male patients.

Treatment of chronic ischaemia of a replanted thumb with iloprost.

A 40-year-old man had chronic ischaemia of his replanted thumb. Angiography revealed occlusion of both digital arteries and weak collaterals. He was treated for 4 weeks with Iloprost which produced a definite and sustained improvement. As the digital arteries remained occluded, the beneficial effect of Iloprost was attributed to increased flow in the microcirculation and collaterals.

Classic risk factors, hypercoagulability and migraine in young women with cerebral lacunar infarctions.

OBJECTIVE: Lacunar cerebral infarctions (LACI) in young women is a rare condition which pathogenesis is still not fully recognized. We explored the presence of classic risk factors, hypercoagulability and migraine in young women with LACI. METHODS: Charts of 192 consecutive premenopausal women suffering cerebrovascular insult [125 (65%) haemorhagic, 58 (30%) ischaemic and 9 (5%) unclassified] during a period of 5 years were reviewed. Sixteen out of 58 (27%) patients with ischaemic stroke were identified to have LACI and included in a study. RESULTS: Ten and seven out of 16 LACI women had at least one classical risk factor (hypertension, hyperlipidaemia, smoking or oral contraceptives) or migraine, respectively. LACI patients had slight hypercoagulable state indicated by shorter thrombin and thromboplastin times, higher fibrinogen and higher t-PA antigen than 47 age matched controls (all P < 0.05). In addition in LACI patients with migraine the trend toward more pronounced hypercoagulable state in comparison to LACI patients without migraine was found. The combination of migraine, at least one classic risk factor and hypercoagulability was present in 5/16 (31.25%) of patients. CONCLUSIONS: The combination of slightly to moderately expressed classic risk factors, hypercoagulability and migraine might be a risk profile for LACI in young women. Further studies are needed to clarify risk profile, rather than isolated risk factors, for LACI in a specific group as young women are.

Do baseline serum leptin levels predict weight regain after dieting in obese women?

AIM: Weight loss achieved during weight reduction programme is difficult to maintain. We investigated the possible role of circulating leptin in failure or success in maintaining weight loss. METHODS: Serum leptin levels were measured in 30 healthy premenopausal obese women before and after 12 weeks of dietary intervention and after 5 months of follow-up. RESULTS: After intervention body mass index (BMI) decreased from 30.6 to 25.4 kg/m2 (p < 0.01) and leptin levels decreased from 16.7 to 7.7 ng/ml (p < 0.01). After 5 months follow-up 12 women regained reduced weight and 18 women maintained weight loss. In the regainers leptin levels increased again, but remained low in the maintainers. Baseline leptin concentrations were lower in the regainers than in the maintainers (12.1 vs. 21.2 ng/ml, p = 0.04). During intervention leptin levels decreased three times more in the maintainers than in the regainers, although weight loss was similar in both groups. CONCLUSIONS: This study shows that obese women who regain weight after dieting have significantly lower baseline leptin levels than women who maintain weight loss. Our results suggest that differences in leptin resistance might exist in similarly obese women which could influence the success of dieting.

Increased levels of antiphospholipid antibodies in a woman with left atrial myxoma and systemic embolisms.

We describe a case of a 45-y-old woman with a left atrial myxoma, mild to moderate constitutional symptoms and systemic embolisms. Increased levels of antiphospholipid antibodies were detected at admission to the hospital and were gradually normalized after the surgical removal of the tumor. It is known that myxomas have the peculiar ability to induce a systemic inflammatory state with constitutional symptoms, probably mediated by the production of inflammatory mediators in the tumor. This case suggests that myxomas might have also been implicated in the production of antiphospholipid antibodies. Antiphospholipid antibodies could be just a by-product of the systemic inflammatory response. However, they could also have a role in the thrombosis on the myxoma surface and systemic embolisms.

Biochemical and biophysical conditions for blood clot lysis.

We have studied how pharmacological dissolution of blood clots was affected by clot retraction, the mode of transport of fibrinolytic agents into the clot and the thickness of the composite fibrin fibers. Retracted clots were resistant to fibrinolysis in a milieu without dissolved plasminogen, because the amount of fibrin-bound plasminogen in retracted clots was insufficient for successful clot lysis. In plasma containing plasminogen, retracted clots were successfully lysed with fibrin-specific plasminogen activators, but not with non-fibrin-specific activators. Preincubation of retracted clots in plasma increased their plasminogen content as well as their sensitivity to fibrinolysis. The rate of lysis was increased up to 100-times when plasminogen activator and plasminogen were introduced into cylindrical clots by pressure-induced bulk flow in comparison with diffusion alone. The magnitude of the increase was similar in retracted and nonretracted clots, but the absolute rate of lysis was faster in non-retracted clots. The influence of fibrin fiber thickness on fibrinolysis was studied by atomic force microscopy. The time to complete lateral section of fibers did not differ between thick and thin composite fibers, and the rate of diameter reduction was faster in thick fibers than in thin ones. Taken together our results suggest that lysis of retracted clots proceeds in circular stages: (a) activation of bound plasminogen followed by partial degradation of fibrin, (b) opening of new plasminogen-binding sites on partly degraded fibrin, (c) binding of plasminogen to the new binding sites which enhances the susceptibility of clots to lysis. Lysis is accelerated by bulk flow of plasminogen activator and plasminogen into clots in comparison to diffusion alone. Fibrinolysis of thick composite fibrin fibers proceeds more efficiently than lysis of thin fibers.

An unusual case of cortical blindness associated with aortography--a case report.

Transient cortical blindness is a rare but well-recognized benign complication of angiography that is due to neurotoxicity of the contrast agent. The blindness completely resolves in a few days. This report describes a patient suffering an unusual course of cortical blindness following aortography resulting in permanent, partial blindness. It was found that blindness was the consequence of bilateral occipital embolisms. This case emphasizes that cortical blindness associated with angiography does not always have a favorable outcome, since it might be, in rare cases, due to isolated occipital embolisms, which initially produce a clinical picture identical to that of the neurotoxic effect of contrast agents.

Successful treatment of bleeding from colonic angiodysplasias with tranexamic acid in a hemodialysis patient.

Colonic angiodysplasias are a common source of gastrointestinal bleeding in patients with end-stage renal disease (ESRD). It is well known that bleeding from angiodysplasias can be a difficult therapeutic problem. This report describes a hemodialysis patient who suffered acute (massive) and chronic gastrointestinal bleeding from colonic angiodysplasias. Because endoscopic ablation could not be performed and resection of the colon was refused, pharmacological treatment with the antifibrinolytic agent tranexamic acid was attempted. A successful management of both the acute and chronic bleeding was achieved. No complications in terms of arterial or venous thrombosis were observed.

Correlation between progressive adsorption of plasminogen to blood clots and their sensitivity to lysis.

The binding of plasminogen to preformed human plasma clots immersed in citrated human plasma was measured and correlated with the sensitivity of these clots to lysis with recombinant tissue-type plasminogen activator (rt-PA), recombinant single-chain urokinase-type plasminogen activator (rscu-PA) or two chain urokinase-type plasminogen activator (tcu-PA, urokinase). When 0.15 ml plasma clots were compressed mechanically to about 1% of their original weight, and immersed in 0.15 ml plasma, 131I-labeled native plasminogen (Glu-plasminogen) adsorbed progressively from the plasma milieu onto the clot; binding was 3 +/- 1% (n = 10) after 1 h, 7 +/- 1% after 12 h and 12 +/- 1% after 48 h. This was associated with an increased sensitivity of the clot to lysis; 50% clot lysis in 4 h was obtained with 65 +/- 5 ng/ml (n = 3) rt-PA before and 30 +/- 5 ng/ml (n = 3) after 48 h preincubation in plasma (p less than 0.01), with corresponding values of 660 +/- 55 ng/ml (n = 3) and 280 +/- 25 ng/ml (n = 3) for rscu-PA, (p less than 0.01), and 800 +/- 85 ng/ml (n = 3) and 270 +/- 35 ng/ml (n = 3) for urokinase (p less than 0.01). Additional binding of plasminogen and increased sensitivity to lysis were reduced or abolished when the clot was preincubated in plasminogen-depleted or in t-PA-depleted plasma, or when 20 mM 6-aminohexanoic acid or 2,000 KIU/ml aprotinin were added.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of retraction on the lysis of human clots with fibrin specific and non-fibrin specific plasminogen activators.

The effect of the serum content of human clots on their sensitivity to lysis with plasminogen activators was studied in a system composed of 125I-fibrin labeled clots immersed in buffer or in citrated plasma. The effect was studied with plasma clots before or after mechanical compression and with whole blood clots before or after retraction, using either the fibrin specific plasminogen activators recombinant tissue-type plasminogen activator (rt-PA) or recombinant single chain urokinase-type plasminogen activator (rscu-PA), and the non-fibrin specific activators recombinant two chain urokinase-type plasminogen activator (rtcu-PA), or streptokinase (SK). In a buffer milieu, all plasminogen activators had a similar fibrinolytic potency towards serum-rich clots (non-compressed plasma clots or non-retracted blood clots): 50% clot lysis in 4 h required 50 to 85 ng plasminogen activator per ml. Serum-poor clots (compressed plasma clots or retracted blood clots) were resistant to lysis in a buffer milieu but became sensitive to lysis following preincubation in plasma for 48 h. These findings indicate that plasma proteins entrapped in clots contribute significantly to their sensitivity to lysis and suggest that the amount of bound or entrapped plasminogen may be a limiting factor. In a plasma milieu, all plasminogen activators lysed serum-rich plasma or blood clots, albeit at higher concentrations (3 to 40 times higher than in the buffer milieu) and with different efficiencies: 50% clot lysis in 4 h required approximately 600 ng/ml of rtcu-PA but 1,500 to 2,000 ng/ml of rscu-PA.(ABSTRACT TRUNCATED AT 250 WORDS)