Cardiovascular and autoimmune diseases in females: The role of microvasculature and dysfunctional endothelium.

Cardiovascular (CV) diseases are becoming increasingly frequent and associated with a high incidence of CV events, disability and death. It is known that there is a relationship between CV burden and systemic autoimmune diseases (SADs) that is mainly due to inflammation and autoimmunity, but the other mechanisms underlying the high CV risk of SAD patients have not yet been fully clarified. The aim of this review article is to discuss some of the specific factors associated with the accelerated atherosclerosis (ATS) characterising SADs (female sex, the microcirculation and the endothelium) in order to highlight the importance of an early diagnosis and the prompt implementation of preventive measures, as well as the possible role of new therapeutic strategies such as vaccine immunomodulation. Finally, as the natural history of ATS begins with endothelial injury (a potentially reversible process that is influenced by various factors) and microvascular damage plays a central role in the etiopathogenesis of SADs, it underlines the crucial need for the development of reliable means of detecting sub-clinical abnormalities in the microcirculation, particularly coronary microcirculation dysfunction.

New parameters for identifying subclinical atherosclerosis in patients with primary Sjögren's syndrome: a pilot study.

OBJECTIVES: We investigated sub-clinical cardiovascular involvement in primary Sjögren's syndrome (pSS) patients by means of ADMA, coronary flow reserve (CFR), intima media thickness (cIMT), pulse wave velocity (PWV) and myocardial deformation. METHODS: The study involved 22 outpatients with pSS (6 males, 16 females; mean age 60.14±7.81 years) and no documentable cardiovascular disease, and 22 age- and gender-matched controls. Dipyridamole transthoracic stress echocardiography was used to evaluate wall motion and CFR. A CFR value of <2.5 was considered a sign of impaired coronary function. We also evaluated cIMT arterial stiffness PWV and plasma ADMA levels, and made a speckle tracking echocardiography (STE) analysis. RESULTS: All of the patients were affected by pSS. Although within the normal range, the patients' CFR was lower than that of the controls (median 2.70; IQR 2.40-2.90 vs. 3.20; IQR 3.06-3.33; p<0.0001), whereas their ADMA levels were significantly higher (median 0.81 µM; IQR 0.79-0.85 µM vs. 0.54 µM; IQR 0.52-0.58 µM; p<0.0001). Both left and right PWV values were significantly higher in the patients than in the controls (median 8.8 m/s right and 8.9 m/s left vs. 6.86 and 6.89 m/s), whereas QIMT was substantially similar in the two groups. CONCLUSIONS: Higher ADMA levels suggest the presence of endothelial dysfunction and sub-clinical atherosclerosis in pSS patients, even in the case of a normal CFR. This finding is supported by the PWV values, which were higher in the pSS patients. ADMA levels and PWV values may be useful markers for identifying early endothelial dysfunction in pSS patients.

Surgical management of a life-threatening retro-pharyngeal haematoma following trans-oesophageal echocardiography.

Trans-oesophageal echocardiography is generally considered a safe procedure, but occasional life-threatening complications have been reported. The aim of this clinical investigation is to outline the need of surgical management in cases of large retro-pharyngeal haematoma following trans-oesophageal echocardiography. In the case reported here, a patient with cervical spondylosis on anti-coagulant therapy was referred to the Head and Neck Department because of a retro-pharyngeal haematoma with severe upper airway obstruction following transoesophageal echocardiography. Tracheotomy was required to guarantee respiratory function, while trans-cervical surgery was performed to evacuate the haematoma. Total recovery was achieved within 10 days. In conclusion, the head and neck surgeon should consider the need of surgical management in cases of retro-pharyngeal haematoma following trans-oesophageal echocardiography.

Cardiovascular involvement in psoriatic arthritis.

Psoriasis is a chronic, genetically determined and immunomediated inflammatory skin disease that affects 2-3% of the Caucasian population. A considerable proportion of these patients develop a form of inflammatory arthritis known as psoriatic arthritis (PsA), although the prevalence of this has not been well defined. Patients with PsA have a higher mortality rate than the general population and the risk of mortality is related to disease severity at the time of presentation. Endothelial dysfunction and early atherosclerosis have been found in patients with PsA without any cardiovascular disease (CVD) risk factors, and experts believe that CVD is one of the leading causes of death, as it is in patients with rheumatoid arthritis (RA). Various disease-related mechanisms may be involved in the development of premature vascular damage in both cases, including an increased synthesis of proinflammatory mediators (such as cytokines, chemokines and adhesion molecules), autoantibodies against endothelial cell components, perturbations in T-cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress, abnormal vascular repair, and iatrogenic factors. In a recent study of 22 patients with PsA without any signs of CVD, we found that the plasma concentration of asymmetric dimethylarginine (ADMA) levels were significantly high and coronary flow reserve (CFR) was significantly reduced. Moreover, there was a significant correlation between CFR and plasma ADMA levels in the PsA group. The significant correlation between the reduced CRF and increased ADMA levels suggests that, like patients with early RA, PsA patients suffer from endothelial dysfunction and impaired coronary microcirculation. Active PsA is a risk factor for CVD, and so PsA patients should be screened for subclinical forms of the disease and its risk factors, and an early treatment approach should be adopted.

Effects of treatment strategy on endothelial function.

A large body of evidence indicates that endothelial dysfunction is a characteristic of patients with arterial hypertension. As functional abnormalities lead to impaired endothelium-dependent vasodilation, this early step of atherogenesis is potentially reversible. In addition to reducing blood pressure, the major families of anti-hypertensive drugs have a number of pleiotropic effects that could improve endothelial function. In particular, the renin-angiotensin system plays an important role in the pathogenesis of both arterial hypertension and endothelial dysfunction, and so drugs capable of limiting the dangerous effects of this hormonal axis, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and renin inhibitors, could help prevent/delay/reverse the atherosclerotic process. New third-generation ß-blockers and 5-phosphodiesterase inhibitors may affect endothelial function. Furthermore, the HMGCoA-reductase inhibitors currently used to reduce cholesterol levels have major pleiotropic anti-inflammatory and anti-hypertensive effects. The preservation or recovery of endothelial function in hypertensive patients is crucial to inhibit the development of atherosclerosis and the onset of cardiovascular events. This review focuses on the ancillary effects of hypertensive drugs and HMGCoA-reductase inhibitors that go beyond lowering blood pressure and cholesterol levels.

From endothelial dysfunction to atherosclerosis.

It has recently emerged that endothelial dysfunction is an early step in the development of atherosclerosis and is mainly characterised by a reduction in the bioavailability of nitric oxide. All of the traditional cardiovascular (CV) risk factors (dyslipidemia, arterial hypertension, hyperglycemia and diabetes) are associated with endothelial dysfunction, and oxidised low-density lipoproteins, the renin-angiotensin axis and insulin resistance play important roles in the pathogenesis of impaired endothelial function. The increased expression of adhesion molecules and pro-inflammatory cytokines leads to abnormal endothelium-dependent vasodilation which could be investigated using vasoreactivity tests such as flow-mediated dilation in the brachial artery. Recently, new evidences showed that the immune system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis with a particular regard towards autoimmunity. The high prevalence of the atherosclerotic process in systemic autoimmune diseases supports the hypothesis of the immune pathogenesis. Evaluating coronary microvascular dysfunction by means of transthoracic echocardiography with non-invasive coronary flow reserve assessment is particularly interesting as it could detect preclinical impairment of coronary microvascular function. The discovery that the mechanisms responsible for endothelial damage have a genetic basis could improve the approach to CV diseases. This review summarises the most important aspects of the pathogenesis and development of endothelial dysfunction, with particular attention to the role of traditional CV risk factors, the usefulness of vasoreactivity tests, and the future perspectives opened by genetic studies.

Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis.

Rheumatoid arthritis (RA) is associated with enhanced atherosclerosis and impaired endothelial function early after the onset of the disease and cardiovascular (CV) disease represents one of the leading causes of morbidity and mortality. It is well known that disease modifying antirheumatic drugs (DMARDs) are able to improve the course of the disease and the quality of life of these patients, but little is known about the effects of DMARDs on CV risk and endothelial dysfunction. Our goal was to examine the effects of long-term therapy with DMARDs on endothelial function and disease activity in early RA (ERA). Twenty-five ERA patients (mean age 52 ± 14.6 years, disease duration 6.24 ± 4.10 months) without evidence of CV involvement were evaluated for disease activity score (DAS-28), 2D-echo derived coronary flow reserve (CFR), common carotid intima-media thickness (IMT) and plasma asymmetric dimethylarginine (ADMA) levels at baseline and after 18 months of treatment with DMARDs (10 patients with methotrexate and 10 with adalimumab). DMARDs significantly reduced DAS-28 (6.0 ± 0.8 vs. 2.0 ± 0.7; P < 0.0001) and improved CFR (2.4 ± 0.2 vs. 2.7 ± 0.5; P < 0.01). Common carotid IMT and plasma ADMA levels did not show significant changes. The present study shows that DMARDs, beyond the well known antiphlogistic effects, are able to improve coronary microcirculation without a direct effect on IMT and ADMA, clinical markers of atherosclerosis. Treatment strategies in ERA patients with high inflammatory activity must be monitored to identify beneficial effects on preclinical markers of vascular function.

[Cardiac involvement in rheumatoid arthritis]. / Il coinvolgimento cardiaco nell'artrite reumatoide.

Rheumatoid arthritis (RA) is a systemic disease of unknown etiology characterized by a chronic inflammatory process mainly leading to destruction of synovial membrane of small and major diarthrodial joints. The prevalence of RA within the general adult population is about 1% and female subjects in fertile age result mostly involved. It's an invalidating disease, associated with changes in life quality and a reduced life expectancy. Moreover, we can observe an increased mortality rate in this population early after the onset of the disease. The mortality excess can be partially due to infective, gastrointestinal, renal or pulmonary complications and malignancy (mainly lung cancer and non-Hodgkin lymphoma). Among extra-articular complications, cardiovascular (CV) involvement represents one of the leading causes of morbidity and mortality. Every cardiac structure can be affected by different pathogenic pathways: heart valves, conduction system, myocardium, endocardium, pericardium and coronary arteries. Consequently, different clinical manifestations can be detected, including: pericarditis, myocarditis, myocardial fibrosis, arrhythmias, alterations of conduction system, coronaropathies and ischemic cardiopathy, valvular disease, pulmonary hypertension and heart failure. Considering that early cardiac involvement negatively affects the prognosis, it is mandatory to identify high CV risk RA patients to better define long-term management of this population.

Assessment of the cardiovascular regulation during robotic assisted locomotion in normal subjects: autoregressive spectral analysis vs empirical mode decomposition.

Robotic assisted locomotion systems are recently gaining appreciation as methods to rehabilitate individuals with lost sensory motor function. In the present study we compare autoregressive power spectral analysis and empirical mode decomposition (EMD) applied to the analysis of short-term heart period variability regarding their ability to typify autonomic response during a robotic assisted locomotion session consisting in the following phases: 1) sitting position; 2) standing position; 3) suspension during subject instrumentation; 4) robotic assisted treadmill locomotion with partial body weight support; 5) standing recovery after exercise. Results showed a significant tachycardia during the suspension phase, but no significant changes of spectral indexes. On the contrary, when spectral indexes were derived according to EMD, changes were evidenced during the suspension and walking phases. The EMD method is more powerful than autoregressive spectral analysis in detecting variations of parasympathetic and sympathetic modulations elicited by a robotic-assisted locomotion protocol.

Nearly automated analysis of coronary Doppler flow velocity from transthoracic ultrasound images: validation with manual tracings.

Coronary flow velocity reserve is obtained by manual tracings of transthoracic coronary Doppler flow velocity profiles as the ratio of stress versus baseline diastolic peak velocities. This approach introduces subjectivity in the measurements and limits the information which could be exploited from the Doppler velocity profile. Accordingly, our goals were to develop a technique for nearly automated detection of Doppler coronary flow velocity profile, and automatically compute both conventional and additional amplitude, derivative and temporal parameters, and validate it with manual tracings. A total of 100 patients (17 normals, 15 patients with severe coronary stenosis, 41 with connective tissue disease and 27 with diabetes mellitus) were studied. Linear correlation and Bland-Altman analyses showed that the proposed method was highly accurate and repeatable compared to the manual measurements. Comparison between groups evidenced significant differences in some of the automated parameters, thus representing potentially additional indices useful for the noninvasive diagnosis of microcirculatory or coronary artery disease.

Semi-automated analysis of coronary flow Doppler images: validation with manual tracings.

Coronary flow velocity reserve (CFVR) is conventionally obtained by manual tracings of Doppler profiles, as ratio of stress vs baseline diastolic peak velocity. When <1.9, this parameter evidences reduced coronary flow and possible microcirculatory disease. Our goals were: 1) to develop a novel technique for semi-automated detection of Doppler flow velocity profile, allowing the automated computation of CFVR and other parameters; 2) to validate this technique in comparison with conventional measurements obtained by manual tracing; 3) to test for differences between normal (N) subjects and patients with rheumatoid arthritis (RA). Linear correlation and Bland-Altman analyses showed that the proposed method was highly accurate and repeatable compared to the manual measurements. Comparison between N and RA groups evidenced significant differences in some of the automated parameters.

Cardiac imaging techniques in systemic autoimmune diseases.

Systemic autoimmune disorders are frequently associated to cardiac involvement and to a high prevalence of ischemic coronary events, often occurring at a younger age than in the normal population. Large increase in mortality is related to premature atherosclerosis with coronary artery disease and stroke in patients with connective tissue diseases. Coronary heart disease is responsible for 40-50% of the deaths of patients with rheumatoid arthritis. Transesophageal or transthoracic echocardiography are the most useful and noninvasive techniques able to detect not only valvular abnormalities, embolic sources or pulmonary hypertension, but also left ventricular systolic or diastolic dysfunction. Furthermore, the introduction of new indexes, contrast agents and software increased the accuracy of this technique. It is possible now to evaluate coronary flow reserve by transthoracic echocardiography in patients with systemic autoimmune disease in order to detect microvasculature disorder. However, an ischemic response in a symptomatic patient requires, in most cases, further evaluation with cardiac catheterization. Coronary artery imaging allows confirmation of the presence, extent and position of atheromatous lesions. More recently, other imaging modalities including magnetic resonance and computerized tomography angiography have been developed to allow imaging of the coronary arteries.

Tumor necrosis factor-alpha, biologic agents and cardiovascular risk.

The increased risk of premature cardiovascular disease (CVD) in rheumatoid arthritis (RA) patients may depend on traditional risk factors but may also be attributable to RA-specific risk factors such as disease-related dyslipidemia, or cytokines such as tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is a proinflammatory cytokine that can produce widespread deleterious effects when expressed in large amounts. It is produced in the heart by both cardiac myocytes and resident macrophages under conditions of cardiac stress, and is thought to be responsible for many of the untoward manifestations of cardiac disease. TNF-alpha may play a role in the triggering and perpetuation of atherosclerosis. Treatment with biologic agents directed against TNF-alpha has significant clinical benefits in inflammatory diseases such as RA and may be able to reduce cardiovascular risk. The disappointing results of the recent studies to antagonize TNF-alpha in CVD may have various explanations. However, the effects of TNF-alpha blockers on incident cases of congestive heart failure (CHF) in RA remains controversial. Due to the lack of evidence of a beneficial effect of anti-TNF-alpha agents in treatment of CHF, they should not be used to treat patients with New York Heart Association (NYHA) class III or IV heart failure.

[Two cases of postpartum pubis diastasis mistaken for neurological complications of epidural analgesia]. / Dos casos de diástasis de pubis postparto interpretados como complicación neurológica de la analgesia epidural.

Two healthy 31- and 34-year-old parturients received uncomplicated epidural analgesia for labor and delivery using standard techniques. Twenty-four and 12 hours postpartum, respectively, they developed severe lower back pain and difficulty moving their lower extremities. At first the symptoms were attributed to neurological complications of epidural analgesia and for this reason the anesthetist was called. Although both women appeared healthy and the neurological examinations were normal, emergency computed tomography scans were performed to rule out spinal compression because of the severity of pain and difficulty of movement. The diagnosis was only established after suspecting pubis diastasis, confirmed by palpation of symphysis gaps of 3 and 2 cm, respectively. Pelvic dysfunction associated with pregnancy and labour is a complication whose incidence varies from 1 in 300 to 1 in 30,000. It presents with severe pain located in the areas supplied by pudendal and genitofemoral nerves. The pain may radiate to the sacroiliac joints and shoot down the buttocks and legs. In the most severe cases it may be accompanied by urinary dysfunction and inability to walk. If the clinical features are not recognized, it can be difficult to differentiate pubis diastasis from severe neurological complications in women who have received a central nervous system block. We report two cases of peripartum pubis symphysis diastasis that were both initially mistaken for neurological complications of epidural analgesia for labor.

The Italian version of the Fibrofatigue Scale, a reliable tool for the evaluation of fibromyalgia symptoms.

OBJECTIVE: To validate a translated Italian version of the Fibrofatigue Scale (FFS). METHODS: The Italian version of FFS was administered to 60 patients affected by fibromyalgia (FM) (57 patients were interviewed again 10 days later) together with the Italian version of the Fibromyalgia Impact Questionnaire (FIQ), the Stanford Health Assessment Questionnaire (HAQ) and the Medical Outcome Survey Short Form-36 (SF-36). All patients were asked about the severity of pain today (10-cm visual analogue scale) and the duration of symptoms. Test-retest reliability was assessed using Spearman correlations. Internal consistency was evaluated with Cronbach's alpha of reliability. Construct validity of the FFS was evaluated by correlations among the FFS, the FIQ and the subscales of the SF-36. RESULTS: Mean duration of symptoms was 7.6 years, and mean age of participants was 56.3 years. Test-retest reliability was between 0.70 and 0.95 for the single items as well as for the total FFS and other components. Internal consistency was 0.90 for the overall FFS. Significant correlations were obtained between the FFS items and the SF-36. CONCLUSIONS: The Italian FFS is a reliable and valid instrument for detecting and measuring functional disability and symptoms severity in Italian patients with FM.

Quantification of coronary flow velocity reserve by means of semiautomated analysis of coronary flow Doppler images.

Coronary flow reserve (CFVR) is conventionally obtained by manual tracings of Doppler profiles, as ratio of control vs stress diastolic peak velocity. This parameter could help in discriminating between normal (N) and microcirculatory pathologic (P) subjects, even the clinical meaning of 1.93) and 15 P (CFVR<1.8) subjects, to assess whose of the new parameters could be able to discriminate between these groups. Results indicated that many of the new parameters were able to evidence significant differences between N and P, thus representing new clinical indices useful for the diagnosis.

Changes in Doppler mitral inflow patterns during parabolic flight.

Aim of the study was to evaluate by transthoracic Doppler the alterations in mitral inflow velocity pattern caused by acute changes in loading conditions occurring during parabolic flights. Each parabola included normogravity (1 Gz, 1 min), mild hypergravity (1.8 Gz, 20 sec), microgravity (0 Gz, 24 sec) and mild hypergravity (1.8 Gz, 20 sec) phases. Pulsed-Doppler images were digitally acquired in 11 unmedicated subjects (46 +/- 5 years), in standing upright position and supine resting. Doppler profiles were semi-automatically traced and inflow parameters extracted and averaged onto three consecutive beats. Only in standing position, significant alterations during microgravity (p<0.05) were noted in several parameters.

Validation of an Italian version of the Fibromyalgia Impact Questionnaire (FIQ-I).

OBJECTIVE: To validate a translated Italian version of the Fibromyalgia Impact Questionnaire (FIQ). METHODS: The Italian version of the FIQ was administered to 50 patients affected by fibromyalgia (FM) (48 patients filled out the questionnaire again 10 days later) together with the Italian version of the Stanford Health Assessment Questionnaire (HAQ), the Medical Outcomes Survey Short Form-36 (SF-36), and a tender point count (TPC) obtained by summing the score (0-3) of each tender point tested by thumb palpation. All patients were asked about the severity of pain today (10 cm visual analog scale) and the duration of symptoms. Test-retest reliability was assessed using Spearman correlations. Internal consistency was evaluated with Cronbach's alpha of reliability. Construct validity of the FIQ was evaluated by correlations between the HAQ and subscales of the SF-36 as well as the TPC. RESULTS: The mean duration of symptoms was 6.5 years and the mean age of the participants was 57.4 years. Test-retest reliability was between 0.74 and 0.95 for physical functioning as well as for the total FIQ and other components. Internal consistency was 0.90 for the overall FIQ. Significant correlations were obtained between the FIQ items, the HAQ and the SF-36. CONCLUSIONS: The Italian FIQ is a reliable and valid instrument for detecting and measuring functional disability and health status in Italian patients with FM.

El remifentanilo como amortiguadorde la respuesta al estrés en la cesáreabajo anestesia general / Remifentanil to attenuate the stress response of cesarean section performed under general anesthesia

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