Giris Jacob

Dysautonomia in the joint hypermobility syndrome

PURPOSEnExtraarticular manifestations of the joint hypermobility syndrome may include the peripheral nervous system. The purpose of this study was to investigate autonomic function in patients with this syndrome.nnnMETHODSnForty-eight patients with the joint hypermobility syndrome who fulfilled the 1998 Brighton criteria and 30 healthy control subjects answered a clinical questionnaire designed to evaluate the frequency of complaints related to the autonomic nervous system. Next, 27 patients and 21 controls underwent autonomic evaluation: orthostatic testing, cardiovascular vagal and sympathetic functions, catecholamine levels, and adrenoreceptor responsiveness.nnnRESULTSnSymptoms related to the autonomic nervous system, such as syncope and presyncope, palpitations, chest discomfort, fatigue, and heat intolerance, were significantly more common among patients. Orthostatic hypotension, postural orthostatic tachycardia syndrome, and uncategorized orthostatic intolerance were found in 78% (21/27) of patients compared with in 10% (2/21) of controls. Patients with the syndrome had a greater mean (+/- SD) drop in systolic blood pressure during hyperventilation than did controls (-11 +/- 7 mm Hg vs. -5 +/- 5 mm Hg, P = 0.02) and a greater increase in systolic blood pressure after a cold pressor test (19 +/- 10 mm Hg vs. 11 +/- 13 mm Hg, P = 0.06). Patients with the syndrome also had evidence of alpha-adrenergic (as assessed by administration of phenylephrine) and beta-adrenergic hyperresponsiveness (as assessed by administration of isoproterenol).nnnCONCLUSIONnThe autonomic nervous system-related symptoms of the patients have a pathophysiological basis, which suggests that dysautonomia is an extraarticular manifestation in the joint hypermobility syndrome.

Role of nitric oxide in the regulation of cerebral blood flow in humans: chemoregulation versus mechanoregulation.

Background—From animal studies it emerged that nitric oxide is important for the modulation of CO2-mediated cerebral blood flow (CBF chemoregulation) but not for the pressor-dependent mechanism (mechanoregulation). This hypothesis was tested in 18 healthy subjects. Methods and Results—Peak velocity (PV), diastolic velocity (DV), and mean velocity (MV) were measured by transcranial Doppler of the middle cerebral artery. Chemoregulation was assessed during normocapnia, hypocapnia, and after inhaled mixture of 95% O2+5% CO2. Mechanoregulation was evaluated by incremental doses of phenylephrine. Measurements were repeated during infusion of sodium nitroprusside (SNP). Regional cerebrovascular resistance (CVR) was calculated as mean blood pressure (BP)/MV. SNP infusion decreased mean BP by 7 mm Hg and CVR decreased from 1.38±0.08 to 1.29±0.09 mm Hg/cm · s−1;P =0.01, resulting in unaffected CBF. Phenylephrine (25 to 250 &mgr;g) caused a similar increase in BP in a dose-response fashion before and during SNP infusion. Despite the increments in BP and CVR, CBF remained unaffected. During hyperventilation (end-tidal CO2 ≈24 mm Hg), CVR increased by 75±3% and PV and DV decreased by 27±2% and 43±2%, respectively (P <0.001 for all). SNP infusion blunted the vasoconstrictive effect of hypocapnia; CVR increased only by 57±5%, and PV and DV decreased by 23±2% and 35±3%, respectively, (P <0.05 for all). Similarly, SNP augmented the vasodilatory effect of hypercapnia. Conclusions—Exogenous nitric oxide donor affects the basal cerebral vascular tone without affecting the CBF mechanoregulation. However, it selectively affects only the chemoregulatory mechanism (CO2-dependent). Thus, the CO2-NO axis is a cardinal pathway for CBF regulation in humans.

Can low-intensity extracorporeal shockwave therapy improve erectile function? A 6-month follow-up pilot study in patients with organic erectile dysfunction.

BACKGROUNDnLow-intensity extracorporeal shockwave therapy (LI-ESWT) is currently under investigation regarding its ability to promote neovascularization in different organs.nnnOBJECTIVEnTo evaluate the effect of LI-ESWT on men with erectile dysfunction (ED) who have previously responded to oral phosphodiesterase type 5 inhibitors (PDE5-I).nnnDESIGN, SETTING, AND PARTICIPANTSnWe screened 20 men with vasculogenic ED who had International Index of Erectile Function ED (IIEF-ED) domain scores between 5-19 (average: 13.5) and abnormal nocturnal penile tumescence (NPT) parameters. Shockwave therapy comprised two treatment sessions per week for 3 wk, which were repeated after a 3-wk no-treatment interval.nnnINTERVENTIONnLI-ESWT was applied to the penile shaft and crura at five different sites.nnnMEASUREMENTSnAssessment of erectile function was performed at screening and at 1 mo after the end of the two treatment sessions using validated sexual function questionnaires, NPT parameters, and penile and systemic endothelial function testing. The IIEF-ED questionnaire was answered at the 3- and 6-mo follow-up examinations.nnnRESULTS AND LIMITATIONSnWe treated 20 middle-aged men (average age: 56.1 yr) with vasculogenic ED (mean duration: 34.7 mo). Eighteen had cardiovascular risk factors. At 1 mo follow-up, significant increases in IIEF-ED domain scores were recorded in all men (20.9 +/- 5.8 vs 13.5+/- 4.1, p<0.001); these remained unchanged at 6 mo. Moreover, significant increases in the duration of erection and penile rigidity, and significant improvement in penile endothelial function were demonstrated. Ten men did not require any PDE5-I therapy after 6-mo follow-up. No pain was reported from the treatment and no adverse events were noted during follow-up.nnnCONCLUSIONSnThis is the first study that assessed the efficacy of LI-ESWT for ED. This approach was tolerable and effective, suggesting a physiologic impact on cavernosal hemodynamics. Its main advantages are the potential to improve erectile function and to contribute to penile rehabilitation without pharmacotherapy. The short-term results are promising, yet demand further evaluation with larger sham-control cohorts and longer follow-up.

Penile and Systemic Endothelial Function in Men with and without Erectile Dysfunction

BACKGROUNDnAssessment of endothelial function can provide essential information about the mechanisms of cardiovascular disease. Emerging data show that erectile dysfunction (ED) can precede the symptoms of ischemic heart disease, and this suggests that endothelial dysfunction is the link between these two clinical entities.nnnOBJECTIVEnTo evaluate penile and systemic endothelial function in subjects with and without ED.nnnDESIGN, SETTING, AND PARTICIPANTSnFifty-nine subjects were enrolled in the study. According to their International Index of Erectile Function (IIEF) ED domain scores, they were divided into two groups: 40 patients with ED and 19 men without ED (control group). Hemodynamic measurements, penile endothelial function, and forearm endothelial function were assessed in all participants using veno-occlusive plethysmography.nnnMEASUREMENTSnWe measured baseline blood flow in both the forearm and the penis and calculated the corresponding vascular resistances. Postischemic changes in blood flow were recorded serially in both organs for the evaluation of endothelial function. Area under the flow-time curve (AUC), and maximal blood flow after ischemia were considered to be the indices of endothelial function.nnnRESULTS AND LIMITATIONSnGeneral characteristics of the two groups of participants were comparable except for age (40.5+/-3.3 yr in the control group vs 53.3+/-2.3 yr in the ED group). Baseline forearm blood flow was similar in the two groups, but the penile blood flow was significantly lower in men with ED compared with that in the men without ED: 6.2+/-0.6 versus 8.6+/-0.6 ml/min per 100ml of tissue (p=0.006). Penile vascular resistance was higher in the ED group compared with the control group. The indices of forearm endothelial function were comparable in both groups (p=0.70 for the AUCs). However, indices of penile endothelial function were significantly higher in the control group compared with those of the ED group (AUC: 950 units+/-130 vs 450+/-80 units, p=0.001).nnnCONCLUSIONSnThe use of veno-occlusive plethysmography for evaluating penile endothelial function is simple and reliable and provides new information on the pathophysiology of ED at the level of penile vasculature. This is the first study that provides evidence of impaired penile endothelial function without the presence of a significant peripheral endothelial dysfunction. Furthermore, these results provide further support for the notion that the development of ED could predict the future onset of cardiovascular disease.

Hormonal and Volume Dysregulation in Women With Premenstrual Syndrome

Premenstrual syndrome (PMS) presents with emotional and physical symptoms. Although the emotional symptoms have been extensively studied, the pathophysiology of the fluid-retention symptoms is not currently known. We tested the hypothesis that the fluid regulatory mechanisms are disturbed in PMS. Nine regularly menstruating women with PMS were compared with 9 healthy age-matched women. Hemodynamic parameters and upright plasma volume shift (extrapolated from changes in hematocrit), plasma renin activity (PRA), and plasma aldosterone and sex hormones were measured at different times during the menstrual cycle. During the early follicular and the midluteal phases, the plasma volume shift, supine and upright PRA, and plasma aldosterone were similar in both groups, and none of the participants had edema. However, during the late luteal phase, ankle edema was present only in women with PMS, and their maximal plasma volume shift was lower compared with controls (11.7±1.3 versus 15.6±0.6; P=0.004). The area under the curve (estimates the amount of the total plasma shift during 30 minutes standing) was 300±28 and 406±16 in PMS and controls, respectively (P=0.01). PRA and aldosterone levels were higher during the late luteal phase in women with PMS compared with controls (supine PRA: 1.4±0.3 [PMS] versus 1.1±0.4 [control; P value not significant], upright PRA: 3.9±0.08 versus 1.6±0.3 ng/mL per hour [P=0.015], supine plasma aldosterone: 131±30 versus 68±17 pg/mL [P=0.09], and upright plasma aldosterone: 208±40 versus 102±16 pg/mL [P=0.03]). We, therefore, conclude that women with PMS have increased plasma fluid-regulatory hormones and disturbed fluid distribution only during their late luteal menstrual phase.

Physiological and catecholamine response to sympathetic stimulation in turner syndrome.

Objectiveu2002 Women with Turner syndrome have increased heart rate and high blood pressure (BP), and have been described as having high tolerance for emotional stress. We hypothesized that women with Turner syndrome have reduced catecholaminergic and physiological response to sympathetic stimulation, and that changes in BP and heart rate are related to their catecholamine response to sympathetic stimulation.

Factor analysis of risk variables associated with low-grade inflammation

BACKGROUNDnChronic subclinical inflammation, manifesting as elevated levels of inflammatory markers such as C-reactive protein (CRP), predicts future atherothrombotic events. The pathophysiology of low-grade inflammation is complex, and multiple intercorrelated conditions have been associated with elevated CRP.nnnMETHODSnPrincipal factor analysis was used to investigate clustering of variables associated with elevated CRP using data from 1435 subjects without known coronary disease. Components of the metabolic syndrome, uric acid, liver enzymes, pulmonary function tests, smoking status, cardiorespiratory fitness (measured by maximal treadmill test), and high-sensitivity C-reactive protein were determined in each subject.nnnRESULTSnFactor analysis identified three factors, which explained 51.0% of the total variance in the dataset (24.4% factor 1, 17.3% factor 2, and 9.3% factor 3). Based on factor loadings of >or=0.5, these factors were interpreted as (1) metabolic factor including BMI, fasting glucose, HDL cholesterol, triglycerides, systolic blood pressure, and uric acid; (2) a cardiorespiratory factor that included fitness level, forced expiratory volume in 1s and sex; and (3) smoking factor that included cigarette smoking and age. Each of these factors was significantly associated with the presence of high-risk CRP (>or=3mg/L) in the study population. The ability of a multivariate model that included these three factors to predict high-risk CRP was comparable to a model containing the original 10 variables (area under the receiver-operator characteristics curve 0.7 vs. 0.72, respectively).nnnCONCLUSIONnMetabolic perturbations, cardiorespiratory fitness, and smoking are separate and largely independent factors in the pathophysiology of chronic, low-grade inflammation.

Effect of Chronic Sildenafil Treatment on Penile Endothelial Function: A Randomized, Double-Blind, Placebo Controlled Study

PURPOSEnAlthough the effect of phosphodiesterase type 5 inhibitors on endothelial function in the systemic circulation has been extensively studied, its effect on penile endothelial function remains unexplored. Therefore, we evaluated the effect of daily sildenafil on penile endothelial function.nnnMATERIALS AND METHODSnA total of 60 patients with erectile dysfunction were randomized blindly to daily placebo or 50 mg sildenafil for 4 weeks. Penile and forearm blood flow as well as endothelial function indices were measured at baseline and after 4 weeks using venoocclusive strain gauge plethysmography for both organs. Sequential changes in flow, maximal blood flow and area under the curve induced by reactive hyperemia after 5 minutes of transient ischemia were considered indices of endothelial function.nnnRESULTSnThere were 34 patients treated with sildenafil and 19 on placebo who completed the study. The general characteristics of both groups were comparable. Mean +/- SEM baseline penile blood flow was 6.2 +/- 1.4 and 7.0 +/- 0.6 ml/dl per minute for the placebo and sildenafil groups, respectively (p = 0.54). Baseline forearm blood flow was similar in both groups. At baseline penile AUC was 420 +/- 50 and 520 +/- 50 (p = 0.18), and in the forearm it was 445 +/- 40 and 410 +/- 40 (p = 0.45) for the placebo and sildenafil groups, respectively. After 4 weeks on the assigned drug penile blood flow increased to 11.2 +/- 2 ml/dl per minute in the sildenafil group (p = 0.02) and remained unchanged in the placebo group. After 4 weeks penile AUC increased to 720 +/- 65 in the sildenafil group (0.04) and remained unchanged in the placebo group. Placebo and sildenafil did not affect the indices of forearm endothelial function.nnnCONCLUSIONSnDaily sildenafil significantly improves penile blood flow and penile endothelial function indices without causing any relevant systemic effects.

Haptoglobin genotype and endothelial function in diabetes mellitus: a pilot study

Endothelial function (EnF) is impaired in patients with diabetes mellitus (DM) due in large part to an increase in oxidative stress. Haptoglobin (Hp) is a potent antioxidant protein which is encoded by two different alleles (1 and 2) with the Hp 1 protein being a superior antioxidant to the Hp 2 protein. We hypothesized that DM individuals with the Hp 2-2 genotype would have greater endothelial dysfunction as compared to DM individuals with the Hp 1-1 genotype. We studied EnF in 16 Hp 2-2, 14 Hp 1-1 DM individuals and 14 healthy subjects. DM patients’ groups were matched in terms of age, cardiovascular risk factors and metabolic characteristics. EnF was assessed using post-ischemic reactive hyperemia and strain gauge plethysmography and expressed either as the maximal flow after the ischemic period or as the area under the flow–time curve (AUC). We showed that EnF indices, AUC and maximal flow, were also higher in the healthy and Hp 1-1 groups compared with Hp 2-2 genotype group (615xa0±xa060 and 600xa0±xa040 vs. 450xa0±xa050xa0mlxa0dl−1, 29xa0±xa02.6 and 25xa0±xa03 vs. 14xa0±xa01.8xa0mlxa0min−1xa0dl−1, Pxa0<xa00.003 and Pxa0<xa00.05, for AUC and maximal flow, one-way ANOVA, respectively). We concluded that Hp 2-2 diabetic patients had a worse EnF than controls and Hp 1-1 diabetic subjects.

Ehlers–Danlos Syndrome—Hypermobility Type: A Much Neglected Multisystemic Disorder

Ehlers–Danlos syndrome (EDS)—hypermobility type (HT) is considered to be the most common subtype of EDS and the least severe one; EDS-HT is considered to be identical to the joint hypermobility syndrome and manifests with musculoskeletal complaints, joint instability, and soft tissue overuse injury. Musculoskeletal complaints manifest with joint pain of non-inflammatory origin and/or spinal pain. Joint instability leads to dislocation or subluxation and involves peripheral joints as well as central joints, including the temporomandibular joints, sacroiliac joints, and hip joints. Soft tissue overuse injury may lead to tendonitis and bursitis without joint inflammation in most cases. Ehlers–Danlos syndrome-HT carries a high potential for disability due to recurrent dislocations and subluxations and chronic pain. Throughout the years, extra-articular manifestations have been described, including cardiovascular, autonomic nervous system, gastrointestinal, hematologic, ocular, gynecologic, neurologic, and psychiatric manifestations, emphasizing the multisystemic nature of EDS-HT. Unfortunately, EDS-HT is under-recognized and inadequately managed, leading to neglect of these patients, which may lead to severe disability that almost certainly could have been avoided. In this review article we will describe the known manifestations of the extra-articular systems.