Yehonatan Sharabi

Low‐frequency power of heart rate variability is not a measure of cardiac sympathetic tone but may be a measure of modulation of cardiac autonomic outflows by baroreflexes

Power spectral analysis of heart rate variability has often been used to assess cardiac autonomic function; however, the relationship of low‐frequency (LF) power of heart rate variability to cardiac sympathetic tone has been unclear. With or without adjustment for high‐frequency (HF) power, total power or respiration, LF power seems to provide an index not of cardiac sympathetic tone but of baroreflex function. Manipulations and drugs that change LF power or LF:HF may do so not by affecting cardiac autonomic outflows directly but by affecting modulation of those outflows by baroreflexes.

Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease

Fabry disease is an X‐linked disorder caused by a deficiency of lysosomal α‐galactosidase A resulting in accumulation of α‐D‐galatosyl conjugated glycosphingolipids. Clinical manifestations include a small‐fiber neuropathy associated with debilitating pain and hypohidrosis. We report the effect of a 3‐year open‐label extension of a previously reported 6‐month placebo‐controlled enzyme replacement therapy (ERT) trial in which 26 hemizygous patients with Fabry disease received 0.2 mg/kg of α‐galactosidase A every 2 weeks. The effect of ERT on neuropathic pain scores while off pain medications, quantitative sensory testing, quantitative sudomotor axon reflex test (QSART), and thermoregulatory sweat test (TST) is reported. In the patients who crossed‐over from placebo to ERT (n = 10), mean pain‐at‐its‐worst scores on a 0–10 scale decreased (from 6.9 to 4.5). There was a significant reduction in the threshold for cold and warm sensation in the foot. At the 3‐year time‐point, pre‐ERT sweat excretion in 17 Fabry patients was 0.24 ± 0.33 μl/mm2 vs. 1.05 ± 0.81 in concurrent controls (n = 38). Sweat function improved 24–72 h post‐enzyme infusion (0.57 ± 0.71 μl/mm2) and normalized in four anhidrotic patients. TST confirmed the QSART results. We conclude that prolonged ERT in Fabry disease leads to a modest but significant improvement in the clinical manifestations of the small‐fiber neuropathy associated with this disorder. QSART may be useful to further optimize the dose and frequency of ERT. Muscle Nerve 28: 703–710, 2003

Circulating adiponectin concentrations in patients with congestive heart failure

Objectives: To determine concentrations of adiponectin and its predictive value on outcome in a cohort of patients with congestive heart failure (CHF). Methods: Serum and clinical data were obtained for outpatients with clinically controlled CHF (n  =  175). Serum concentrations of adiponectin, C reactive protein, N-terminal pro-brain natriuretic peptide (NT-proBNP), interleukin (IL) -1β, IL-6, IL-8, IL-10, IL-12, tumour necrosis factor α and CD-40 ligand were determined. The association of adiponectin with the clinical severity of CHF was sought as well as the predictive value of this adipokine on mortality, CHF hospitalisations or the occurrence of each of these end points. Results: Concentrations of adiponectin were significantly increased in patients with CHF. Patients with higher New York Heart Association class had significantly higher serum concentrations of adiponectin. Adiponectin serum concentrations were lower in patients with diabetes and CHF as well as in patients with ischaemic cardiomyopathy. Serum adiponectin concentration was positively associated with age and NT-proBNP but was negatively correlated with C reactive protein concentrations. Serum adiponectin above the 75th centile was found to be an independent predictor of total mortality, CHF hospitalisations or a composite of these end points over a two-year prospective follow up. Conclusion: Adiponectin is increased in CHF patients and predicts mortality and morbidity.

Association Between Supine Hypertension and Orthostatic Hypotension in Autonomic Failure

Abstract—Supine hypertension occurs commonly in primary chronic autonomic failure. This study explored whether supine hypertension in this setting is associated with orthostatic hypotension (OH), and if so, what mechanisms might underlie this association. Supine and upright blood pressures, hemodynamic responses to the Valsalva maneuver, baroreflex-cardiovagal gain, and plasma norepinephrine (NE) levels were measured in pure autonomic failure (PAF), multiple-system atrophy (MSA) with or without OH, and Parkinson’s disease (PD) with or without OH. Controls included age-matched, healthy volunteers and patients with essential hypertension or those referred for dysautonomia. Baroreflex-cardiovagal gain was calculated from the relation between the interbeat interval and systolic pressure during the Valsalva maneuver. PAF, MSA with OH, and PD with OH all featured supine hypertension, which was equivalent in severity to that in essential hypertension, regardless of fludrocortisone treatment. Among patients with PD or MSA, those with OH had higher mean arterial pressure during supine rest (109±3 mm Hg) than did those lacking OH (96±3 mm Hg, P =0.002). Baroreflex-cardiovagal gain and orthostatic increments in plasma NE levels were markedly decreased in all 3 groups with OH. Among patients with PD or MSA, those with OH had much lower mean baroreflex-cardiovagal gain (0.74±0.10 ms/mm Hg) than did those lacking OH (3.13±0.72 ms/mm Hg, P =0.0002). In PAF, supine hypertension is linked to both OH and low baroreflex-cardiovagal gain. The finding of lower plasma NE levels in patients with than without supine hypertension suggests involvement of pressor mechanisms independent of the sympathetic nervous system.

Hypertension and socioeconomic status.

Purpose of review The impact of socioeconomic status on hypertension is complicated and unclear. In this article, we review the findings of recently published studies pertaining to the association between socioeconomic status and hypertension. Specifically, we focus on several potentially modifiable modes of pathogenesis involved in this association, including education, occupation, and social environment. We also review several mechanisms through which the effects of socioeconomic status on hypertension may be mediated. Recent findings Several modifiable socioeconomic determinants, such as education and occupation, are associated with hypertension. Additional socioeconomic status markers such as urban or rural dwelling and individual, local or national economic conditions are also associated with hypertension, although these associations are complicated and at times somewhat contradictory. Possible explanations for this impact include awareness of hypertension prevention and control and better accessibility and adherence to medical treatment among higher socioeconomic status groups, as well as low birth weight and higher job strain among lower socioeconomic status groups. Summary Low socioeconomic status is associated with higher blood pressure. There is a need to develop and test culturally appropriate interventions to reduce the prevalence of hypertension among these populations to minimize the resultant cardiovascular morbidity and mortality.

Prevalence of Prehypertension and Associated Cardiovascular Risk Profiles Among Young Israeli Adults

Recently the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure introduced the term “prehypertension” for systolic blood pressure levels of 120 to 139 mm Hg and diastolic BP levels of 80 to 89 mm Hg. Little is known about the prevalence of this entity and the cardiovascular risk factors associated with it. We aimed to determine the prevalence of prehypertension and the cardiovascular risk factors associated with it in a large population-based sample of young Israeli adults. We studied 36 424 Israel Defense Forces employees during the years 1991 to 1999. Subjects completed a detailed questionnaire and underwent physical examination, and blood samples were drawn after a 14-hour fast. Prehypertension was defined as a systolic blood pressure of 120 to 139 mm Hg, and/or a diastolic blood pressure of 80 to 89 mm Hg. We calculated the age- and sex-specific prevalence of prehypertension and other cardiovascular risk factors associated with this condition. Prehypertension was observed among 50.6% of men and 35.9% of women. The prehypertensive group had higher levels of blood glucose, total cholesterol, low-density lipoprotein cholesterol, and triglycerides, higher body mass index, and lower levels of high-density lipoprotein cholesterol than did the normotensive group. Multivariate logistic regression analysis showed that body mass index was the strongest predictor of prehypertension among both males and females (odds ratio, 1.100; 95% CI, 1.078 to 1.122 and odds ratio, 1.152; 95% CI, 1.097 to 1.21, respectively, for every 1 kg/m2 increase). Our findings support the recommendation of lifestyle modification for prehypertensive patients. Further prospective studies are required to determine the role of pharmacotherapy in prehypertension.

Neurogenic orthostatic hypotension: a pathophysiological approach.

Orthostatic hypotension (OH) is defined as a persistent, consistent, orthostatic fall in systolic blood pressure of ≥20 mm Hg or diastolic pressure of ≥10 mm Hg by 3 minutes of standing up.1 Acute, unexpected, episodic falls in blood pressure while standing, as in neurocardiogenic syncope, do not satisfy criteria for OH. Medical records for ≈0.4% of all hospitalizations in the United States include OH as a diagnosis, and of these ≈17% have OH as the primary diagnosis.2 OH is associated with increased mortality in middle-aged adults3 and occurs especially commonly in the elderly, with a prevalence in the United States of ≈12%.4 The rate of hospitalization for nonacute OH increases exponentially with age.2 Therefore, as the US population ages, the prevalence of OH and the incidence of OH-related morbidity are likely to increase. OH can be an asymptomatic sign or manifest as symptoms that range from lightheadedness to loss of consciousness. In our experience, patients with OH do not typically present with recurrent syncope because they come to recognize and respond to premonitory symptoms such as generalized weakness, dizziness, fading vision, or lightheadedness that are relieved by lying down. Instead, OH patients often present with orthostatic intolerance and recurrent falls, an important risk factor for hip fracture and head trauma. Moreover, OH often occurs concurrently with supine hypertension, which can be severe.5 The combination of OH and supine hypertension poses a challenging clinical dilemma because the clinician must balance the risk of chronic high blood pressure versus the immediate risk of falls and consequent morbid events. Many causes of OH have been identified. The listing in Table 1⇓ stratifies these in terms of drugs, secondary nonneurogenic causes, secondary neurogenic causes, and primary neurogenic causes. Accordingly, the clinical approach to a patient with OH …

Diuretic induced hyponatraemia in elderly hypertensive women.

Diuretics are recommended as first-line antihypertensive treatment in elderly patients. Although attention is usually paid to prevent hypokalaemia with diuretic therapy, risk of hyponatraemia is often ignored. We performed this study to characterise hypertensive patients at increased risk to develop hyponatraemia. We reviewed charts of hypertensive patients hospitalised in Chaim Sheba Medical Center for hyponatraemia from 1990 to 1997. Patients with other causes of hyponatraemia were excluded. The General Practice Maccabi database was used to estimate age and sex distribution of patients prescribed diuretics for hypertension. We identified 180 hypertensive patients (149 F, 31 M; mean age 76.4 ± 9.2 years) hospitalised because of hyponatraemia. Across all age groups, odds ratio (OR) to develop hyponatraemia was three times higher for women vs men (OR 3.10, 95% confidence interval (CI): 2.07–4.67). One hundred and sixty-two patients (90%) were older than 65 years. Patients of both sexes older than 65 years were 10 times (and if they were older than 75 years 16 times) more likely to develop hyponatraemia than those younger than 65 years (OR 9.87, 95%, CI: 5.93–16.64). Most patients (74.5%) used a thiazide-based diuretic; only 10% used a low dose (<25 mg/day). In 37% of patients diuretics were used for more than 1 year before hyponatraemia developed. Diuretic-induced hyponatraemia may be insidious and appear even after prolonged diuretics use. Elderly women seem to be at particularly high risk. In this population diuretic use should be associated with close monitoring of sodium and potassium levels.

Neurocirculatory Abnormalities in Parkinson Disease With Orthostatic Hypotension: Independence From Levodopa Treatment

Patients with Parkinson disease often have orthostatic hypotension. Neurocirculatory abnormalities underlying orthostatic hypotension might reflect levodopa treatment. Sixty-six Parkinson disease patients (36 with orthostatic hypotension, 15 off and 21 on levodopa; 30 without orthostatic hypotension) had tests of reflexive cardiovagal gain (decrease in interbeat interval per unit decrease in systolic pressure during the Valsalva maneuver; orthostatic increase in heart rate per unit decrease in pressure); reflexive sympathoneural function (decrease in pressure during the Valsalva maneuver; orthostatic increment in plasma norepinephrine); and cardiac and extracardiac noradrenergic innervation (septal myocardial 6-[18F]fluorodopamine-derived radioactivity; supine plasma norepinephrine). Severity of orthostatic hypotension did not differ between the levodopa-untreated and levodopa-treated groups with Parkinson disease and orthostatic hypotension (−52±6 [SEM] versus −49±5 mm Hg systolic). The 2 groups had similarly low reflexive cardiovagal gain (0.84±0.23 versus 1.33±0.35 ms/mm Hg during Valsalva; 0.43±0.09 versus 0.27±0.06 bpm/mm Hg during orthostasis); and had similarly attenuated reflexive sympathoneural responses (97±29 versus 71±23 pg/mL during orthostasis; −82±10 versus −73±8 mm Hg during Valsalva). In patients off levodopa, plasma norepinephrine was lower in those with (193±19 pg/mL) than without (348±46 pg/mL) orthostatic hypotension. Low values for reflexive cardiovagal gain, sympathoneural responses, and noradrenergic innervation were strongly related to orthostatic hypotension. Parkinson disease with orthostatic hypotension features reflexive cardiovagal and sympathoneural failure and cardiac and partial extracardiac sympathetic denervation, independent of levodopa treatment.

Plasma levels of catechols and metanephrines in neurogenic orthostatic hypotension

Background: Neurogenic orthostatic hypotension (NOH) usually results from deficient release of the sympathetic neurotransmitter norepinephrine (NE) when the patient stands up. In pure autonomic failure (PAF) and PD with NOH, sympathetic denervation can explain this deficiency, whereas in multiple-system atrophy (MSA), deficient baroreflex regulation of sympathetic traffic to intact terminals probably causes the NOH. From the concept of a unitary sympathoadrenomedullary system, one might predict parallel sympathoneural and adrenomedullary abnormalities in NOH. Objective: To test the concept of parallel sympathoneural and adrenomedullary abnormalities in NOH by simultaneous measurements of plasma levels of catechols and metanephrines. Methods: Antecubital venous blood drawn via an indwelling cannula with the subject supine was assayed for catecholamines (NE, epinephrine [EPI]), dihydroxyphenylglycol (DHPG), and metanephrines (normetanephrine [NMN] and metanephrine [MN]) in patients with PAF, PD + NOH, or MSA + NOH. Control subjects had PD lacking NOH or were normal volunteers at least 35 years old. Cardiac sympathetic innervation was assessed by 6-[18F]fluorodopamine PET scanning. Results: The three NOH groups differed clearly in patterns of plasma catechols and metanephrines. The PAF group had low NE, DHPG, NMN, EPI, and MN levels, the group with MSA + NOH had generally normal levels, and the PD + NOH group low NMN levels and low DHPG levels for given NE levels but normal mean NE, EPI, and MN levels. All patients with PAF or PD + NOH had markedly decreased 6-[18F]fluorodopamine-derived radioactivity throughout the left ventricular myocardium; all patients with MSA + NOH had normal radioactivity. Conclusions: PAF involves generalized loss of sympathoadrenomedullary cells, MSA + NOH intact sympathoadrenomedullary cells, and PD + NOH intact adrenomedullary cells but organ-selective sympathetic denervation, especially in the heart.