Demetri G. A. Veliotes

β-Adrenergic Activation Initiates Chamber Dilatation in Concentric Hypertrophy

Abstract—It is uncertain whether chronic &bgr;-adrenoreceptor (&bgr;-AR)–activation in hypertension could initiate the progression from compensated left ventricular (LV) hypertrophy to pump dysfunction. It is also uncertain if this effect is through adverse LV remodeling (chamber dilatation with wall thinning and pump dysfunction) or intrinsic myocardial contractile dysfunction. We evaluated the effect of 5 months of isoprenaline (0.02 mg · kg−1 · d−1) on hemodynamics, LV wall thickness, cavity size, and interstitial characteristics in spontaneously hypertensive rats (SHR) with compensated LV hypertrophy. In the absence of myocyte necrosis, changes in volume preload, pressure afterload, and heart rate or decreases in baseline systolic myocardial elastance (load independent measure of intrinsic myocardial contractility), ISO produced a right shift in LV diastolic pressure–volume (P-V) relations (chamber dilatation), a decrease in LV wall thickness despite a further increase in LV weight in SHR, LV pump dysfunction (right shift in LV systolic P-V relations), and deleterious interstitial remodeling (increments in total and noncrosslinked myocardial collagen concentrations). The isoprenaline-induced LV geometric, chamber performance, and interstitial changes were similar to alterations noted during decompensation in older SHR. In summary, in the absence of tissue necrosis and baseline intrinsic myocardial contractile dysfunction, chronic &bgr;-AR activation induces interstitial and chamber remodeling and, hence, pump dysfunction. These data suggest that chronic sympathetic activation initiates the progression from compensated concentric LV hypertrophy in hypertension to cardiac dysfunction primarily through deleterious cardiac remodeling rather than intrinsic myocardial contractile dysfunction.

Aldosterone Receptor Blockade Prevents the Transition to Cardiac Pump Dysfunction Induced by β-Adrenoreceptor Activation

The transition from compensated to decompensated left ventricular hypertrophy (LVH) in hypertension involves excessive &bgr;-adrenoreceptor (&bgr;-AR) stimulation. To explore whether aldosterone receptor activation contributes toward &bgr;-AR–induced left ventricular (LV) decompensation in hypertensive LVH, the effect of spironolactone (SPIRO; 80 mg · kg−1 · day−1) on LV cavity dimensions, function, and chamber remodeling mechanisms was evaluated in spontaneously hypertensive rats (SHR) receiving a low dose of the &bgr;-AR agonist isoproterenol (ISO) at 0.02 to 0.04 mg · kg−1 · day for 4.5 months. ISO administered to SHR resulted in an increased 24-hour urinary aldosterone excretion and LV cavity dimensions, a right shift in LV diastolic pressure-volume relations, a decreased LV relative wall thickness, and increased total, noncross-linked, type I and type III myocardial collagen concentrations without further enhancing increased myocardial norepinephrine (NE) release. ISO reduced pump function without modifying intrinsic myocardial systolic function or inducing further myocyte necrosis or apoptosis. ISO only increased LV cavity volumes after prolonged periods of administration. SPIRO abolished ISO-induced chamber dilatation, wall thinning, and pump dysfunction and reduced total, noncross-linked, type I and type III myocardial collagen concentrations but failed to modify blood pressure, volume preloads, intrinsic myocardial systolic function, myocardial NE release, or the degree of necrosis or apoptosis. In conclusion, these results suggest that aldosterone receptor blockade, through load-independent effects, may be useful in preventing the transition from compensated LVH to dilatation and pump dysfunction mediated by chronic &bgr;-AR activation.

Aldosterone-to-renin ratio and the relationship between urinary salt excretion and blood pressure in a community of African ancestry.

BACKGROUND Although aldosterone influences the effect of salt intake on blood pressure (BP), the extent to which this occurs at a population level is uncertain. We therefore aimed to determine, at a community level in a group of African descent, whether in the absence of primary aldosteronism, the relationship between salt intake and BP is modified by circulating aldosterone, and the extent to which this occurs. METHODS In 575 participants of African ancestry (age >16 years), we assessed whether aldosterone-to-renin ratio (ARR) is associated with the relationship between urinary sodium (Na(+))-to-potassium (K(+)) ratio (urinary Na(+)/K(+)) (from 24-h urine samples), an index of salt intake, and BP. RESULTS With adjustments for confounders, interactions between ARR and urinary Na(+)/K(+) were independently associated with systolic BP (SBP) (P < 0.0001), an effect that was accounted for by interactions between serum aldosterone concentrations and urinary Na(+)/K(+) (P < 0.0001), but not between plasma renin concentrations and urinary Na(+)/K(+) (P = 0.52). The interaction between ARR and urinary Na(+)/K(+) translated into a marked difference in the relationship between urinary Na(+)/K(+) and SBP in participants above compared to below the median for ARR (effect of 1 s.d. increase in urinary Na(+)/K(+) on SBP: ARR > median = 4.2 ± 0.6 mm Hg; ARR < median = 1.2 ± 0.4 mm Hg, P < 0.0001). In addition, participants with urinary Na(+)/K(+) above the median had higher multivariate-adjusted SBP (P < 0.001) only if ARR was also above the median. CONCLUSIONS In groups of African descent, in the absence of primary aldosteronism, an increased aldosterone concentration relative to renin modifies a substantial proportion of the relationship between urinary Na(+)/K(+) and BP at a community level.

The accuracy of subjective clinical assessments of the patellar reflex.

Introduction: Measurement precision and accuracy of spinal reflexes plays an essential role in the clinical neurological examination. Reflexes are conventionally assessed either electromyographically or with rating scales. In this study we compared objective kinematic T‐reflex and subjective assessments of patellar reflexes in 15 normal healthy subjects. Methods: Randomized recordings of objectively quantified reflexes were rated by 24 medical students, 16 general practitioners, and 12 neurologists, using a visual analog scale and the NINDS and Mayo clinical reflex scales. Results: For all groups of raters, Spearman rank correlations showed that subjective ratings significantly correlated with change of knee angle (R2 = 0.72–0.79, P < 0.001) and maximum T‐reflex amplitude (R2 = 0.84–0.94, P < 0.001). Stepwise multiple regression analysis showed that all subjective rater groups relied most on the change of knee angle to assess the reflex. Conclusions: These findings show that subjective assessments of reflexes using reflex rating scales correlate strongly with biomechanical and electromyographic measures. Muscle Nerve, 2013

Impact of Aldosterone Receptor Blockade on the Deleterious Cardiac Effects of Adrenergic Activation in Hypertensive Rats

Although in hypertension β-adrenoreceptor activation promotes the transition from cardiac hypertrophy to pump dysfunction, the use of β-blockers is controversial. As adrenergic activation may mediate adverse effects on the heart through the renin-angiotensin-aldosterone system, we evaluated the effects of the aldosterone receptor blocker, spironolactone (SPIRO), on isoproterenol (ISO)-induced changes in left ventricular cavity size and pump function and the determinants thereof in spontaneously hypertensive rats (SHR). ISO administered for 4.5 months resulted in increases in left ventricular dimensions and a decrease in pump function in SHR but not in normotensive rats, changes that, without affecting blood pressure, were abolished by SPIRO. In SHR, 4-5 days of ISO increased myocardial matrix metalloproteinase-2 activity, which was associated with matrix metalloproteinase-2 but not tissue inhibitor of MMP expression; persisted at 4.5 months; and was prevented by SPIRO. Moreover, after 4.5 months, ISO increased non-cross-linked myocardial collagen concentrations in SHR, which was abolished by SPIRO. Although after 4.5 months, ISO was not associated with increased cardiomyocyte apoptosis, an early (4-5 days) ISO-induced apoptotic effect was noted, which was prevented by SPIRO. Hence, aldosterone receptor blockade may be sufficient to prevent those adverse effects of β-adrenoreceptor activation responsible for the transition from concentric cardiac hypertrophy to pump dysfunction in hypertension.

The agreement between reaction-board measurements and kinematic estimation of adult male human whole body centre of mass location during running

The segmental method for estimating the centre of mass (COM) location of the human body has been widely used since 1889. How closely this method agrees with direct measurements of the location and movement of COM during activity however, remains unclear. To test this, a novel reaction-board utilizing life sized projections of human subjects is designed for measuring COM location. Agreement between the segmental method and the more direct reaction-board measurement method is then assessed. Our data demonstrate that the reaction-board system has a physical maximum error of 1.28 cm and 1.95 cm for locating COM along the vertical (board length) and horizontal (board width) axes respectively, and show that the reaction-board and segmental methods agree to within limits of 6.0 cm for the location of COM and to within 5.6 cm for the movement of COM between two points, in recumbent individuals. Applied to running, the segmental method agrees to within limits of 4.8 cm for oscillation of COM and 5.3 cm for stride median COM height. The segmental method agrees with a more direct technique of known accuracy, the reaction-board method, most closely when measuring averaged oscillation over repeated strides, where it displays a measurement error range of 5.1 cm to 0.1 cm in runners.

Kinematic and kinetic analysis of the inter- and intra-applicator assessment of the Babinski reflex

AIMS OF THE STUDY The first aim was to quantify variability in the mechanical technique used by neurologists to elicit the Babinski reflex. The second aim of the study was to assess if the mechanical technique is an important determinant of the subsequent reflex response. MATERIALS AND METHODS In this study, twelve neurologists elicited the Babinski reflex five times on the same foot of the same participant using a special reflex hammer which recorded the force and duration of the stroke. Hallux movement, tibialis anterior maximum EMG amplitude and pain felt by the participant for each stroke were recorded. RESULTS A large inter- and intra-applicator variability was shown amongst the neurologists. The change in hallux angle was significantly correlated with the duration of the stroke (R(2)=0.18, P<0.01), maximum (R(2)=0.14, P=0.01) and average (R(2)=0.17, P<0.01) force used to elicit the reflex. No correlations were shown between the hammer forces and duration and the maximum amplitude of the tibialis anterior. Significant correlations were shown between the pain score and the maximum (R(2)=0.15, P<0.01) and average (R(2)=0.17, P=0.001) force used to elicit the Babinski reflex. CONCLUSION These results indicate that there was substantial variation when performing the Babinski reflex test within and between neurologists which could lead to differences in the resultant reflex and therefore may affect subsequent diagnoses.

Development, Validation, and Field-Testing of an Instrument for Clinical Assessment of HIV-Associated Neuropathy and Neuropathic Pain in Resource-Restricted and Large Population Study Settings

HIV-associated sensory peripheral neuropathy (HIV-SN) afflicts approximately 50% of patients on antiretroviral therapy, and is associated with significant neuropathic pain. Simple accurate diagnostic instruments are required for clinical research and daily practice in both high- and low-resource setting. A 4-item clinical tool (CHANT: Clinical HIV-associated Neuropathy Tool) assessing symptoms (pain and numbness) and signs (ankle reflexes and vibration sense) was developed by selecting and combining the most accurate measurands from a deep phenotyping study of HIV positive people (Pain In Neuropathy Study–HIV-PINS). CHANT was alpha-tested in silico against the HIV-PINS dataset and then clinically validated and field-tested in HIV-positive cohorts in London, UK and Johannesburg, South Africa. The Utah Early Neuropathy Score (UENS) was used as the reference standard in both settings. In a second step, neuropathic pain in the presence of HIV-SN was assessed using the Douleur Neuropathique en 4 Questions (DN4)-interview and a body map. CHANT achieved high accuracy on alpha-testing with sensitivity and specificity of 82% and 90%, respectively. In 30 patients in London, CHANT diagnosed 43.3% (13/30) HIV-SN (66.7% with neuropathic pain); sensitivity = 100%, specificity = 85%, and likelihood ratio = 6.7 versus UENS, internal consistency = 0.88 (Cronbach alpha), average item-total correlation = 0.73 (Spearman’s Rho), and inter-tester concordance > 0.93 (Spearman’s Rho). In 50 patients in Johannesburg, CHANT diagnosed 66% (33/50) HIV-SN (78.8% neuropathic pain); sensitivity = 74.4%, specificity = 85.7%, and likelihood ratio = 5.29 versus UENS. A positive CHANT score markedly increased of pre- to post-test clinical certainty of HIV-SN from 43% to 83% in London, and from 66% to 92% in Johannesburg. In conclusion, a combination of four easily and quickly assessed clinical items can be used to accurately diagnose HIV-SN. DN4-interview used in the context of bilateral feet pain can be used to identify those with neuropathic pain.

The Interrater Reliability of Subjective Assessments of the Babinski Reflex

ABSTRACT The Babinski reflex is a clinical diagnostic tool; however, the interrater reliability of this tool is currently greatly contested. A comparison between rater groups with objective measurements of the Babinski reflex was therefore conducted. Fifteen recorded Babinski reflexes were assessed by 12 neurologists and 12 medical students as being either pathological or nonpathological. Kinematic and electromyographic variables were collected and used to assess which aspects of the Babinski reflex predict classification. Substantial interrater agreement within the neurologist and student groups (κ = .72 and .67, respectively) was shown; however, there were some differing aspects between what neurologists and students used to assess the reflex as determined by objective kinematic measurements.