Abstract-It is uncertain whether chronic ␤-adrenoreceptor (␤-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 ⅐ kg Ϫ1 ⅐ d Ϫ1 ) 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 ␤-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.

Abstract-The transition from compensated to decompensated left ventricular hypertrophy (LVH) in hypertension involvesexcessive ␤-adrenoreceptor (␤-AR) stimulation. To explore whether aldosterone receptor activation contributes toward ␤-AR-induced left ventricular (LV) decompensation in hypertensive LVH, the effect of spironolactone (SPIRO; 80 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) on LV cavity dimensions, function, and chamber remodeling mechanisms was evaluated in spontaneously hypertensive rats (SHR) receiving a low dose of the ␤-AR agonist isoproterenol (ISO) at 0.02 to 0.04 mg ⅐ kg Ϫ1 ⅐ 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 loadindependent effects, may be useful in preventing the transition from compensated LVH to dilatation and pump dysfunction mediated by chronic ␤-AR activation. Key Words: remodeling Ⅲ collagen Ⅲ sympathetic nervous system Ⅲ aldosterone T here is substantial evidence to indicate that in hypertension, the transition from compensated left ventricular hypertrophy (LVH) to heart failure involves chronic ␤-adrenoreceptor (␤-AR) activation. Indeed, in LVH, increased circulating norepinephrine (NE) concentrations 1,2 as well as myocardial NE release 3 precede heart failure. Moreover, in hypertensive LVH, prolonged ␤-AR agonist administration 4 or genetically enhanced sympathetic effects 5 increase the susceptibility to decompensation without blood pressure (BP) changes. Despite data to support a notion that ␤-AR activation induces the transition to heart failure in hypertensive LVH, whether the renin-angiotensin-aldosterone system (RAAS) mediates this effect is unknown. This question arises because ␤-AR stimulation provokes the RAAS, ␤-AR blockers inhibit the RAAS in hypertension, 6 and aldosterone receptor antagonists attenuate left ventricular (LV) dilatation. 7-9 Because ␤-AR blockers have a limited impact on LVH 10 and increase the chance of new onset diabetes mellitus, 11 identification of downstream targets from ␤-ARs responsible for LV decompensation that modify LVH but not metabolic pathways is desirable. Therefore, in the present stud...

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.

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.