David G. Edwards

Arterial elastance and wave reflection augmentation of systolic blood pressure : deleterious effects and implications for therapy

Systolic and pulse blood pressures are stronger predictors of stroke, coronary heart disease, myocardial infarction, heart failure, end-stage renal disease, and cardiovascular mortality than diastolic pressure. Furthermore, diastolic pressure is inversely related to coronary heart disease and cardiovascular mortality. Increased elastance (or stiffness, inverse of compliance) of the central elastic arteries is the primary cause of increased systolic and pulse pressure with advancing age and in patients with cardiovascular disease, including hypertension, and is due to degeneration and hyperplasia of the arterial wall; diastolic pressure decreases as arterial elastance increases. As elastance increases, transmission velocity of both forward and backward (or reflected) traveling waves increases, which causes the reflected wave to arrive earlier in the central aorta and augments pressure in late systole. These changes in arterial wall properties cause an increase in left ventricular afterload and myocardial oxygen consumption and a decrease in myocardial perfusion pressure, which may induce an imbalance in the supply-demand ratio, especially in hypertrophied hearts with coronary artery disease. Also, an increase in systolic pressure increases arterial wall circumferential stress, which promotes fatigue and development of athersclerosis. Vasodilator drugs have little direct active effect on large elastic arteries but can markedly reduce wave reflection amplitude and augmentation index by decreasing elastance of the muscular arteries and reducing pulse wave velocity of the reflected wave from the periphery to the heart. This decrease in intensity (or amplitude) and increase in travel time (or delay) of the reflected wave causes a generalized decrease in systolic pressure and arterial wall stress and an increase in ascending aortic flow during the deceleration phase. The decrease in systolic pressure brought about by this mechanism is grossly underestimated when systolic pressure is measured in the brachial artery.

Exaggerated sympathetic and pressor responses to handgrip exercise in older hypertensive humans: role of the muscle metaboreflex

Recent animal studies have reported that exercise pressor reflex (EPR)-mediated increases in blood pressure are exaggerated in hypertensive (HTN) rodents. Whether these findings can be extended to human hypertension remains unclear. Mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and venous metabolites were measured in normotensive (NTN; n = 23; 60 ± 1 yr) and HTN (n = 15; 63 ± 1 yr) subjects at baseline, and during static handgrip at 30 and 40% maximal voluntary contraction (MVC) followed by a period of postexercise ischemia (PEI) to isolate the metabolic component of the EPR. Changes in MAP from baseline were augmented in HTN subjects during both 30 and 40% MVC handgrip (P < 0.05 for both), and these group differences were maintained during PEI (30% PEI trial: Δ15 ± 2 NTN vs. Δ19 ± 2 HTN mmHg; 40% PEI trial: Δ16 ± 1 NTN vs. Δ23 ± 2 HTN mmHg; P < 0.05 for both). Similarly, in HTN subjects, MSNA burst frequency was greater during 30 and 40% MVC handgrip (P < 0.05 for both), and these differences were maintained during PEI [30% PEI trial: 35 ± 2 (NTN) vs. 44 ± 2 (HTN) bursts/min; 40% PEI trial: 36 ± 2 (NTN) vs. 48 ± 2 (HTN) bursts/min; P < 0.05 for both]. No group differences in metabolites were observed. MAP and MSNA responses to a cold pressor test were not different between groups, suggesting no group differences in generalized sympathetic responsiveness. In summary, compared with NTN subjects, HTN adults exhibit exaggerated sympathetic and pressor responses to handgrip exercise that are maintained during PEI, indicating that activation of the metabolic component of the EPR is augmented in older HTN humans.

Exercise Following Heart Transplantation

During the past 2 decades, heart transplantation has evolved from an experimental procedure to an accepted life-extending therapy for patients with end-stage heart failure. However, with dramatic improvements in organ preservation, surgery and immunosuppressive drug management, short term survival is no longer the pivotal issue for most heart transplant recipients (HTR). Rather, a return to functional lifestyle with good quality of life is now the desired procedural outcome. To achieve this outcome, aggressive exercise rehabilitation is essential.HTR present unique exercise challenges. Preoperatively, most of these patients had chronic debilitating cardiac illness. Many HTR have had prolonged pretransplantation hospitalisation for inotropic support or a ventricular assist device. Decrements in peak oxygen consumption (V̇O2peak) and related cardiovascular parameters regress approximately 26% within the first 1 to 3 weeks of sustained bed rest. Consequently, extremely poor aerobic capacity and cardiac cachexia are not unusual occurrences in HTR who have required mechanical support or been confined to bed rest. Moreover, HTR must also contend with de novo exercise challenges conferred by chronic cardiac denervation and the multiple sequelae resulting from immunosuppression therapy.There is ample evidence that both endurance and resistance training are well tolerated in HTR. Moreover, there is growing clinical consensus that specific endurance and resistance training regimens in HTR can be efficacious adjunctive therapies in the prevention of immunosuppression-induced adverse effects and the reversal of pathophysiological consequences associated with cardiac denervation and antecedent heart failure. For example, some HTR who remain compliant during strenuous long term endurance training programmes achieve peak heart rate and V̇O2peak values late after transplantation that approach age-matched norms (up to approximately 95% of predicted). These benefits are not seen in HTR who do not participate in structured endurance exercise training. Rather, peak heart rate and V̇O2peak values in untrained HTR remain approximately 60 to 70% of predicted indefinitely. However, the mechanisms responsible for improved peak heart rate, V̇O2peak and total exercise time are not completely understood and require further investigation. Recent studies have also demonstrated that resistance exercise training may be an effective countermeasure for corticosteroid-induced osteoporosis and skeletal muscle myopathy. HTR who participate in specific resistance training programmes successfully restore bone mineral density (BMD) in both the axial and appendicular skeleton to pretransplantation levels, increase lean mass to levels greater than pretransplantation, and reduce body fat. In contrast, HTR who do not participate in resistance training lose approximately 15% BMD from the lumbar spine early in the postoperative period and experience further gradual reductions in BMD and muscle mass late after transplantation.

High Dietary Sodium Intake Impairs Endothelium-Dependent Dilation in Healthy Salt-Resistant Humans

Background: Excess dietary sodium has been linked to the development of hypertension and other cardiovascular diseases. In humans, the effects of sodium consumption on endothelial function have not been separated from the effects on blood pressure. The present study was designed to determine if dietary sodium intake affected endothelium-dependent dilation (EDD) independently of changes in blood pressure. Method: Fourteen healthy salt-resistant adults were studied (9M, 5F; age 33 ± 2.4 years) in a controlled feeding study. After a baseline run-in diet, participants were randomized to a 7-day high-sodium (300–350 mmol/day) and 7-day low-sodium (20 mmol/day) diet. Salt resistance, defined as a 5 mmHg or less change in a 24-h mean arterial pressure, was individually assessed while on the low-sodium and high-sodium diets and confirmed in the participants undergoing study (low-sodium: 85 ± 1 mmHg; high-sodium: 85 ± 2 mmHg). EDD was determined in each participant via brachial artery flow-mediated dilation on the last day of each diet. Results: Sodium excretion increased during the high-sodium diet (P < 0.01). EDD was reduced on the high-sodium diet (low: 10.3 ± 0.9%, high: 7.3 ± 0.7%; P < 0.05). The high-sodium diet significantly suppressed plasma renin activity (PRA), plasma angiotensin II, and aldosterone (P < 0.05). Conclusion: These data demonstrate that excess salt intake in humans impairs endothelium-dependent dilation independently of changes in blood pressure.

Dietary Sodium and Health: More Than Just Blood Pressure

Sodium is essential for cellular homeostasis and physiological function. Excess dietary sodium has been linked to elevations in blood pressure (BP). Salt sensitivity of BP varies widely, but certain subgroups tend to be more salt sensitive. The mechanisms underlying sodium-induced increases in BP are not completely understood but may involve alterations in renal function, fluid volume, fluid-regulatory hormones, the vasculature, cardiac function, and the autonomic nervous system. Recent pre-clinical and clinical data support that even in the absence of an increase in BP, excess dietary sodium can adversely affect target organs, including the blood vessels, heart, kidneys, and brain. In this review, the investigators review these issues and the epidemiological research relating dietary sodium to BP and cardiovascular health outcomes, addressing recent controversies. They also provide information and strategies for reducing dietary sodium.

Dietary sodium loading impairs microvascular function independent of blood pressure in humans: role of oxidative stress.

•  Pre‐clinical studies suggest that acute dietary sodium loading impairs vascular function without alterations in blood pressure; however, human data are lacking. •  In this study, normotensive salt‐resistant adults participated in a controlled feeding study, in which they consumed a low‐sodium diet for 1 week and a high‐sodium diet for 1 week, in random order. During each diet, microvascular function was assessed. •  Here we report the novel finding of sodium‐induced impairments in microvascular function independent of blood pressure in healthy adults. •  We additionally show that function was improved by the administration of the anti‐oxidant ascorbic acid. •  Therefore, in addition to its well‐known importance for blood pressure control, lowering sodium intake may have beneficial effects on microvascular function in healthy normotensive adults.

Exaggerated exercise pressor reflex in adults with moderately elevated systolic blood pressure: role of purinergic receptors

The neurocirculatory responses to exercise are exaggerated in hypertension, increasing cardiovascular risk, yet the mechanisms remain incompletely understood. The aim of this study was to examine the in vitro effectiveness of pyridoxal-5-phosphate as a purinergic (P2) receptor antagonist in isolated murine dorsal root ganglia (DRG) neurons and the in vivo contribution of P2 receptors to the neurocirculatory responses to exercise in older adults with moderately elevated systolic blood pressure (BP). In vitro, pyridoxal-5-phosphate attenuated the ATP-induced increases in [Ca(2+)](i) (73 ± 15 vs. 11 ± 3 nM; P < 0.05). In vivo, muscle sympathetic nerve activity (MSNA; peroneal microneurography) and arterial BP (Finometer) were assessed during exercise pressor reflex activation (static handgrip followed by postexercise ischemia; PEI) during a control trial (normal saline) and localized P2 receptor blockade (pyridoxal-5-phosphate). Compared with normotensive adults (63 ± 2 yr, 117 ± 2/70 ± 2 mmHg), adults with moderately elevated systolic BP (65 ± 1 yr, 138 ± 5/79 ± 3 mmHg) demonstrated greater increases in MSNA and BP during handgrip and PEI. Compared with the control trial, local antagonism of P2 receptors during PEI partially attenuated MSNA (39 ± 4 vs. 34 ± 5 bursts/min; P < 0.05) in adults with moderately elevated systolic BP. In conclusion, these data demonstrate pyridoxal-5-phosphate is an effective P2 receptor antagonist in isolated DRG neurons, which are of particular relevance to the exercise pressor reflex. Furthermore, these findings indicate that exercise pressor reflex function is exaggerated in older adults with moderately elevated systolic BP and further suggest a modest role of purinergic receptors in evoking the abnormally large reflex-mediated increases in sympathetic activity during exercise in this clinical population.

Ascorbic acid or l-arginine improves cutaneous microvascular function in chronic kidney disease

We sought to determine whether oxidative stress or a relative deficit of l-arginine plays a role in reducing cutaneous vasodilation in response to local heating in chronic kidney disease (CKD). Eight patients with stage 3-4 CKD and eight age- and sex-matched healthy control (HC) subjects were instrumented with four microdialysis (MD) fibers for the local delivery of 1) Ringers solution (R), 2) 20 mM ascorbic acid (AA), 3) 10 mM l-arginine (l-Arg), and 4) 10 mM N(G)-nitro-l-arginine methyl ester (l-NAME). Red blood cell (RBC) flux was measured via laser Doppler flowmetry. A standardized nonpainful local heating protocol (42°C) was used. Cutaneous vascular conductance (CVC) was calculated as RBC flux/MAP and all data were expressed as a percentage of the maximum CVC at each site (28 mM sodium nitroprusside, T(loc) = 43°C). The plateau %CVC(max) was attenuated in CKD (CKD: 76 ± 4 vs. HC: 91 ± 2%CVC(max); P < 0.05) and the NO contribution to the plateau was lower in CKD (CKD: 39 ± 7, HC: 54 ± 5; P < 0.05). The plateau %CVC(max) in the CKD group was significantly greater at the AA and l-Arg sites compared with R (AA: 89 ± 2; l-Arg: 90 ± 1; R: 76 ± 4; P < 0.05) and did not differ from HC. Initial peak %CVC(max) was also significantly attenuated at the R and l-Arg sites in CKD (P < 0.05) but did not differ at the AA site. These results suggest that cutaneous microvascular function is impaired in stage 3-4 CKD and that oxidative stress and a deficit of l-arginine play a role in this impairment.

Peripheral Vascular Dysfunction in Chronic Kidney Disease

There is an increased prevalence of cardiovascular disease- (CVD-) related mortality in patients with chronic kidney disease (CKD). Endothelial dysfunction is a primary event in the development of atherosclerosis and hypertension and likely contributes to the elevated cardiovascular risk in CKD. Endothelial dysfunction has been shown to occur in the peripheral vasculature of patients with both severe and moderate CKD. Mechanisms include oxidative stress, L-arginine deficiency, and elevated plasma levels of ADMA. Interventions designed to restore vascular function in patients with CKD have shown mixed results. Evidence from cell culture studies suggest that the accumulation of uremic toxins inhibits L-arginine transport and reduces nitric oxide production. The results of these studies suggest that endothelial dysfunction may become less reversible with advancing kidney disease. The purpose of this paper is to present the current literature pertaining to potential mechanisms of peripheral vascular dysfunction in chronic kidney disease and to identify possible targets for treatment.

Vascular effects of sildenafil in hypertensive cardiac transplant recipients

BACKGROUND Sildenafil is commonly used in the treatment of erectile dysfunction in hypertensive male cardiac transplant recipients (CTR); however, little is known about the vascular effects of sildenafil in these patients. METHODS Central and peripheral arterial blood pressure (BP), heart rate, and brachial artery reactivity were determined in 15 hypertensive male CTR before and after oral sildenafil (50 mg) administration. RESULTS Sildenafil improved brachial and aortic systolic BP, pulse pressure, aortic augmentation index, left ventricular tension time index, travel time of the reflected aortic pressure wave, and brachial artery reactivity (P <.01 for each comparison). No patient became hypotensive with sildenafil despite continuation of usual antihypertensive medications. CONCLUSIONS Sildenafil (50 mg) is well tolerated in hypertensive CTR and improves BP, aortic augmentation index, and endothelial function. By decreasing the amplitude of the reflected pressure wave and delaying its return to the heart, sildenafil reduces left ventricular afterload and systolic stress.