Status of Early-Career Academic Cardiology: A Global Perspective.

Early-career academic cardiologists, who many believe are an important component of the future of cardiovascular care, face myriad challenges. The Early Career Section Academic Working Group of the American College of Cardiology, with senior leadership support, assessed the progress of this cohort from 2013 to 2016 with a global perspective. Data consisted of accessing National Heart, Lung, and Blood Institute public information, data from the American Heart Association and international organizations, and a membership-wide survey.

Challenges facing early career academic cardiologists.

Early career academic cardiologists currently face unprecedented challenges that threaten a highly valued career path. A team consisting of early career professionals and senior leadership members of American College of Cardiology completed this white paper to inform the cardiovascular medicine profession regarding the plight of early career cardiologists and to suggest possible solutions. This paper includes: 1) definition of categories of early career academic cardiologists; 2) general challenges to all categories and specific challenges to each category; 3) obstacles as identified by a survey of current early career members of the American College of Cardiology; 4) major reasons for the failure of physician-scientists to receive funding from National Institute of Health/National Heart Lung and Blood Institute career development grants; 5) potential solutions; and 6) a call to action with specific recommendations.

The mammalian exercise pressor reflex in health and disease.

The exercise pressor reflex (a peripheral neural reflex originating in skeletal muscle) contributes significantly to the regulation of the cardiovascular system during exercise. Exercise-induced signals that comprise the afferent arm of the reflex are generated by activation of mechanically (muscle mechanoreflex) and chemically sensitive (muscle metaboreflex) skeletal muscle receptors. Activation of these receptors and their associated afferent fibres reflexively adjusts sympathetic and parasympathetic nerve activity during exercise.

Mechanoreflex mediates the exaggerated exercise pressor reflex in heart failure.

Background: In heart failure, exercise elicits excessive increases in mean arterial pressure (MAP) and heart rate (HR). Using a novel rat model, we previously demonstrated that this exaggerated cardiovascular responsiveness is mediated by an overactive exercise pressor reflex (EPR). Although we previously determined that abnormalities in the group IV afferent neuron population (associated with the metabolic component of the reflex) initiate the development of the exaggerated EPR in heart failure, these fibers do not mediate the enhanced circulatory responses to exercise.

The capsaicin-sensitive afferent neuron in skeletal muscle is abnormal in heart failure.

Background: In heart failure, the cardiovascular response to activation of the skeletal muscle exercise pressor reflex (EPR) is exaggerated. Group IV afferent neurons, primarily stimulated by the metabolic by-products of skeletal muscle work, contribute significantly to the EPR. Therefore, it was postulated that alterations in the activity of group IV neurons contribute to the EPR dysfunction manifest in heart failure.

Independent modification of baroreceptor and exercise pressor reflex function by nitric oxide in nucleus tractus solitarius.

It has been suggested that nitric oxide (NO) is a key modulator of both baroreceptor and exercise pressor reflex afferent signals processed within the nucleus tractus solitarius (NTS). However, studies investigating the independent effects of NO within the NTS on the function of each reflex have produced inconsistent results. To address these concerns, the effects of microdialyzing 10 mM L-arginine, an NO precursor, and 20 mM N(G)-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, into the NTS on baroreceptor and exercise pressor reflex function were examined in 17 anesthetized cats.

Role of the exercise pressor reflex in rats with dilated cardiomyopathy.

Background: In heart failure, there is a sympathetically mediated hyperkinetic cardiovascular response to exercise that limits tolerance to physical activity. Alterations in skeletal muscle morphology and metabolism have led to the hypothesis that the exercise pressor reflex (EPR) becomes hyperactive after the development of cardiomyopathy and contributes to the exaggerated circulatory response elicited.

Methods And Results: To test this hypothesis, Sprague-Dawley rats were divided into the following groups: control, sham, and dilated cardiomyopathy (DCM, induced by ischemic injury).

Nitric oxide synthase (NOS) coexists with activated neurons by skeletal muscle contraction in the brainstem of cats.

Contraction of skeletal muscle evokes increases in arterial blood pressure and heart rate. Some regions of the brainstem have been implicated for expression of the cardiovascular responses to muscle contraction. Previous studies have reported that static muscle contraction induced c-Fos protein in the nucleus of tractus solitarii (NTS), lateral reticular nucleus (LRN), lateral tegmental field (FTL), subretrofacial nucleus (SRF), A1 region and periaqueductal gray (PAG) of the brainstem.

Effect of nitric oxide on release of glutamate in the subretrofacial nucleus (SRF) during the exercise pressor reflex in cats.

The subretrofacial nucleus (SRF) has been known to play a crucial role in the expression of the exercise pressor reflex. Previously, we have reported that the release of glutamate (Glu) in the SRF was increased during muscle contraction in anesthetized cats. In this study, static muscle contraction of the triceps surae for 4 min was induced by electrical stimulation of L7 and S1 ventral roots.

Electrically induced static exercise elicits a pressor response in the decerebrate rat.

1. The purpose of this investigation was to determine if activation of the exercise pressor reflex in the decerebrate rat induced circulatory responses comparable to those reported in large mammalian species. 2.

NO formation in nucleus tractus solitarii attenuates pressor response evoked by skeletal muscle afferents.

We have previously shown that static muscle contraction induces the expression of c-Fos protein in neurons of the nucleus tractus solitarii (NTS) and that some of these cells were codistributed with neuronal NADPH-diaphorase [nitric oxide (NO) synthase]-positive fibers. In the present study, we sought to determine the role of NO in the NTS in mediating the cardiovascular responses elicited by skeletal muscle afferent fibers. Static contraction of the triceps surae muscle was induced by electrical stimulation of the L7 and S1 ventral roots in anesthetized cats.

Activation of skeletal muscle afferents evokes release of glutamate in the subretrofacial nucleus (SRF) of cats.

The subretrofacial nucleus (SRF) is a region of the rostral ventrolateral medulla known to play a crucial role in sympathoexcitation. SRF neurons send direct projections to the intermediolateral cell columns of the spinal cord where they form synaptic contact with preganglionic sympathetic motor neurons. Activation of this neural pathway increases sympathetic outflow to the heart and blood vessels affecting cardiac function and vasomotor tone.

Reflex cardiovascular responses evoked by selective activation of skeletal muscle ergoreceptors.

It is well known that the exercise pressor reflex (EPR) is mediated by group III and IV skeletal muscle afferent fibers, which exhibit unique discharge responses to mechanical and chemical stimuli. Based on the difference in discharge patterns of group III and IV muscle afferents, we hypothesized that activation of mechanically sensitive (MS) fibers would evoke a different pattern of cardiovascular responses compared with activation of both MS and chemosensitive (CS) fibers. Experiments were conducted in chloralose-urethane-anesthetized cats (n = 10).

c-Fos expression in the midbrain periaqueductal gray during static muscle contraction.

The periaqueductal gray (PAG) of the midbrain is involved in the autonomic regulation of the cardiovascular system. The purpose of this study was to determine if static contraction of the skeletal muscle, which increases arterial blood pressure and heart rate, activates neuronal cells in the PAG by examining Fos-like immunoreactivity (FLI). Muscle contraction was induced by electrical stimulation of the L7 and S1 ventral roots of the spinal cord in anesthetized cats.

Cardiovascular responses to static exercise in patients with Brown-Séquard syndrome.

1. The purpose of this study was to determine the contributions of central command and the exercise pressor reflex in regulating the cardiovascular response to static exercise in patients with Brown-Sequard syndrome. In this rare condition, a hemisection of the spinal cord typically leaves one side of the body with diminished sensation and normal motor function and the other side with diminished motor function and normal sensation.

Skeletal muscle afferent fibres release substance P in the nucleus tractus solitarii of anaesthetized cats.

1. The tachykinin substance P was recovered from the commissural subdivision of the nucleus tractus solitarii (cNTS) using in vivo microdialysis during activation of cardiorespiratory and skeletal muscle receptors in thirteen chloralose-anaesthetized cats. 2.

Cardiovascular effects of intravenous administration of clonidine in conscious cats.

We previously reported that cardiovascular effects elicited by intracerebroventricular (i.c.v.

Reduction in arterial compliance alters carotid baroreflex control of cardiac output in a model of hypertension.

Baroreflex regulation of cardiac output is determined by the performance of the heart as well as the available blood flow returning to the heart (i.e., venous return).

Central interaction between carotid baroreceptors and skeletal muscle receptors inhibits sympathoexcitation.

To determine the potential of an inhibitory interaction between the carotid sinus baroreflex (CSB) and the exercise pressor reflex (EPR), both pathways were activated to produce sympathoexcitation. It was hypothesized that, under conditions when the baroreflex increased sympathetic outflow, the interaction between CSB and EPR would be inhibitory. Bilateral carotid occlusion (BCO), electrically induced muscle contraction (EMC), and passive muscle stretch (PMS) were used to evoke sympathoexcitation.

Mechanisms for increasing stroke volume during static exercise with fixed heart rate in humans.

Ten patients with preserved inotropic function having a dual-chamber (right atrium and right ventricle) pacemaker placed for complete heart block were studied. They performed static one-legged knee extension at 20% of their maximal voluntary contraction for 5 min during three conditions: 1) atrioventricular sensing and pacing mode [normal increase in heart rate (HR; DDD)], 2) HR fixed at the resting value (DOO-Rest; 73 +/- 3 beats/min), and 3) HR fixed at peak exercise rate (DOO-Ex; 107 +/- 4 beats/min). During control exercise (DDD mode), mean arterial pressure (MAP) increased by 25 mmHg with no change in stroke volume (SV) or systemic vascular resistance.

Cardiovascular effects of central administration of clonidine in conscious cats.

The effects on arterial blood pressure and heart rate after an intracerebroventricular (i.c.v.