The cardiovascular mighty mini‐ruler

Chronic heart failure (CHF) is an ever-increasing phenomenon in the ageing population. In the United States, for example, roughly 5 million people experience CHF with 20% of patients dying within 1 year and ∼80% mortality within 8 years. Multiple mechanisms seem responsible for it, but neurohumoral activation also appears to have a significant role. Carotid body (CB) activation of the sympathetic nervous system (SNS) can provoke lethal ventricular arrhythmias, which may account for as much as 50% of all deaths that are sudden and unexpected (Tomaselli and Zipes 2004; Paterson 2005). A key question, then, is how does this tiny CB have such a critical impact? The CB is arguably the most important interoceptor for maintaining the organism's homeostasis. The organ is bilaterally located at the bifurcation of the common carotid artery into its external and internal branches. In humans the CB weighs ∼18 mg and has a volume of ∼12.3 mm3 (Heath & Smith, 1992). Blood flow within the cat CB is the highest of any measured in the organism, >2 litres min−1 (100 g tissue)−1 (Daly et al. 1964). The CB senses arterial blood for the partial pressures therein of oxygen (), carbon dioxide (), hydrogen ions and glucose, primarily. less than the normal 90–100 mmHg, or elevated (>38–40 mmHg) stimulates the CB, as well as do increases in H+ or decreases in glucose concentration. Increased neural output from the CB proceeds into nucleus tractus solitarii where the activity is distributed to several important nuclei in the brainstem. A remarkable array of systemic reflex responses ensue, including those affecting heart and vasculature (Parker et al. 1975). In an article in a recent issue of The Journal of Physiology, Ding et al. (2011), using rabbit as their animal model, fashioned an ingenious set of experiments. One set of rabbits was subjected to cardiac pacing for 3 weeks until heart failure was observed. Among the many observations, a reduction in blood flow by ∼36% in the common carotid artery was recorded. This reduced blood flow in the carotid body. Increases in CB neural output were recorded, as was increased renal sympathetic nerve output. A second set of rabbits was fitted with cuffs around their common carotid arteries. The cuffs were maintained inflated for the same duration as that used in the paced rabbits suffering CHF. A similar reduction in carotid artery blood flow, as well as increases in CB and renal sympathetic nerve output were observed. The investigators concluded that CB blood flow was a critical factor. But how could this ‘critical factor’ operate to produce the increase in the SNS? With changes in blood flow come changes in shear stress on the vascular endothelial cells in the CB. Since in some systems laminar shear stress is responsible for increased eNOS mRNA, it would seem a reduction in blood flow would decrease eNOS and, presumably therefore, NO. Well known is the fact that NO reduces CB neural output (Wang et al. 1994); this happens at least in part by the reduction in the release of the CB-contained excitatory neurotransmitter ACh. Ding et al. show other factors involved in reduced blood flow which increase CB activity, such as an increase in ROS, which blocks conductance in some of the K+ channels in the transmitter-containing glomus cells of the CB. Simple hypoxia is also thought to have its effect by blocking K+ channels. The effect of K+ channel blockage is to depolarize the glomus cell, opening voltage-gated Ca2+ channels. In rushes extracellular calcium, enabling the transmitter-containing vesicles to dock at the inner membrane of the glomus cell and exocytose their contents into the synaptic-like cleft between glomus cell and the abutting afferent neuron. The activity is carried to the nucleus tractus solitarii, distributed, and reflex increases in ventilation and SNS output ensue. Other factors are also involved, such as the upregulation of angiotensin II and the angiotensin I receptor. The finding that reduced carotid artery blood flow is an important factor in CB behaviour is a major discovery. Why? Though some CHF patients can be hypoxic with values as low as 65–70 mmHg, many are not. And in the CHF rabbit experiments the values were absolutely normal as they were in the rabbits with compressed carotid arteries. The decreased blood flow and reduced eNOS/NO would therefore seem to be the source of the increased CB neural output and renal sympathetic nerve activity. An interesting result of this group's extensive study of the CB's role in CHF is that with a programme of modest exercise for their CHF rabbits the blood flow increased, reducing both the CB neural output and renal sympathetic nerve output. There have been several clinical trials to see if a programme of modest exercise would benefit CHF patients. Most concluded that it did. A recent study (O’Connor et al. 2009) modified that conclusion. But this HF-ACTION study did support a prescribed exercise training programme for patients with reduced left ventricular function and heart failure symptoms. But what about CHF patients who are unable or unwilling to exercise? A point of speculation with respect to potential therapy for these CHF patients in this age of nanotechnology would be to explore the possibility of loading nanospheres with the gene for eNOS and delivering it with an appropriate tissue-specific marker to the CB. Previous studies by the above investigators have shown the beneficial effects of delivering an adenovirus containing the gene to the CBs of the CHF rabbits (Li et al. 2005). A potential new therapy to regulate this mighty mini-ruler of so injurious a threat to the homeostasis of the organism would indeed have enormously important public health and clinical implications.