Towards precision medicine for hypertension: a review of genomic, epigenomic, and microbiomic effects on blood pressure in experimental rat models and humans

Compelling evidence for the inherited nature of essential hypertension has led to extensive research in rats and humans. Rats have served as the primary model for research on the genetics of hypertension resulting in identification of genomic regions that are causally associated with hypertension. In more recent times, genome-wide studies in humans have also begun to improve our understanding of the inheritance of polygenic forms of hypertension. Based on the chronological progression of research into the genetics of hypertension as the "structural backbone," this review catalogs and discusses the rat and human genetic elements mapped and implicated in blood pressure regulation. Furthermore, the knowledge gained from these genetic studies that provide evidence to suggest that much of the genetic influence on hypertension residing within noncoding elements of our DNA and operating through pervasive epistasis or gene-gene interactions is highlighted. Lastly, perspectives on current thinking that the more complex "triad" of the genome, epigenome, and the microbiome operating to influence the inheritance of hypertension, is documented. Overall, the collective knowledge gained from rats and humans is disappointing in the sense that major hypertension-causing genes as targets for clinical management of essential hypertension may not be a clinical reality. On the other hand, the realization that the polygenic nature of hypertension prevents any single locus from being a relevant clinical target for all humans directs future studies on the genetics of hypertension towards an individualized genomic approach

In-flight angina pectoris; an unusual presentation

Background: An unusual case of typical angina which occurred on a long haul flight is presented. This case is notable as this was the index presentation, with no previous symptoms prior to this. Physiological changes at altitude can be marked, and include hypoxia, tachycardia and an increase in cardiac output. These changes were enough to expose underlying angina in our patient. Case presentation: A 68 year old man presented with typical cardiac chest pain on a long haul flight. His symptoms first started 10-15 min after take-off and resolved on landing. This was his index presentation, and there were no similar symptoms in the past. Background history included hypercholesterolaemia and benign prostatic hypertrophy only. He led a rather sedentary lifestyle. A CT coronary angiogram showed significant disease in the proximal left anterior descending artery and proximal right coronary artery. He went on to have a coronary angiogram with invasive physiological measurements, which determined both lesions were physiologically significant. Both arteries were treated with drug eluting stents. Since treatment, he once again embarked on a long haul flight, and was completely asymptomatic. Conclusion: The presentation of symptoms in this individual was rather unusual, but clearly caused by significant coronary artery disease. Potentially his sedentary lifestyle was not enough in day-to-day activities to promote anginal symptoms. When his cardiovascular system was physiologically stressed during flight, brought about by hypoxia, raised sympathetic tone and increased cardiac output, symptoms emerged. In turn, when landing, with atmospheric conditions normalised, physiological stress was removed, and symptoms resolved. Clinically therefore, one should not exclude symptoms that occur with differing physiological states, such as stress and altitude, as they are also potential triggers for myocardial ischaemia, despite absence of day-to-day symptoms

Trigonometric Regressive Spectral Analysis Reliably Maps Dynamic Changes in Baroreflex Sensitivity and Autonomic Tone: The Effect of Gender and Age

BACKGROUND: The assessment of baroreflex sensitivity (BRS) has emerged as prognostic tool in cardiology. Although available computer-assisted methods, measuring spontaneous fluctuations of heart rate and blood pressure in the time and frequency domain are easily applicable, they do not allow for quantification of BRS during cardiovascular adaption processes. This, however, seems an essential criterion for clinical application. We evaluated a novel algorithm based on trigonometric regression regarding its ability to map dynamic changes in BRS and autonomic tone during cardiovascular provocation in relation to gender and age. METHODOLOGY/PRINCIPAL FINDINGS: We continuously recorded systemic arterial pressure, electrocardiogram and respiration in 23 young subjects (25+/-2 years) and 22 middle-aged subjects (56+/-4 years) during cardiovascular autonomic testing (metronomic breathing, Valsalva manoeuvre, head-up tilt). Baroreflex- and spectral analysis was performed using the algorithm of trigonometric regressive spectral analysis. There was an age-related decline in spontaneous BRS and high frequency oscillations of RR intervals. Changes in autonomic tone evoked by cardiovascular provocation were observed as shifts in the ratio of low to high frequency oscillations of RR intervals and blood pressure. Respiration at 0.1 Hz elicited an increase in BRS while head-up tilt and Valsalva manoeuvre resulted in a downregulation of BRS. The extent of autonomic adaption was in general more pronounced in young individuals and declined stronger with age in women than in men. CONCLUSIONS/SIGNIFICANCE: The trigonometric regressive spectral analysis reliably maps age- and gender-related differences in baroreflex- and autonomic function and is able to describe adaption processes of baroreceptor circuit during cardiovascular stimulation. Hence, this novel algorithm may be a useful screening tool to detect abnormalities in cardiovascular adaption processes even when resting values appear to be normal

Carotid Baroreflex Activation: Past, Present, and Future

Electrical activation of the carotid baroreceptor system is an attractive therapy for the treatment of resistant hypertension. In the past, several attempts were made to directly activate the baroreceptor system in humans, but the method had to be restricted to a few selected patients. Adverse effects, the need for better electrical devices and better surgical techniques, and the lack of knowledge about long-term effects has greatly hampered developments in this area for many years. Recently, a new and promising device was evaluated in a multicenter feasibility trial, which showed a clinically and statistically significant reduction in office systolic blood pressure (>20 mm Hg). This reduction could be sustained for at least 2 years with an acceptable safety profile. In the future, this new device may stimulate further application of electrical activation of the carotid baroreflex in treatment-resistant hypertension

Modeling the differentiation of A- and C-type baroreceptor firing patterns

The baroreceptor neurons serve as the primary transducers of blood pressure for the autonomic nervous system and are thus critical in enabling the body to respond effectively to changes in blood pressure. These neurons can be separated into two types (A and C) based on the myelination of their axons and their distinct firing patterns elicited in response to specific pressure stimuli. This study has developed a comprehensive model of the afferent baroreceptor discharge built on physiological knowledge of arterial wall mechanics, firing rate responses to controlled pressure stimuli, and ion channel dynamics within the baroreceptor neurons. With this model, we were able to predict firing rates observed in previously published experiments in both A- and C-type neurons. These results were obtained by adjusting model parameters determining the maximal ion-channel conductances. The observed variation in the model parameters are hypothesized to correspond to physiological differences between A- and C-type neurons. In agreement with published experimental observations, our simulations suggest that a twofold lower potassium conductance in C-type neurons is responsible for the observed sustained basal firing, whereas a tenfold higher mechanosensitive conductance is responsible for the greater firing rate observed in A-type neurons. A better understanding of the difference between the two neuron types can potentially be used to gain more insight into the underlying pathophysiology facilitating development of targeted interventions improving baroreflex function in diseased individuals, e.g. in patients with autonomic failure, a syndrome that is difficult to diagnose in terms of its pathophysiology.Comment: Keywords: Baroreflex model, mechanosensitivity, A- and C-type afferent baroreceptors, biophysical model, computational mode

Precision tau physics

Precise measurements of the lepton properties provide stringent tests of the Standard Model and accurate determinations of its parameters. We overview the present status of tau physics, highlighting the most recent developments, and discuss the prospects for future improvements. The leptonic decays of the tau lepton probe the structure of the weak currents and the universality of their couplings to the W boson. The universality of the leptonic Z couplings has also been tested through Z -> l(+)l(-) decays. The hadronic tau decay modes constitute an ideal tool for studying low-energy effects of the strong interaction in very clean conditions. Accurate determinations of the QCD coupling and the Cabibbo mixing V-us have been obtained with tau data. The large mass of the tau opens the possibility to study many kinematically-allowed exclusive decay modes and extract relevant dynamical information. Violations of flavour and CP conservation laws can also be searched for with tau decays. Related subjects such as μdecays, the electron and muon anomalous magnetic moments, neutrino mixing and B-meson decays into tau leptons are briefly covered. Being one the fermions most strongly coupled to the scalar sector, the tau lepton is playing now a very important role at the LHC as a tool to test the Higgs properties and search for new physics at higher scales