The Valsalva maneuver (VM) is a diagnostic protocol examining sympathetic and parasympathetic activity in patients with autonomic dysfunction (AD) impacting cardiovascular control. Because direct measurement of these signals is costly and invasive, AD is typically assessed indirectly by analyzing heart rate and blood pressure response patterns. This study introduces a mathematical model that can predict sympathetic and parasympathetic dynamics. Our model-based analysis includes two control mechanisms: respiratory sinus arrhythmia (RSA) and the baroreceptor reflex (baroreflex). The RSA submodel integrates an electrocardiogram-derived respiratory signal with intrathoracic pressure, and the baroreflex submodel differentiates aortic and carotid baroreceptor regions. Patient-specific afferent and efferent signals are determined for 34 control subjects and 5 AD patients, estimating parameters fitting the model output to heart rate data. Results show that inclusion of RSA and distinguishing aortic/carotid regions are necessary to model the heart rate response to the VM. Comparing control subjects to patients shows that RSA and baroreflex responses are significantly diminished. This study compares estimated parameter values from the model-based predictions to indices used in clinical practice. Three indices are computed to determine adrenergic function from the slope of the systolic blood pressure in phase II [ α (a new index)], the baroreceptor sensitivity ( β), and the Valsalva ratio ( γ). Results show that these indices can distinguish between normal and abnormal states, but model-based analysis is needed to differentiate pathological signals. In summary, the model simulates various VM responses and, by combining indices and model predictions, we study the pathologies for 5 AD patients. NEW & NOTEWORTHY We introduce a patient-specific model analyzing heart rate and blood pressure during a Valsalva maneuver (VM). The model predicts autonomic function incorporating the baroreflex and respiratory sinus arrhythmia (RSA) control mechanisms. We introduce a novel index ( α) characterizing sympathetic activity, which can distinguish control and abnormal patients. However, we assert that modeling and parameter estimation are necessary to explain pathologies. Finally, we show that aortic baroreceptors contribute significantly to the VM and RSA affects early VM.

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Intestinal adaptation is an important response and a natural repair mechanism in acute intestinal injury and is critical for recovery. Glucagon-like peptide 2 (GLP-2) has been demonstrated to enhance mucosal repair following intestinal damage. In this study, we aimed to investigate the role of GLP-2 receptor activation on intestinal protection and adaptation upon chemotherapy-induced intestinal injury. The injury was induced with a single injection of 5-fluorouracil in female GLP-2 receptor knockout (GLP-2R(-/-)) mice and their wild type (WT) littermates. The mice were euthanized in the acute or the recovery phase of the injury; the small intestines were analysed for weight changes, morphology, histology, inflammation, apoptosis and proliferation. In the acute phase, only inflammation was slightly increased in the GLP-2R(-/-) mice compared to WT. In the recovery phase, we observed the natural compensatory response with an increase in small intestinal weight, crypt depth and villus height in WT mice, and this was absent in the GLP-2R(-/-) mice. Both genotypes responded with hyperproliferation. From this, we concluded that GLP-2R signalling does not have a major impact on acute intestinal injury but is pivotal for the adaptive response in the small intestine.

Using the specific Takeda G protein-receptor-5 (TGR5) agonist RO5527239 and GLP-2 receptor knockout mice, we show that activation of TGR5 led to the increase in colonic GLP-1 and GLP-2 concomitant with a GLP-2 dependent growth response in the proximal portion of the small intestine.