Thomas Andrew Jepps

Aims: The mechanisms underlying colchicine’s cardiovascular benefits in patients with coronary artery disease remain unclear and warrant further translational investigation. Methods and results: In a randomized, double-blind, placebo-controlled trial, 111 patients with chronic coronary artery disease and aortic or carotid target-to-background ratio ≥1.6 were assigned to colchicine 0.6 mg daily (n=55) or placebo (n=56) for 24 weeks. Arterial inflammation was assessed using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) of the ascending aorta. The primary endpoint was the change in mean maximum target-to-background ratio over 24 weeks. Secondary and exploratory objectives included evaluation of systemic inflammatory markers and blood pressure. To support interpretation of the clinical findings, a complementary hypertensive rodent model, the spontaneously hypertensive rat (SHR), was treated with colchicine for 4 weeks to explore vascular and inflammatory pathways potentially influenced by colchicine using immunohistochemistry, myography and proteomics. Colchicine did not reduce aortic FDG uptake compared with placebo (adjusted mean change 0.05 [95% CI −0.02 to 0.12] vs 0.01 [95% CI −0.06 to 0.08]; p=0.38). In secondary and exploratory analyses, colchicine was associated with a reduction in neutrophil-to-lymphocyte ratio (adjusted mean change −0.36 vs −0.08; p=0.033), a trend toward lower high-sensitivity C-reactive protein (adjusted geometric mean percentage change −28.2% vs −5.8%; p=0.060) and attenuation of increases in systolic (adjusted mean change 0.88 mmHg vs. 4.94 mmHg; p=0.046) and diastolic (1.41 mmHg vs. 4.35 mmHg; p=0.048) blood pressure. In SHRs, colchicine had no effect on the aorta but attenuated the progression of hypertension and reduced inflammation and extracellular matrix remodelling in mesenteric resistance arteries, while enhancing vasodilator responses. Reductions in CXCL10, CXCL2, NLRP3 and IL-18 expression were observed in mesenteric arteries from the SHR following colchicine treatment. Conclusions: These findings support the hypothesis that vascular effects of colchicine likely extend beyond large conduit arteries, while the specific pathways and relevance to coronary atherosclerosis require further investigation.

Aims: This trial investigated whether colchicine, an anti-inflammatory treatment, affects cardiovascular structure and function, assessed by arterial stiffness, blood pressure, and biochemistry, compared with placebo. Methods and results: COHERENT was a randomized, double-blind, placebo-controlled trial of the effects of colchicine on arterial stiffness in adults with pharmacologically treated hypertension without cardiovascular disease. Eligible patients were randomized 1:1 to colchicine 0.5 mg daily or placebo for 6 months. Assessment of arterial stiffness, echocardiography, and biomarker measurement were performed at baseline and 6 months. The primary endpoint was change in carotid-femoral pulse wave velocity (cfPWV). Secondary endpoints included change in blood pressure (BP), left ventricular mass index, as well as change in cardiac and inflammatory biomarkers. Of 183 screened, 150 were randomized (75 per group). The mean age was 64.5 (±8.0) years, 53 (35.3%) were female, and mean systolic blood pressure was 140.3 (±16.5) mmHg. At 6 months, cfPWV did not differ between groups [between-group difference in ΔcfPWV −0.1 m/s, 95% confidence interval (CI): −0.5 to 0.3 m/s, P = 0.53]. Office systolic BP decreased significantly more in the placebo group than in the colchicine group (between-group difference in Δoffice systolic BP 5.7 mmHg, 95% CI: 1.0 to 10.5 mmHg, P = 0.018). hsCRP decreased significantly in the colchicine group compared with the placebo group (between-group difference in % change in hsCRP −39.8%, 95% CI: −59.1 to −11.4%, P = 0.010). The left ventricular mass index or cardiac biomarkers did not differ between groups. Conclusion: Six months of colchicine did not affect arterial stiffness in pharmacologically treated hypertension without cardiovascular disease. Colchicine significantly decreased hsCRP. Registration: ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT04916522

Chelonian systemic arteries exhibit predominantly α ₂ -adrenoceptor-mediated contraction, with minimal functional contribution from α ₁ -adrenoceptors, contrasting with mammalian vascular regulation. Medetomidine and detomidine induce robust vasoconstriction that is abolished by the peripherally acting α ₂ -adrenoceptor antagonist vatinoxan. These findings identify a distinct adrenergic hierarchy in chelonian vasculature, provide a mechanistic basis for the cardiovascular effects of α ₂ -agonist sedation, and establish chelonians as a comparative model of α ₂ -adrenoceptor-mediated vascular regulation.

KV7 (KCNQ) channels generate slowly activating, non-inactivating K+ currents that stabilize the membrane potential and limit cellular excitability [1–3]. Within the cardiovascular and visceral syst...

The voltage‐gated potassium channel K _V 7.1 (KCNQ1) is essential for cardiac repolarization. Loss‐of‐function mutations prolong the action potential and cause long QT syndrome 1, predisposing to malignant arrhythmias. Pharmacological activators of K _V 7.1 are therefore of therapeutic interest. Among them, the 1,4‐benzodiazepine derivative (R)‐L3 is a potent activator that not only increases current amplitude but also slows activation and deactivation kinetics and abolishes inactivation by uncoupling the voltage sensor from the pore. To explore the structure–activity relationships (SAR) of (R)‐L3, we synthesized and functionally characterized a series of novel 1,4‐benzodiazepine derivatives and examined their effects on K _V 7.1 gating. Human K _V 7.1 channels were heterologously expressed in Xenopus laevis oocytes. Two‐electrode voltage clamp recordings were performed to assess current amplitude and kinetic parameters of activation, deactivation, and inactivation. 1,4‐Benzodiazepines modified at 1‐position reproduced the canonical effects of (R)‐L3, including increased current amplitude and suppression of inactivation to varying degrees. Some derivatives displayed completely altered profiles: Modulation of activation, altered (de‐)activation kinetics or exerting attenuated effects on inactivation could be uncoupled. These differences suggest that modifications of the 1,4‐benzodiazepine scaffold at 1‐position shift the interaction between pore binding and voltage sensor–pore uncoupling to isolate kinetic effects. Our data demonstrates that (R)‐L3 analogues can differentially modulate K _V 7.1 gating. By identifying structural determinants of efficacy, this study provides a framework for rational design of next‐generation K _V 7.1 activators. Such compounds may serve as pharmacological tools for dissecting electromechanical coupling in K _V 7.1 and hold promise as candidates for antiarrhythmic therapy in long QT syndrome.

Hypertension is a prevalent and significant risk factor for cardiovascular disease (CVD). The immune system and inflammatory response are involved in the pathophysiology of hypertension. We hypothesize that treating hypertension with colchicine on top of standard therapy, will decrease pulse wave velocity (PWV), left ventricular mass, cardiac/inflammatory biomarkers. COHERENT was an investigator‐initiated, single‐center, prospective, randomized, double‐blind, placebo‐controlled study of the effects of colchicine in patients with hypertension. Potential participants were identified through nationwide health registries. Eligible patients were randomized 1:1 to colchicine 0.5 mg daily or placebo and treated for 6 months. Assessment of vascular function, echocardiography, and measurement of biomarkers were performed at baseline and at 6 months. The primary endpoint of the trial was change from baseline in carotid‐femoral PWV at 6 months. Secondary endpoints included blood pressure, echocardiographic measurements, and cardiac/inflammatory biomarkers. We screened 183 potential participants, of whom 150 were randomized from August 2021 to July 2025. A total of 75 (50%) were assigned to receive colchicine. Participants had a mean age of 64.5 years (SD 8.0) and 53 (35%) were female, 82 (55%) were active or former smokers, mean systolic blood pressure was 140 mmHg (SD 16.5), mean diastolic pressure was 86 mmHg (10.5), and median high sensitivity C‐reactive protein was 0.97 mg/L (IQR: 0.52–2.05). COHERENT is the first trial to investigate the effects of colchicine in patients with hypertension without other known CVD. The trial will provide important data on whether anti‐inflammatory therapy should be considered for patients with hypertension. Clinical Trial registration : Clinicaltrials.gov: NCT04916522, registered June 3, 2021, https://clinicaltrials.gov/study/NCT04916522 Practical Applications COHERENT has the potential to determine whether colchicine can modulate pathological processes in hypertension, such as increased arterial stiffness and blood pressure. If the trial outcome is positive, it could impact therapy for millions of hypertensive patients. Since the socio‐economic costs of therapy and care related to hypertension and heart disease are enormous, the results from the study may also be important at a broader societal level, given that colchicine is relatively inexpensive, already approved for treatment in patients following myocardial infarction, and widely considered safe to use with an acceptable low level of side effects when used in low doses. Furthermore, this study can help elucidate the pathophysiological pathways from early‐stage cardiovascular disease ‐ where only hypertension is present ‐ and determine whether anti‐inflammatory therapy such as colchicine can help prevent deleterious vascular function changes and potentially prevent progression to overt cardiovascular disease.

The endothelium plays a central role in maintaining vascular homeostasis by orchestrating vascular tone, inflammation, healing, permeability, and thrombosis. Assessing endothelial function in vascular tissue is essential for understanding the cellular and molecular mechanisms underlying cardiovascular physiology and pathology. Traditional approaches, such as wire and pressure myography, have been instrumental in defining endothelium-dependent responses and identifying key pharmacological targets. However, the complexity and heterogeneity of endothelial cells across vascular beds and their dynamic phenotypic changes in health and disease necessitate the incorporation of new investigative strategies. Emerging methodologies, including bulk and single-cell transcriptomics, proteomics, and advanced imaging, now provide unprecedented insights into endothelial cell diversity and function. A team of leading experts in the field, who collectively reached a consensus on the most widely used techniques to evaluate endothelial function, developed these guidelines. The document establishes best practices for assessing endothelial function, from endothelial cell cultures to isolated vascular tissues, integrating conventional functional assays with modern molecular approaches. By fostering methodological consistency and embracing innovation, our goal is to enhance rigor, reproducibility, understanding, and discovery in endothelial biology.

Untreated hypertension is a risk factor for late-onset Alzheimer’s disease (AD); however, this association is not well understood. The aim of this study was to reveal protein signatures that bridge the pathophysiological changes in hypertension to AD. Using untargeted proteomics, we analyzed brain samples from aged (30- and 40-week-old) spontaneously hypertensive rats (SHRs, n = 12), and age-matched normotensive Wistar Kyoto (WKY, n = 8) controls, and human AD patients (Braak stages 4–6) ( n = 30), cerebral amyloid angiopathy (CAA) ( n = 5), non-demented controls (Braak stages 0–3) ( n = 37). Differential expression and pathway analyses in SHRs highlighted the ‘extracellular exosome’ pathway. This pathway also showed significant associations to differentially expressed proteins in AD and CAA patients. Comparison between species identified 24 proteins in SHRs and AD, whose trajectory pattern over the progression of hypertension, aligned with those observed during AD Braak stage progression, compared to respective controls. The proteins were similarly associated with extracellular exosomes. Immunostaining and spatial proteomics support vesicle accumulation and dysregulated exosome protein signatures in the cerebrovasculature of both SHR and AD brains. Additionally, the extracellular exosome pathway-association was not identified in a traditional model of familial AD (5xFAD). Our findings demonstrate cross-species translatability between AD and the SHR and provide novel mechanistic insights into a shared dysregulation of cerebral artery-associated exosomes. Graphical Abstract

BACKGROUND: Hypertension is a significant risk factor for several neurological disorders, including stroke and dementia, yet the molecular mechanisms underlying these risks remain poorly understood. In this study, we investigated temporal proteomic remodeling of the cerebrovasculature in male spontaneously hypertensive rats and normotensive Wistar-Kyoto controls at 30 and 40 weeks of age, representing the effect of untreated hypertension from early adulthood to midlife. METHODS: Using male 30- and 40-week-old spontaneously hypertensive rats and Wistar-Kyoto rats, we have performed discovery-based proteomics, histological imaging, and RNA-sequencing data analysis. RESULTS: Proteomic analysis displayed a significant age-dependent change in the protein composition of the cerebrovasculature in the spontaneously hypertensive rat model, which is partly mediated via reduced SRF (serum response factor) expression and associated regulon. Pathway analysis revealed a transient upregulation of mitotic (M-phase) proteins at 30 weeks, indicative of maladaptive smooth muscle proliferation. By 40 weeks, the expression of these proteins was normalized; however, ECM (extracellular matrix)–associated proteins diverged substantially. The ECM remodeling was supported by increased media-to-circumference ratio and collagen deposition from histological analysis. CONCLUSIONS: Our findings demonstrate that hypertension drives a temporal shift in cerebrovascular remodeling, transitioning from early maladaptive smooth muscle proliferation to later ECM-driven structural changes. This progression suggests that the pathogenic mechanisms underlying hypertensive vascular injury are dynamic across the life course, with distinct phases that may require different and timely therapeutic approaches to mitigate the risks of neurovascular diseases.