Keisuke Shinohara

Atrial fibrillation (AF) is frequently accompanied by hypertension; however, the relationship between mid-term blood pressure variability (BPV) assessed using home blood pressure (BP) measurements and prognosis in patients with AF remains unclear. We examined the association between home BPV and cardiovascular outcomes in elderly patients with non-valvular AF using data from the ANAFIE (All Nippon AF In the Elderly) Registry. This post hoc analysis of a prospective registry included 4885 patients aged ≥75 years who performed standardized home BP measurements in the morning and evening (two measurements at each time point) over seven consecutive days. Mid-term BPV was quantified using the coefficient of variation of systolic home BP and categorized into quartiles. The primary endpoint was a net cardiovascular outcome, defined as a composite of stroke, systemic embolism, and major bleeding. Associations were assessed using multivariable Cox proportional hazards models adjusted for mean BP and established risk factors. Over a median follow-up of two years, the net cardiovascular outcome occurred in 171 patients. Compared with the lowest BPV quartile, patients in the highest quartile had a significantly higher risk of the net cardiovascular outcome (HR 2.03, 95% CI 1.21–3.40). Higher risks were also observed for stroke/systemic embolism, intracranial hemorrhage, and bleeding. Findings were consistent when BPV was assessed using the standard deviation and across subgroups. In conclusion, greater mid-term home BPV was independently associated with increased cardiovascular risk beyond average BP in elderly patients with non-valvular AF.

Background: We investigated associations between the low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (L/H ratio) and cardiovascular events in high-risk type 2 diabetes (T2D) patients with diabetic retinopathy receiving statins.Methods and Results: We conducted a post hoc analysis of the EMPATHY study, a randomized controlled trial comparing intensive vs. standard statin therapy in T2D patients with retinopathy and hypercholesterolemia without cardiovascular disease. Baseline and 12-month (12M) L/H ratios were assessed as single and serial measures. Baseline data were available for 5,006 patients (median L/H ratio 2.016), categorized as having either a high (≥2.0) or low (<2.0) L/H ratio. Over a median 36.8-month follow-up, 184 cardiovascular events occurred. The risk of cardiovascular events was higher in the group with a high than low L/H ratio, even after adjusting for age, sex, and LDL-C (hazard ratio 1.89; 95% confidence interval 1.31–2.73; P<0.001); 12M L/H ratio analysis yielded similar results. In serial categories, both low-high (baseline <2.0; 12M ≥2.0) and high-high (baseline ≥2.0; 12M ≥2.0) groups had higher risk than the low-low group (baseline <2.0; 12M <2.0). No significant interactions were observed by age, sex, LDL-C, HDL-C, or statin intensity.Conclusions: An L/H ratio ≥2.0 identifies increased cardiovascular risk in statin-treated T2D patients with diabetic retinopathy and hypercholesterolemia without prior cardiovascular disease. Serial L/H ratio assessment may aid risk stratification in this high-risk population.

Tirzepatide, a dual agonist for glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has shown robust efficacy in treating diabetes and obesity, and in obese patients with heart failure with preserved ejection fraction (HFpEF), it reduced weight, lowered blood pressure, and improved outcomes. However, its cardiovascular effects in non-obese, non-diabetic hypertension remain unclear. We investigated the impact of tirzepatide on blood pressure, cardiac function, and sympathetic nervous system activity in stroke-prone spontaneously hypertensive rats. Starting at 8 weeks of age, rats received tirzepatide (TZP, 25 nmol/kg, every two days), vehicle (VEH), or pair-fed vehicle (VEH–PF) to control for differences in food intake for 4 weeks. Tirzepatide significantly reduced food intake and body weight. Contrary to prior clinical observations, tirzepatide elevated mean blood pressure (197.4 ± 16.6 vs. 153.7 ± 5.4 mmHg at Day 28; TZP vs. VEH–PF, n = 9 vs. 8; p < 0.05) and increased heart rate, accompanied by left ventricular hypertrophy, myocardial fibrosis, and impaired diastolic function. Sympathetic activation was evident, with higher plasma norepinephrine levels and increased ΔFosB expression—a marker of sustained neuronal excitation—in the parvocellular paraventricular nucleus and the rostral ventrolateral medulla. Moreover, ΔFosB expression was increased in anorexigenic proopiomelanocortin neurons within the hypothalamic arcuate nucleus, which reduce feeding and have been implicated in promoting sympathetic excitation. These findings point to a central mechanism underlying increased sympathetic outflow. In conclusion, tirzepatide increased blood pressure and sympathetic activity in hypertensive rats without cardiac protection, highlighting context-dependent cardiovascular actions. The alt text for this image may have been generated using AI. Tirzepatide increased blood pressure, impaired LV diastolic function, and induced cardiac hypertrophy and fibrosis, as well as sympathetic overactivation in SHRSP

BACKGROUND: Sympathetic activation plays a role in heart failure (HF) development. Afferent renal nerve input may induce sympathoexcitation via the hypothalamic paraventricular nucleus (PVN), which projects to the rostral ventrolateral medulla, a center for sympathetic regulation. Central dendritic release of vasopressin from PVN neurons reportedly stimulates neighboring presympathetic neurons, causing sympathoexcitation. This study investigated whether afferent renal nerves contribute to hypertensive cardiac dysfunction and whether the afferent renal nerve-PVN axis mediates sympathoexcitation via central vasopressin using salt-loaded Dahl salt-sensitive rats, a model of hypertensive HF. METHODS: Salt loading began at 6 weeks of age, with selective afferent renal denervation and total renal denervation performed at 9 weeks in Dahl salt-sensitive rats. HF phenotypes were examined at 16 weeks, while sympathomodulation by afferent renal denervation was assessed at 12 weeks, the pre-HF phase. RESULTS: At 16 weeks, afferent renal denervation and total renal denervation similarly improved left ventricular systolic dysfunction, reduced myocardial fibrosis and related mRNA levels, and lowered plasma norepinephrine levels without reducing blood pressure in hypertensive rats. At 12 weeks, afferent renal denervation attenuated the increase in plasma norepinephrine and presympathetic neuron activity in the PVN and rostral ventrolateral medulla in hypertensive rats, while decreasing vasopressin-producing PVN neuron activity. In acute experiments, afferent renal nerve stimulation increased sympathetic outflow, but vasopressin V1a and V1b receptor blockade in the PVN suppressed this sympathoexcitation in hypertensive rats. CONCLUSIONS: Afferent renal nerve input activates the sympathetic nervous system before left ventricular systolic dysfunction and contributes to hypertensive HF, with PVN vasopressin driving this sympathoexcitation.

Hypertension is both a driver and a consequence of brain dysfunction. The brain regulates circulation via control of autonomic nervous system tone by integrating neural and humoral signals. It is also a vulnerable target of blood pressure (BP)–related injury, ranging from overt stroke to covert small-vessel disease. Recognizing this bidirectional relationship is essential for advancing precision in prevention and treatment. On the mechanistic side, recent work has clarified how the brain renin–angiotensin system, sodium–glucose cotransporter 2, the melanocortin system, and the gut–brain axis shape autonomic output. In addition, renewed attention has been given to centrally acting sympatholytics, imidazoline receptor agonists, which demonstrate antihypertensive efficacy and metabolic neutrality in contemporary trials. Collectively, these studies reinforce that central pathways remain viable therapeutic targets for modulating sympathetic activity. Clinically, multiple investigations highlight that cerebrovascular outcomes depend not only on mean BP but also on patterns and cumulative injury. Total small-vessel disease burden integrates lifetime vascular damage and predicts prognosis after stroke. Nocturnal BP surges and visit-to-visit variability further stratify cerebrovascular risk, while beat-to-beat fluctuations after reperfusion influence recovery. Pulse pressure after intracerebral hemorrhage links systemic hemodynamics with renal and neurological outcomes, and prevention gaps such as untreated hypertension remain striking, especially in younger patients. Together, these advances emphasize that brain health and BP regulation are inseparable. This review highlights recent advances in both central mechanisms of sympathoexcitation and clinical perspectives on cerebrovascular outcomes in hypertension.

This study demonstrated that chronic treatment with activated factor X (FXa) inhibitor ameliorated NF-κB-IL-6-mediated perivascular inflammation in a rat model with pulmonary arterial hypertension, which is associated with elevated FXa activity. FXa may act on pulmonary arterial smooth muscle cells, inducing cell proliferation and inflammatory response via upregulated PAR₁, thereby contributing to pulmonary vascular remodeling. Understanding the patient-specific pathophysiology is a prerequisite for applying FXa-targeted therapy to the treatment of pulmonary arterial hypertension.