Morning blood pressure surge as a predictor of cardiovascular events in patients with hypertension.

BACKGROUND: The prognostic value of ambulatory blood pressure (BP) monitoring (ABPM) is poorly understood in Latin American populations. METHODS: A prospective observational study was conducted on 1339 patients with hypertension who underwent 24-h BP monitoring between 2015 and 2019. The incidence of serious adverse cardiovascular events (MACE) was analysed using a Cox proportional hazards model adjusted for potential confounders. Three previously reported morning surge definitions were evaluated for SBP and DBP using different ABPM components: sleep-through morning surge, pre-awakening, and morning night-time difference. RESULTS: The mean age was 62 years, 52% were female, 32.8% had dyslipidaemia, 27.2% were smokers, and 7.8% had diabetes. During a median follow-up period of 32 months, 197 MACE occurred. In men, the adjusted hazard ratio (HR) was 1.84 [95% confidence interval (CI), 1.35-2.49; P < 0.001). The HR increased to 2.03 (95% CI, 1.89-2.17; P < 0.001) with a cut-off value of 35 mmHg for a 10 mmHg increase in sleep-through morning surge. The increased adjusted HR associated with the morning rise persisted for each secondary endpoint, including 21 cardiovascular deaths [HR: 2.70 (95% CI, 2.03-3.60; P < 0.001)], 78 myocardial infarctions [HR: 1.92 (95% CI, 1.72-2.15; P < 0.001)], 24 hospitalisations for heart failure [HR: 1.77 (95% CI, 1.48-2.12; P < 0.001)], 22 strokes [HR: 2.32 (95% CI, 1.85-2.91; P < 0.001)], and 52 atrial fibrillations [HR: 1.94 (95% CI, 1.71-2.20; P < 0.001)]. CONCLUSION: The morning BP rise was the most important circadian prognostic factor for MACE in patients with hypertension, which deserves more attention.

Reperfusion Arrhythmias Increase after Superior Cervical Ganglionectomy Due to Conduction Disorders and Changes in Repolarization.

Pharmacological concentrations of melatonin reduce reperfusion arrhythmias, but less is known about the antiarrhythmic protection of the physiological circadian rhythm of melatonin. Bilateral surgical removal of the superior cervical ganglia irreversibly suppresses melatonin rhythmicity. This study aimed to analyze the cardiac electrophysiological effects of the loss of melatonin circadian oscillation and the role played by myocardial melatonin membrane receptors, SERCA2A, TNFα, nitrotyrosine, TGFß, KATP channels, and connexin 43. Three weeks after bilateral removal of the superior cervical ganglia or sham surgery, the hearts were isolated and submitted to ten minutes of regional ischemia followed by ten minutes of reperfusion. Arrhythmias, mainly ventricular tachycardia, increased during reperfusion in the ganglionectomy group. These hearts also suffered an epicardial electrical activation delay that increased during ischemia, action potential alternants, triggered activity, and dispersion of action potential duration. Hearts from ganglionectomized rats showed a reduction of the cardioprotective MT2 receptors, the MT1 receptors, and SERCA2A. Markers of nitroxidative stress (nitrotyrosine), inflammation (TNFα), and fibrosis (TGFß and vimentin) did not change between groups. Connexin 43 lateralization and the pore-forming subunit (Kir6.1) of KATP channels increased in the experimental group. We conclude that the loss of the circadian rhythm of melatonin predisposes the heart to suffer cardiac arrhythmias, mainly ventricular tachycardia, due to conduction disorders and changes in repolarization.

Ischemic Postconditioning Reduces Reperfusion Arrhythmias by Adenosine Receptors and Protein Kinase C Activation but Is Independent of KATP Channels or Connexin 43.

Ischemic postconditioning (IPoC) reduces reperfusion arrhythmias but the antiarrhythmic mechanisms remain unknown. The aim of this study was to analyze IPoC electrophysiological effects and the role played by adenosine A1, A2A and A3 receptors, protein kinase C, ATP-dependent potassium (KATP) channels, and connexin 43. IPoC reduced reperfusion arrhythmias (mainly sustained ventricular fibrillation) in isolated rat hearts, an effect associated with a transient delay in epicardial electrical activation, and with action potential shortening. Electrical impedance measurements and Lucifer-Yellow diffusion assays agreed with such activation delay. However, this delay persisted during IPoC in isolated mouse hearts in which connexin 43 was replaced by connexin 32 and in mice with conditional deletion of connexin 43. Adenosine A1, A2A and A3 receptor blockade antagonized the antiarrhythmic effect of IPoC and the associated action potential shortening, whereas exogenous adenosine reduced reperfusion arrhythmias and shortened action potential duration. Protein kinase C inhibition by chelerythrine abolished the protective effect of IPoC but did not modify the effects on action potential duration. On the other hand, glibenclamide, a KATP inhibitor, antagonized the action potential shortening but did not interfere with the antiarrhythmic effect. The antiarrhythmic mechanisms of IPoC involve adenosine receptor activation and are associated with action potential shortening. However, this action potential shortening is not essential for protection, as it persisted during protein kinase C inhibition, a maneuver that abolished IPoC protection. Furthermore, glibenclamide induced the opposite effects. In addition, IPoC delays electrical activation and electrical impedance recovery during reperfusion, but these effects are independent of connexin 43.

Melatonin receptor activation protects against low potassium-induced ventricular fibrillation by preserving action potentials and connexin-43 topology in isolated rat hearts.

Hypokalemia prolongs the QRS and QT intervals, deteriorates intercellular coupling, and increases the risk for arrhythmia. Melatonin preserves gap junctions and shortens action potential as potential antiarrhythmic mechanisms, but its properties under hypokalemia remain unknown. We hypothesized that melatonin protects against low potassium-induced arrhythmias through the activation of its receptors, resulting in action potential shortening and connexin-43 preservation. After stabilization in Krebs-Henseleit solution (4.5 mEq/L K+ ), isolated hearts from Wistar rats underwent perfusion with low-potassium (1 mEq/L) solution and melatonin (100 µmol/L), a melatonin receptor blocker (luzindole, 5 µmol/L), melatonin + luzindole or vehicle. The primary endpoint of the study was the prevention of ventricular fibrillation. Electrocardiography was used, and epicardial action potentials and heart function were measured and analyzed. The ventricular expression, dephosphorylation, and distribution of connexin-43 were examined. Melatonin reduced the incidence of low potassium-induced ventricular fibrillation from 100% to 59%, delayed the occurrence of ventricular fibrillation and induced a faster recovery of sinus rhythm during potassium restitution. Melatonin prevented QRS widening, action potential activation delay, and the prolongation of action potential duration at 50% of repolarization. Other ECG and action potential parameters, the left ventricular developed pressure, and nonsustained ventricular arrhythmias did not differ among groups. Melatonin prevented connexin-43 dephosphorylation and its abnormal topology (lateralization). Luzindole abrogated the protective effects of melatonin on electrophysiological properties and connexin-43 misdistribution. Our results indicate that melatonin receptor activation protects against low potassium-induced ventricular fibrillation, shortens action potential duration, preserves ventricular electrical activation, and prevents acute changes in connexin-43 distribution. All of these properties make melatonin a remarkable antifibrillatory agent.

Grape pomace extract induced beige cells in white adipose tissue from rats and in 3T3-L1 adipocytes.

This study investigated the effects of a grape pomace extract (GPE) rich in phenolic compounds on brown-like adipocyte induction and adiposity in spontaneously hypertensive (SHR) and control normotensive Wistar-Kyoto (WKY) rats fed a high-fat diet (HFD). HFD consumption for 10 weeks significantly increased epididymal white adipose tissue (eWAT) in WKY but not in SHR rats. Supplementation with GPE (300 mg/kg body weight/day) reduced adipocyte diameter and increased levels of proteins that participate in adipogenesis and angiogenesis, i.e., peroxisome-proliferator activated receptor gamma (PPARγ), vascular endothelial grow factor-A (VEGF-A) and its receptor 2 (VEGF-R2), and partially increased the uncoupling protein 1 (UCP-1) in WKY. In both strains, GPE attenuated adipose inflammation. In eWAT from SHR, GPE increased the expression of proteins involved in adipose tissue "browning," i.e., PPARγ-coactivator-1α (PGC-1α), PPARγ, PR domain containing 16 (PRDM16) and UCP-1. In primary cultures of SHR adipocytes, GPE-induced UCP-1 up-regulation was dependent on p38 and ERK activation. Accordingly, in 3T3-L1 adipocytes treated with palmitate, the addition of GPE (30 µM) activated the ß-adrenergic signaling cascade (PKA, AMPK, p38, ERK). This led to the associated up-regulation of proteins involved in mitochondrial biogenesis (PGC-1α, PPARγ, PRDM16 and UCP-1) and fatty acid oxidation (ATGL). These effects were similar to those exerted by (-)-epicatechin and quercetin, major phenolic compounds in GPE. Overall, in HFD-fed rats, supplementation with GPE promoted brown-like cell formation in eWAT and diminished adipose dysfunction. Thus, winemaking residues, rich in bioactive compounds, could be useful to mitigate the adverse effects of HFD-induced adipose dysfunction.

Grape pomace and grape pomace extract improve insulin signaling in high-fat-fructose fed rat-induced metabolic syndrome.

In this study the effect of diet supplementation with grape pomace (GP) and grape pomace extract (GPE) on insulin sensitive tissues (adipose, liver and muscle) was evaluated in an experimental model of metabolic syndrome (MetS). MetS was developed by giving a high-fat-fructose (HFF) diet to Wistar rats. Six weeks of HFF diet induced weight gain, which was partially attenuated by GP (1 g per kg per day) and GPE (300 mg per kg per day) supplementation. HFF diet increased systolic blood pressure, triglycerides, insulin resistance (HOMA:IR) and inflammation (c-reactive protein (CRP)). Supplementation with GP prevented SBP, triglycerides and CRP increased and partially attenuated insulin resistance. On the other hand, GPE partially reduced SBP and triglycerides and significantly prevented insulin resistance and inflammation. Also, HFF diet induced higher triglycerides content and enhanced NADPH oxidase activity in the liver. Also, HFF diet increased the epididymal adipose tissue weight, enlarged adipocyte size, and c-jun N-terminal kinase (JNK) activation, probably contributing to a pro-inflammatory cytokine pattern (higher resistin) and lower adiponectin protein expression. These alterations may result in an impairment of insulin signaling cascade observed in adipose, liver and muscle tissue (IRS1, Akt, and extracellular signal-regulated kinases (ERK1/2)) from HFF rats. Supplementation with GP and to a greater extent GPE attenuated liver triglyceride content and adiposity and restored adipose, liver and muscle response to insulin. These findings show that supplementation with GP and GPE to a greater extent can counteract adiposity, inflammation, liver damage and impaired insulin signaling associated to MetS, supporting the utilization of winemaking residues in food industry/human health due to their high amount of bioactive compounds.

Melatonin, given at the time of reperfusion, prevents ventricular arrhythmias in isolated hearts from fructose-fed rats and spontaneously hypertensive rats.

Melatonin reduces reperfusion arrhythmias when administered before coronary occlusion, but in the clinical context of acute coronary syndromes, most of the therapies are administered at the time of reperfusion. Patients frequently have physiological modifications that can reduce the response to therapeutic interventions. This work determined whether acute melatonin administration starting at the moment of reperfusion protects against ventricular arrhythmias in Langendorff-perfused hearts isolated from fructose-fed rats (FFR), a dietary model of metabolic syndrome, and from spontaneous hypertensive rats (SHR). In both experimental models, we confirmed metabolic alterations, a reduction in myocardial total antioxidant capacity and an increase in arterial pressure and NADPH oxidase activity, and in FFR, we also found a decrease in eNOS activity. Melatonin (50 µm) initiated at reperfusion after 15-min regional ischemia reduced the incidence of ventricular fibrillation from 83% to 33% for the WKY strain, from 92% to 25% in FFR, and from 100% to 33% in SHR (P = 0.0361, P = 0.0028, P = 0.0013, respectively, by Fisher's exact test, n = 12 each). Although, ventricular tachycardia incidence was high at the beginning of reperfusion, the severity of the arrhythmias progressively declined in melatonin-treated hearts. Melatonin induced a shortening of the action potential duration at the beginning of reperfusion and in the SHR group also a faster recovery of action potential amplitude. We conclude that melatonin protects against ventricular fibrillation when administered at reperfusion, and these effects are maintained in hearts from rats exposed to major cardiovascular risk factors. These results further support the ongoing translation to clinical trials of this agent.

Efecto del poscondicionamiento isquémico sobre las arritmias de reperfusión en un modelo de hipertrofia miocárdica

Introducción: el poscondicionamiento isquémico (PCI) es una estrategia protectora contra la injuria por reperfusión con propiedades antiarrítmicas. La hipertrofia cardíaca secundaria a la hipertensión arterial aumenta el riesgo de sufrir arritmias y, además, reduce la respuesta a algunos tratamientos. Objetivo: determinar si el efecto antiarrítmico del PCI se mantiene en corazones hipertróficos. Método: los corazones aislados de ratas Wistar Kyoto (WKY) y de ratas espontáneamente hipertensas (SHR) de la misma edad, fueron perfundidos según la técnica de Langendorff y sometidos a 15 min de isquemia regional. Al momento de la reperfusión se dividieron en: a) WKY, b) WKY-PCI, c) SHR, d) SHR-PCI (n=13 por grupo). El PCI consistió en tres ciclos de 30 s de reperfusión y 30 s de isquemia, al inicio de la reperfusión. Se clasificaron las arritmias ventriculares observadas en el ECG. Se estimó la hipertrofia por el peso cardíaco relativo. Resultados: la hipertensión arterial en las ratas SHR provocó hipertrofia miocárdica. Todos los corazones sufrieron una alta incidencia de fibrilación ventricular al inicio de la reperfusión (SHR 92,3% y WKY 77%, ns). El PCI restituyó el ritmo sinusal en los corazones de las ratas normotensas (WKY-PCI 61,5% vs WKY 23,1%, p=0,0236 por test de ji2) y en los de las SHR (SHR-PCI 69,2% vs SHR 15,4%, p=0,0016 test de ji2). Conclusión: el PCI fue capaz de restituir el ritmo sinusal en la mayoría de los corazones que presentaron arritmias ventriculares de reperfusión y el efecto antiarrítmico se mantuvo en corazones hipertróficos provenientes de ratas SHR.

Introduction: ischemic postconditioning (IPC) is a protective strategy against reperfusion injury with antiarrhythmic properties. Cardiac hypertrophy secondary to hypertension increases the risk of arrhythmias and also reduces the response to some treatments. Objective: to determine whether the antiarrhythmic effect of IPC was maintained in hypertrophic hearts. Methods: isolated rat hearts from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) of the same age, were perfused according to Langendorff technique and subjected to 15 min regional ischemia. At the moment of reperfusion, hearts were divided into: a) WKY, b) WKY-IPC, c) SHR, d) SHR-IPC (each group, n= 13). The IPC consisted of 3 cycles of 30 s of reperfusion and 30 s of ischemia at the onset of reperfusion. Ventricular arrhythmias were diagnosed using ECG records. Hypertrophy was estimated by relative heart weight. Results: hypertension in SHR induce myocardial hypertrophy. All hearts underwent a high incidence of ventricular fibrillation (SHR 92,3% and WKY 77%, ns). IPC restored sinus rhythm in the hearts of normotensive rats (WKY-PCI 61,5% versus WKY 23,1%, p = 0,0236 by chi2 test) and in those from SHR (SHR-PCI 69% versus SHR 15,4%, p = 0,0016 chi2 test). Conclusion: IPC is able to restore sinus rhythm from most of the hearts that developed reperfusion ventricular arrhythmias and the antiarrhythmic effect remains in hypertrophic hearts from SHR rats.

Garlic and onion attenuates vascular inflammation and oxidative stress in fructose-fed rats.

This study evaluates the antioxidant and the anti-inflammatory properties of garlic (G) and onion (O) in fructose-fed rats (FFR). Thirty-day-old male Wistar rats were assigned to control (C), F (10% fructose in drinking water), F+T (tempol 1 mM as control antioxidant), F+G, and F+O. Aqueous G and O extracts were administered orally in doses of 150 and 400 mg/kg/d respectively, and along with tempol, were given during the last 8 weeks of a 14-week period. At the end of the study, FFR had developed insulin resistance, aortic NADPH oxidase activity, increased SBP, plasma TBARS and vascular cell adhesion molecule-1 (VCAM-1) expression in mesenteric arteries, and a decrease in heart endothelial nitric oxide synthase (eNOS). Garlic and onion administration to F rats reduced oxidative stress, increased eNOS activity, and also attenuated VCAM-1 expression. These results provide new evidence showing the anti-inflammatory and antioxidant effect of these vegetables.

Aqueous garlic extracts prevent oxidative stress and vascular remodeling in an experimental model of metabolic syndrome.

The organosulfur profile and the effect on oxidative stress and vascular remodeling in fructose-fed rats (FFR) were evaluated in Fuego INTA and Morado INTA garlic cultivars. Wistar rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. During the last 6 weeks of a 12 week period of the corresponding diet, a subgroup of control and FFR received an aqueous extract of Fuego INTA and Morado INTA. Fuego INTA showed higher levels of total thiosulfinates, allicin, and pungency than Morado INTA. FFR showed an increase of systolic blood pressure, aortic NAD(P)H oxidase activity, plasma thiobarbituric acid reactive substances, and vascular remodeling that was significantly reduced after both garlic administrations. The beneficial effect was slightly higher when Fuego INTA was administered. Both aqueous garlic extracts prevent oxidative stress and vascular remodeling in rats with metabolic syndrome, suggesting the existence of slight differences among cultivars.

Dealcoholized red wine reverse vascular remodeling in an experimental model of metabolic syndrome: role of NAD(P)H oxidase and eNOS activity.

The present study examines the effect of chronic administration of dealcoholized red wine Malbec (DRW) on vascular remodeling and NAD(P)H oxidase and endothelial nitric oxide synthase activity (eNOS) in an experimental model of metabolic syndrome induced by fructose administration. Thirty-day old male Wistar rats were fed a normal rat diet (control) or the same diet plus 10% fructose in drinking water (FFR). During the last 4 weeks of a 10-week period of the corresponding diet, a subgroup of control and FFR (n=8 each) received DRW in their drinking water. Systolic blood pressure (SBP), a homeostasis model assessment of insulin resistance (HOMA-IR), aortic NAD(P)H oxidase and eNOS activity in the heart and vascular tissue were evaluated. Vascular remodeling was evaluated in the left carotid artery (CA) and interlobar, arcuate and interlobular renal arteries (RA) through lumen to media (L/M) ratio determination. At the end of the study FFR increased the SBP (p < 0.001), HOMA-IR (p < 0.001), and aortic NAD(P)H oxidase activity (p < 0,05) but reduced cardiac and vascular eNOS activity (p < 0.01), L/M ratio in CA (p < 0.001) and RA (p < 0.01) compared with the C group. DRW reduced SBP (p < 0.05), aortic NAD(P)H oxidase (p < 0.05), and recovered eNOS activity (p < 0.001) and L/M in CA (p < 0.001) and RA (p < 0.001) compared with FFR. This study provides new data about the beneficial effect of DRW on oxidative stress and vascular remodeling in the experimental model of metabolic syndrome. Data suggest the participation of mechanisms involving oxidative stress in FFR alterations and the usefulness of natural antioxidant substances present in red wine in the reversion of these changes.

A novel electrophysiologic effect of melatonin on ischemia/reperfusion-induced arrhythmias in isolated rat hearts.

Reperfusion after a short period of cardiac ischemia triggers ventricular arrhythmias attributable to ionic imbalance and oxidative stress. Melatonin offers some degree of protection, but its effects on the cardiac action potentials are unknown. We evaluated the effects of 5, 10, 20 and 50 microM melatonin in isolated perfused rat hearts subjected to 10 min of regional ischemia. ECG and membrane potentials were synchronously displayed. After 15 min of reperfusion, total antioxidant capacity (TAC) was determined. Melatonin did not change the ischemic depolarization nor the action potential amplitude depression, but at the end of ischemia the action potential duration (APD) decreased in control and 5 microM melatonin-treated hearts. By contrast, it returned to preischemic levels in hearts given 20 and 50 microM melatonin. Melatonin reduced the incidence of reperfusion arrhythmias from 100% in control to 50% in 5 and 10 microM, to 40% in 20 microM and 30% in 50 microM hearts. TAC values were higher at all melatonin concentrations. We conclude that melatonin reduced the incidence of reperfusion arrhythmias because of its antioxidant effects. In addition, at 20 and 50 microM lengthened APD and promoted an improved protection. This latter effect should be considered when in vivo applications of melatonin are considered.