Pharmaco-invasive therapy: Early implementation of statins and proprotein convertase subtilisin/kexin type 9 inhibitors after acute coronary syndrome.

Elevated LDL-cholesterol (LDL-C) plays a major role in atheroma formation and inflammation. Medical therapy to lower elevated LDL-C is the cornerstone for reducing the progression of atherosclerotic cardiovascular disease. Statin therapy, and more recently, other drugs such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven efficacy in long-term lowering of LDL-C and therefore diminish cardiovascular risk. During an acute coronary syndrome (ACS), a systemic inflammatory response can destabilize other non-culprit atherosclerotic plaques. Patients with these vulnerable plaques are at high risk of experiencing recurrent cardiovascular events in the first few years post-ACS. Initiating intensive LDL-C lowering therapy in these patients with statins or PCSK9 inhibitors can be beneficial via several pathways. High-intensity statin therapy can reduce inflammation by directly lowering LDL-C, but also through its pleiotropic effects. PCSK9 inhibitors can directly lower LDL-C to recommended guideline thresholds, and could have additional effects on inflammation and plaque stability. We discuss the potential role of early implementation of statins combined with PCSK9 inhibitors to influence these cascades and to mediate the associated cardiovascular risk, over and above the well-known long-term beneficial effects of chronic LDL-C lowering.

The association between treatment and systemic inflammation in acromegaly.

OBJECTIVE: Acromegaly is characterized by an excess of growth hormone (GH) and insulin like growth-factor 1 (IGF1), and it is strongly associated with cardiovascular diseases (CVD). Both acute and long-lasting pro-inflammatory effects have been attributed to IGF1. Previous results suggest the presence of systemic inflammation in treated patients. Here we assessed the association between treatment of acromegaly, systemic inflammation and vascular function. DESIGN: Ex vivo cytokine production and circulating inflammatory markers were assessed in peripheral blood from treated and untreated acromegaly patients (N = 120), and compared them with healthy controls. A more comprehensive prospective inflammatory and vascular assessment was conducted in a subgroup of six treatment-naive patients with follow-up during treatment. RESULTS: Circulating concentrations of VCAM1, E-selectin and MMP2 were higher in patients with uncontrolled disease, whereas the concentrations of IL18 were lower. In stimulated whole blood, cytokine production was skewed towards a more pro-inflammatory profile in patients, especially those with untreated disease. Prospective vascular measurements in untreated patients showed improvement of endothelial function during treatment. CONCLUSIONS: Acromegaly patients are characterized by a pro-inflammatory phenotype, most pronounced in those with uncontrolled disease. Treatment only partially reverses this pro-inflammatory bias. These findings suggest that systemic inflammation could contribute to the increased risk of CVD in acromegaly patients.

Cerebrotendinous xanthomatosis without neurological involvement.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism. Neurological symptoms are considered to be a clinical hallmark of untreated adult patients. We describe a 'milder CTX phenotype', without neurological involvement. METHODS: We performed a retrospective patient file study in 79 genetically confirmed Dutch patients with CTX (55 patients aged ≥ 21 years) to study the clinical heterogeneity of CTX. We studied the frequency of adult patients with CTX without neurological involvement at diagnosis, in our Dutch cohort, and included a family from South Africa and patients from Italy, USA, Chile and Asia from the literature. RESULTS: In total, we describe 19 adult patients with CTX from 16 independent families, without neurological symptoms at diagnosis. A relatively small percentage (21%, n = 4) had a history of cataract. The majority, 84% (n = 16), presented with tendon xanthomas as the sole or predominant feature. The majority of patients showed increased plasma cholesterol levels. No correlation was found between this 'milder phenotype', the cholestanol levels and the CYP27A1 genotype. In addition, we describe three novel mutations in the CYP27A1 gene. CONCLUSIONS: This study shows the clinical heterogeneity of CTX, highlighting the existence of a 'milder phenotype', that is without neurological involvement at diagnosis. Adult patients with CTX may present with tendon xanthomas as the sole or predominant feature, mimicking familial hypercholesterolemia. It is important to realize that the absence of neurological symptoms does not rule out the development of future neurological symptoms. As CTX is a treatable disorder, early diagnosis and initiation of treatment when additional clinical signs occur is therefore essential.

Remote ischaemic preconditioning does not modulate the systemic inflammatory response or renal tubular stress biomarkers after endotoxaemia in healthy human volunteers: a single-centre, mechanistic, randomised controlled trial.

BACKGROUND: Remote ischaemic preconditioning (RIPC) consists of repeated cycles of limb ischaemia and reperfusion, which may reduce perioperative myocardial ischaemic damage and kidney injury. We hypothesised that RIPC may be beneficial by attenuating the systemic inflammatory response. We investigated whether RIPC affects the response in humans to bacterial endotoxin (lipopolysaccharide [LPS]) by measuring plasma cytokines and renal cell-cycle arrest mediators, which reflect renal tubular stress. METHODS: Healthy male volunteers were randomised to receive either daily RIPC for 6 consecutive days (RIPCmultiple, n=10) plus RIPC during the 40 min preceding i.v. LPS (2 ng kg-1), RIPC only during the 40 min before LPS (RIPCsingle, n=10), or no RIPC preceding LPS (control, n=10). As a surrogate marker of renal tubular stress, the product of urinary concentrations of two cell-cycle arrest markers was calculated (tissue inhibitor of metalloproteinases-2 [TIMP2]*insulin-like growth factor binding protein-7 [IGFBP7]). Data are presented as median (inter-quartile range). RESULTS: In both RIPC groups, RIPC alone increased [TIMP2]*[IGFBP7]. LPS administration resulted in fever, flu-like symptoms, and haemodynamic alterations. Plasma cytokine concentrations increased profoundly during endotoxaemia (control group: tumor necrosis factor alpha [TNF-α] from 14 [9-16] pg ml-1 at baseline to 480 [284-709] pg ml-1 at 1.5 h after LPS; interleukin-6 [IL-6] from 4 [4-4] pg ml-1 at baseline to 659 [505-1018] pg ml-1 at 2 h after LPS). LPS administration also increased urinary [TIMP2[*[IGFBP7]. RIPC had no effect on LPS-induced cytokine release or [TIMP2]*[IGFBP7]. CONCLUSIONS: RIPC neither modulated systemic cytokine release nor attenuated inflammation-induced tubular stress after LPS. However, RIPC alone induced renal markers of cell-cycle arrest. CLINICAL TRIAL REGISTRATION: NCT02602977.

Plant-based sterols and stanols in health & disease: "Consequences of human development in a plant-based environment?"

Dietary plant sterols and stanols as present in our diet and in functional foods are well-known for their inhibitory effects on intestinal cholesterol absorption, which translates into lower low-density lipoprotein cholesterol concentrations. However, emerging evidence suggests that plant sterols and stanols have numerous additional health effects, which are largely unnoticed in the current scientific literature. Therefore, in this review we pose the intriguing question "What would have occurred if plant sterols and stanols had been discovered and embraced by disciplines such as immunology, hepatology, pulmonology or gastroenterology before being positioned as cholesterol-lowering molecules?" What would then have been the main benefits and fields of application of plant sterols and stanols today? We here discuss potential effects ranging from its presence and function intrauterine and in breast milk towards a potential role in the development of non-alcoholic steatohepatitis (NASH), cardiovascular disease (CVD), inflammatory bowel diseases (IBD) and allergic asthma. Interestingly, effects clearly depend on the route of entrance as observed in intestinal-failure associated liver disease (IFALD) during parenteral nutrition regimens. It is only until recently that effects beyond lowering of cholesterol concentrations are being explored systematically. Thus, there is a clear need to understand the full health effects of plant sterols and stanols.

Postural orthostatic tachycardia syndrome (POTS): a common but unfamiliar syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a condition in which a change from a supine to an upright position causes an abnormally large increase in heart rate which may be accompanied by a variety of physical complaints. We report two cases illustrating the heterogeneity of this syndrome. We give an update on the etiology of POTS, which is still poorly understood, and its overlap with other syndromes such as chronic fatigue syndrome. Clinicians should be aware of POTS, a fairly common clinical entity, that can result in significant impairments to a patient's quality of life. Lifestyle measures (under which adequate fluid and salt intake, exercise) are a first line of treatment; if insufficient, pharmacotherapy can be considered to improve quality of life.

Role of gut microbiota in chronic low-grade inflammation as potential driver for atherosclerotic cardiovascular disease: a systematic review of human studies.

A hallmark of obesity is chronic low-grade inflammation, which plays a major role in the process of atherosclerotic cardiovascular disease (ACVD). Gut microbiota is one of the factors influencing systemic immune responses, and profound changes have been found in its composition and metabolic function in individuals with obesity. This systematic review assesses the association between the gut microbiota and markers of low-grade inflammation in humans. We identified 14 studies which were mostly observational and relatively small (n = 10 to 471). The way in which the microbiome is analysed differed extensively between these studies. Lower gut microbial diversity was associated with higher white blood cell counts and high sensitivity C-reactive protein (hsCRP) levels. The abundance of Bifidobacterium, Faecalibacterium, Ruminococcus and Prevotella were inversely related to different markers of low-grade inflammation such as hsCRP and interleukin (IL)-6. In addition, this review speculates on possible mechanisms through which the gut microbiota can affect low-grade inflammation and thereby ACVD. We discuss the associations between the microbiome and the inflammasome, the innate immune system, bile acids, gut permeability, the endocannabinoid system and TMAO. These data reinforce the importance of human research into the gut microbiota as potential diagnostic and therapeutic strategy to prevent ACVD.

Characterization of a model of systemic inflammation in humans in vivo elicited by continuous infusion of endotoxin.

Investigating the systemic inflammatory response in patients with critical illness such as sepsis, trauma and burns is complicated due to uncertainties about the onset, duration and severity of the insult. Therefore, in vivo models of inflammation are essential to study the pathophysiology and to evaluate immunomodulatory therapies. Intravenous bolus administration of endotoxin to healthy volunteers is a well-established model of a short-lived systemic inflammatory response, characterized by increased plasma cytokine levels, flu-like symptoms and fever. In contrast, patients suffering from systemic inflammation are often exposed to inflammatory stimuli for an extended period of time. Therefore, continuous infusion of endotoxin may better reflect the kinetics of the inflammatory response encountered in these patients. Herein, we characterize a novel model of systemic inflammation elicited by a bolus infusion of 1 ng/kg, followed by a 3hr continuous infusion of 1 ng/kg/h of endotoxin in healthy volunteers, and compared it with models of bolus administrations of 1 and 2 ng/kg of endotoxin. The novel model was well-tolerated and resulted in a more pronounced increase in plasma cytokine levels with different kinetics and more prolonged symptoms and fever compared with the bolus-only models. Therefore, the continuous endotoxin infusion model provides novel insights into kinetics of the inflammatory response during continuous inflammatory stimuli and accommodates a larger time window to evaluate immunomodulating therapies.

[Ischemic stroke in young women]. / Herseninfarct bij jonge vrouwen.

- In virtually all age groups, the incidence of ischemic stroke is higher in men. However, in women aged between 25-49 years the prevalence is higher than in men. Female-specific risk factors and disorders may explain this peak.- Pregnancy and the post-partum period are associated with physiological changes which can increase blood coagulation. Complications during pregnancy may also increase the risk of ischaemic stroke.- Migraine with aura and antiphospholipid syndrome are disorders which are also associated with an increased risk of ischaemic stroke. These disorders are more common in women compared to men. Furthermore, hormonal contraceptives containing oestrogen are also identified to increase the incidence of ischaemic stroke.- The acute treatment and secondary prevention of ischaemic stroke in young women is identical to that in elderly stroke patients, be it men or women, although thrombolysis and platelet aggregation inhibition in pregnant women should be approached with care.- Clinical outcomes after stroke for women under the age of 50 are worse compared to age-matched men.

[Hypertension due to fibromuscular dysplasia: look for additional disease sites]. / Hypertensie door fibromusculaire dysplasie.

Fibromuscular dysplasia (FMD) is a non-inflammatory, non-atherosclerotic vasculopathy that can lead to arterial stenosis, occlusion, aneurysms, and dissection. FMD of the renal arteries can lead to renovascular hypertension. Percutaneous angioplasty of the renal arteries (PTRA) can lead to normalization of blood pressure in 45% of patients with renal artery stenosis caused by FMD, particularly in younger patients and patients with a short history of hypertension. A considerable number of the patients with renovascular FMD also have cervical FMD, which can lead to ischaemic or haemorrhagic stroke. In this article we discuss diagnostic and therapeutic options, illustrated by two cases of patients with renovascular and carotid FMD. Most of the recommendations are based on data from retrospective studies and expert opinion; prospective studies on the optimal diagnostic strategy and treatment are therefore, urgently required.

The effect of dipyridamole on the pharmacokinetics of metformin: a randomized crossover study in healthy volunteers.

PURPOSE: Concomitant treatment with the glucose-lowering drug metformin and the platelet aggregation inhibitor dipyridamole often occurs in patients with type 2 diabetes mellitus who have suffered a cerebrovascular event. The gastrointestinal uptake of metformin is mediated by the human equilibrative nucleoside transporter 4 (ENT4), which is inhibited by dipyridamole in preclinical studies. We hypothesized that dipyridamole lowers the plasma exposure to metformin. METHODS: Eighteen healthy volunteers (mean age 23 years; 9 male) were randomized in an open-label crossover study. Subjects were allocated to treatment with metformin 500 mg twice daily in combination with dipyridamole slow-release 200 mg twice daily or to metformin alone for 4 days. After a washout period of 10 days, the volunteers were crossed over to the alternative treatment arm. Blood samples were collected during a 10-h period after intake of the last metformin dose. The primary endpoint was the area under the plasma concentration-time curve (AUC0-12h) and the maximum plasma metformin concentration (C max). RESULTS: In healthy subjects, dipyridamole did not significantly affect Cmax nor AUC0-12h of metformin under steady-state conditions. CONCLUSIONS: Previous in vitro studies report that dipyridamole inhibits the ENT4 transporter that mediates gastrointestinal uptake of metformin. In contrast, co-administration of dipyridamole at therapeutic dosages to healthy volunteers does not have a clinically relevant effect on metformin plasma steady-state exposure. This observation is reassuring for patients who are treated with this combination of drugs.

Effect of dipyridamole on myocardial reperfusion injury: A double-blind randomized controlled trial in patients undergoing elective coronary artery bypass surgery.

Dipyridamole reduces reperfusion-injury in preclinical trials and may be beneficial in patients undergoing coronary angioplasty, but its effect on patients undergoing coronary artery bypass grafting (CABG) is unknown. We hypothesized that dipyridamole limits myocardial reperfusion-injury in patients undergoing CABG. The trial design was a double-blind trial randomizing between pretreatment with dipyridamole or placebo. In all, 94 patients undergoing elective on-pump CABG were recruited between February 2010 and June 2012. The primary endpoint was plasma high-sensitive (hs-) troponin-I at 6, 12, and 24 hours after reperfusion. Secondary endpoints were the occurrence of bleeding, arrhythmias, need for inotropic support, and intensive care unit length of stay. Finally, 79 patients (33 dipyridamole) were included in the per-protocol analysis. Dipyridamole did not significantly affect postoperative hs-troponin-I (change in plasma hs-troponin I -3% [95% confidence interval -23% to 36%]; P > 0.1). Secondary endpoints did not differ between groups. Dipyridamole prior to CABG does not significantly reduce postoperative hs-troponin release.

Ticagrelor Does Not Inhibit Adenosine Transport at Relevant Concentrations: A Randomized Cross-Over Study in Healthy Subjects In Vivo.

BACKGROUND AND PURPOSE: In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo. EXPERIMENTAL APPROACH: In a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg) affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was measured. Primary endpoint was adenosine-induced vasodilation. KEY RESULTS: Ticagrelor did not affect adenosine- or dipyridamole-induced forearm vasodilation. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was not affected by ticagrelor. In vitro, ticagrelor dose-dependently inhibited nucleoside uptake, but only at supra-physiological concentrations. CONCLUSION AND IMPLICATIONS: In conclusion, at relevant plasma concentration, ticagrelor does not affect adenosine transport, nor adenosine formation in healthy subjects. Therefore, it is unlikely that this mechanism is a relevant pleiotropic effect of ticagrelor. TRIAL REGISTRATION: ClinicalTrials.gov NCT01996735.

[Antihypertensives: better evenings than mornings]. / Antihypertensiva: beter's avonds dan's ochtends?

In a reasonably large proportion of patients who take antihypertensive drugs (10-30%), hypertension appears to be therapy resistant; even the use of three antihypertensives does not lower the blood pressure sufficiently. The average nocturnal blood pressure is a better predictor of cardiovascular events than blood pressure measured during the day. Antihypertensives have a stronger effect on nocturnal blood pressure when taken in the evening rather than in the morning. The exact mechanism of this has not yet been unravelled, but randomised, non-blinded studies suggest that this so-called chronotherapy does indeed lower cardiovascular risk in certain groups. The authors regard this as a promising strategy for patients with therapy-resistant hypertension in whom a nocturnal blood pressure dip does not occur.

Measurement of the endogenous adenosine concentration in humans in vivo: methodological considerations.

The endogenous nucleoside adenosine has profound tissue protective effects in situations of ischaemia or inflammation. Animal studies have shown that various drugs can activate this protective mechanism by interfering with the metabolism of adenosine. Translation of this concept to the clinical arena is hampered by the difficulties encountered in measuring the adenosine concentration, due to the rapid cellular uptake and degradation of adenosine, which continues unabated after blood sampling, and due to the metabolically active endothelial barrier for adenosine. In the current paper, we critically discuss the various methods to measure the adenosine concentration in humans in vivo. For the measurement of circulating adenosine, we conclude that the use of a pharmacological blocker solution (containing inhibitors of the enzymes ecto-5'-nucleotidase, adenosine deaminase, and adenosine kinase, and of the equilibrative nucleoside transporter) and a purpose-built syringe which mixes the blood with this solution immediately at the tip of the needle, seems to be the most sensitive technique. However, for the measurement of adenosine concentrations in interstitial tissue, microdialysis is a suitable method, when used with an appropriate method to determine the recovery of adenosine across the semipermeable membrane to calculate the absolute adenosine concentration. Consistent use of these methods could help in the comparison of the various studies focussed on endogenous adenosine and could help to facilitate the use of drugs that modulate the adenosine concentration to protect tissues in the clinical arena.

Dipyridamole enhances ischaemia-induced reactive hyperaemia by increased adenosine receptor stimulation.

BACKGROUND AND PURPOSE: Dipyridamole enhances post-occlusive reactive hyperaemia (PORH) in the human forearm vascular bed. We hypothesize that this effect is completely mediated by increased adenosine receptor stimulation. To test this hypothesis, the effect of caffeine (an adenosine receptor antagonist) on dipyridamole-induced augmentation of PORH was explored. EXPERIMENTAL APPROACH: The forearm vasodilator responses to three increasing periods of forearm ischaemia (2, 5 and 13 min) were determined during placebo infusion. Forty minutes after the last reperfusion period, this procedure was repeated during intra-arterial infusion of dipyridamole (7.4 nmol min(-1) per 100 ml forearm). At least 2 weeks later, this whole procedure was repeated, but now in the presence of caffeine (90 microg min(-1) per 100 ml volume). KEY RESULTS: After 2, 5 and 13 min of ischaemia, the average forearm blood flow increased to 5.6+/-0.7, 9.7+/-1.3 and 34.5+/-2.1 ml min(-1) per 100 ml. After infusion of dipyridamole into the brachial artery, these numbers were significantly increased to 7.7+/-0.8, 12.5+/-1.5 and 41.6+/-3.1 ml min(-1) per 100 ml. This response was abolished by the concomitant infusion of caffeine (6.6+/-0.5, 10.2+/-0.6, 35.1+/-2.2 (caffeine) versus 7.4+/-0.4, 10.5+/-0.6, 33.7+/-2.2 ml min(-1)per 100 ml (caffeine/dipyridamole)). CONCLUSIONS AND IMPLICATIONS: Caffeine prevented the augmenting effect of dipyridamole on PORH. This indicates that dipyridamole-induced augmentation of PORH is mediated via increased adenosine receptor stimulation as a result of elevated extracellular formation of adenosine during ischaemia.

Methotrexate modulates the kinetics of adenosine in humans in vivo.

BACKGROUND: Animal studies suggest that the anti-inflammatory effect of methotrexate (MTX) is mediated by increased adenosine concentrations. OBJECTIVE: To assess the effect of MTX on the vasodilator effects of adenosine and the nucleoside uptake inhibitor, dipyridamole, in humans in vivo as a marker for changes in adenosine kinetics. METHODS: Ten patients with active arthritis were treated with MTX (15 mg/week). Measurements were performed before and after 12 weeks of treatment. At these time points, the activity of adenosine deaminase was measured in isolated lymphocytes, and forearm blood flow (FBF) was determined by venous occlusion plethysmography during administration of adenosine and dipyridamole into the brachial artery. RESULTS: The Vmax of adenosine deaminase in lymphocytes was reduced by MTX treatment (p<0.05). MTX significantly enhanced vasodilator response to adenosine (0.5 and 1.5 microg/min/dl of forearm tissue; mean (SE) FBF ratio increased from 1.2 (0.2) to 1.4 (0.2) and 2.2 (0.2) ml/dl/min, respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 3.2 (0.5) ml/dl/min during MTX treatment; p<0.05). Also, dipyridamole-induced vasodilatation (30 and 100 microg/min/dl) was enhanced by MTX (FBF ratio increased from 1.2 (0.2) to 1.5 (0.3) and 1.8 (0.2), respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 2.4 (0.4) during MTX treatment; p<0.05). CONCLUSIONS: MTX treatment inhibits deamination of adenosine and potentiates adenosine-induced vasodilatation. Also dipyridamole-induced vasodilatation is enhanced by MTX treatment, suggesting an increased extracellular formation of adenosine. These effects on the adenosine kinetics in humans may contribute to the therapeutic efficacy of MTX.

Recurrent pancreatitis after trimethoprim-sulfamethoxazole rechallenge.

We report a female patient who repeatedly developed pancreatitis after trimethoprim-sulfamethoxazole (TMP/SMX) use. During childhood she had undergone an ureterosigmoidostomy after which she had been on TMP/SMX 480 mg daily as prophylaxis for pyelonephritis for many years. The patient presented with abdominal pain caused by acute pancreatitis. No other cause, except for TMP/SMX use, could be identified. A causal relationship was confirmed by relapse of the pancreatitis after rechallenge. Our case is unique in demonstrating that acute pancreatitis related to the use of TMP/SMX may occur even after long-term treatment. We advise that the medication is discontinued immediately if a causal relationship with pancreatitis is suspected.