Current Vascular Pharmacology - Volume 16, Issue 4, 2018

Inodilators are a heterogeneous group of drugs with vasodilatory and inotropic effects. The cardioprotective effect of levosimendan is multifactorial, but now research on levosimendan is focused on the organ-protective properties of this drug in different settings, the regimen that seems to provide the greatest cardiologic and systemic benefits is early administration of levosimendan. We try to answer four questions in this review, which type of patients need this drug? what is the best time to start with it? and the best way that we could give it and finally the reasons for use it.

The implementation of cardioprotective strategies involving pre-, intra-, and postoperative interventions is key during cardiac surgery requiring extracorporeal circulation (ECC). The primary goal of this study was to review the physiopathology and protection strategies against myocardial damage secondary to ECC during cardiac surgery. The administration halogenated anesthetics for cardiac anesthesia is common place due to their well-known cardioprotective effects and their capacity to ensure hypnosis. An optimal myocardial protection strategy requires that a comprehensive approach should be adopted to cover pre-, intra-, and post-operative interventions. Pre-conditioning and post-conditioning share numerous pathways, mainly based on mitochondrial signaling, antiapoptotic pathways, and reduced inflammatory mediators. However, volatile anesthetic can also be administered during ECC, in which mechanism of action has been scantly investigated, during this period and its biology is still unknown.

Regardless of the degree of advances in neuroprotective strategies, and despite the technological progress in neuromonitoring, brain injury still remains the “Achilles' heel” in cardiac surgery. A large number of pharmacological and non-pharmacological therapeutic interventions have been investigated during the last two decades. Recently, both theoretical and experimental findings suggest benefits of pharmacological cerebral protection, although, there is no conclusive evidence of clinical superiority of specific agents that have been applied as neuroprotectants, in human randomized controlled trials. Pre-ischemic conditioning has also been used in an attempt to reduce the incidence of brain injury following cardiac surgery. In light of previous evidence showing that pharmacologic preconditioning with a single dose of erythromycin induces tolerance against transient global cerebral ischemia in rats, we examined whether erythromycin would reduce the number of apoptotic neurons in the neocortex in our acute porcine model of hypothermic circulatory arrest (HCA). Pre-ischemic conditioning with a single dose of the antibiotic erythromycin, applied 12 h before HCA, significantly reduced neuronal injury in the neocortex of the porcine brain, suggesting that cerebral protection may be achieved with erythromycin pharmacological preconditioning in cardiac surgery on an experimental basis. Since erythromycin has been effectively used in clinical practice with few side effects, these findings suggest that it could be a promising candidate for potential clinical neuroprotective strategy.

Halogenated anesthetic agents (desflurane, isoflurane and sevoflurane) may have cardioprotective properties at therapeutic doses against myocardial intraoperative ischemia-reperfusion injury. Cardioprotection mechanisms are related to mitochondrial and anti-apoptotic signaling pathways. Experimentals and human studies have proven that their use may reduce morbidity and mortality in the setting of cardiac surgery, including a reduction in myocardial infarct size and mechanical ventilation needs. In contrast, total intra-venous propofol based anesthesia may be detrimental. In the present review, we show the rationale for the perioperative use of halogenated anesthetics based on mechanisms of action, experimental research and human studies. Considerations and major concerns regarding their use, the present evidence for their use in other areas, such as major non-cardiac surgery and intensive care unit patients, and future perspectives are also discussed.

Undersea diving is a sport and commercial industry. Knowledge of potential problems began with Caisson disease or “the bends”, first identified with compressed air in the construction of tunnels under rivers in the 19th century. Subsequently, there was the commercially used old-fashioned diving helmet attached to a suit, with compressed air pumped down from the surface. Breathhold diving, with no supplementary source of air or other breathing mixture, is also a sport as well as a commercial fishing tool in some parts of the world. There has been an evolution to self-contained underwater breathing apparatus (SCUBA) diving with major involvement as a recreational sport but also of major commercial importance. Knowledge of the physiology and cardiovascular plus other medical problems associated with the various forms of diving have evolved extensively. The major medical catastrophes of SCUBA diving are air embolism and decompression sickness (DCS). Understanding of the essential referral to a hyperbaric recompression chamber for these problems is critical, as well as immediate measures until that recompression is achieved. These include the administration of 100% oxygen and rehydration with intravenous normal saline. Undersea diving continues to expand, especially as a sport, and a basic understanding of the associated preventive and emergency medicine will decrease complications and save lives.

Background: Vitamin D is a fat soluble vitamin involved in calcium and bone metabolism; recently its deficiency has been related to cardiovascular disease. In cardiac tissue, vitamin D suppresses metalloproteinases (MMPs) expression, enzymes directly associated with vulnerable plaque. Objective: To investigate whether the association between vitamin D and leptin is related to markers of vulnerable plaque, such as MMPs in patients with acute myocardial infarction. Methods: We studied 66 male patients with acute myocardial infarction, undergoing primary angioplasty. Blood samples were obtained at admission and 24hs after the surgery. Leptin and vitamin D concentrations in serum and MMP-2 and -9 activities in plasma were determined. Results: MMP-2 activity was increased in Vitamin D deficient/insufficient patients at admission (p=0.04) and 24 hs later (p=0.05). In a linear regression model, vitamin D explained 24% of the variance of MMP-2 activity (F=2.839 p=0.04). At admission, vitamin D correlated with serum leptin (r=-0.302 p=0.033), and explained 39.5% of its variation (F=4.432 p=0.003). Conclusion: In the studied population, vitamin D was inversely related to MMP-2 and leptin which are involved in coronary artery disease and acute myocardial infarction. The decrease in this hormone levels would be associated with a worse metabolic profile in acute coronary syndrome patients.

Background: We described lifestyle changes one year after acute coronary syndrome (ACS) among patients in Arabian Gulf countries. Methodology: Data of patients admitted to 29 hospitals in 4 countries with the diagnosis of ACS were analysed from Gulf citizens with ACS events (Gulf COAST) registry. A total of 3565 ACS patients recruited in the Gulf COAST registry had a one-year follow up available. There was a significant correlation between return to work and the age of patient (p < .001). At one-year post ACS, the majority were performing their usual activities (93%), but only 39% were exercising. Smoking cessation was successful in 60% of patients and most non-quitters tried or considered quitting (18 and 21% of the total population of smokers, respectively). Sexual activity was reported from 2290 male patients at one-year follow up. The majority reported performing sexual activity (66%) with no fear of sexual intercourse (57%). Results and Conclusion: At one year after an ACS, the majority of our patients returned to their work, sexual activity and other usual activity. Clearly, improvement is needed when it comes to smoking cessation and exercise.

Background: Dyslipidaemia is a risk factor for macrovascular complications in patients with type 2 diabetes mellitus (T2DM). Our aim was to assess the use of lipid lowering drugs (LLDs) in patients with T2DM and co-existing dyslipidaemia. Method: A multicentre, non-interventional survey conducted in 6 Middle Eastern countries (Bahrain, Oman, Qatar, United Arab Emirates, Kingdom of Saudi Arabia and Kuwait). Patients with T2DM (n = 3338) taking LLD treatment for ≥3 months with no dose change for ≥6 weeks were enrolled. Results: The mean age (SD) of T2DM patients was 56.6 ±10.6 years; the majority (99%) were on statin monotherapy. Only 48% of these patients achieved their low density lipoprotein cholesterol (LDL-C) goal and 67.7% of the patients had a high cardiovascular disease (CVD) risk according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines. Of those who achieved LDL-C goals (n=1589), approximately one-third were at very high CVD risk and the patients who had received statin monotherapy showed the highest proportion in LDL-C goal attainment, followed by those treated with fibrate monotherapy. In a multivariate logistic regression model, taking drugs daily (odds ratio, OR: 1.64, 95% CI 1.25, 2.15) and older age (OR: 1.09, 95% CI 1.01, 1.18) were significantly associated with better odds of attaining LDL-C target. In contrast, patients with higher levels of ApoA1 (OR: 0.73, 95% CI [0.67,0.79]), Metabolic Syndrome (OR: 0.64, 95% CI [0.53, 0.76]), higher CV risk (OR: 0.33, 95% CI 0.27, 0.41), those who forgot to take their medication (OR: 0.74, 95% CI 0.62,0.88) and those who stopped taking medication when cholesterol became normal (OR: 0.67, 95% CI 0.55,0.82) were significantly associated with lower odds of attaining LDL-C target. Conclusion: The results of this study highlight the suboptimal management of dyslipidaemia in T2DM patients at high and very high risk of CVD.

Background: Apolipoproteins A-I and B (apoA-I and apoB) may be better indicators of the risk of cardiovascular and cerebrovascular diseases than conventional risk factors (RFs). The onset of ischemic stroke (IS) may be preceded by the development of atherosclerotic changes in carotid arteries, which can be detected by ultrasound. Only a certain % of patients with IS have an (underlying) carotid etiology. Objective: The aim of our study was to determine the association between ultrasound indicators of carotid atherosclerosis and the presence of apolipoproteins and other biomarkers in patients with IS. Methods: The study included 120 patients with clinically first, non-cardioembolic ischemic stroke in the carotid circulation. For all patients the following data were recorded: risk factors (hypertension, diabetes, hyperlipoproteinemia, smoking, obesity, metabolic syndrome, (MetS) hyperhomocysteinemia and inflammation), and levels of blood pressure, glucose, glycosylated hemoglobin, lipids, apoA-I and apoB apolipoproteins, body mass index, homocysteine, and C-reactive protein (CRP). Carotid duplex ultrasound was used to measure carotid intima media thickness (cIMT) and determine the presence of an unstable (hypoechogenic) plaque. Results: The most significant associations were found between cIMT and older age (β=0.230; p=0.006), lower concentrations of apoA-I (β=-0.244; p=0.008) and a higher apoB/apoA-I ratio (β=0.247; p=0.007). The presence of a hypoechogenic plaque was most significantly associated with increased concentrations of apoB (OR=2.29; 95% CI=4.9-173.5; p<0.0001), the presence of MetS (OR=9.2; 95% CI=2.9-29.2; p<0.0001) and elevated CRP (OR=2.7; 95% CI=1.1-6.9; p = 0.046). Conclusion: Among RFs and their biomarkers, apoA-I, apoB and the apoB/apoA-I ratio showed strong association with ultrasound indicators of carotid atherosclerosis in IS patients.

Background: Enhanced postprandial lipaemia has been reported in patients with obesity, hypertension, metabolic syndrome and type 2 diabetes mellitus (T2DM). We compared 2 oral fat meal tests (LIPOLD: 149g of fat, 56g of carbohydrates and 11.7g of proteins administrated per 2m2 of body surface) and LIPOTEST: 75g of fat, 25g of carbohydrates and 10g of protein with the addition of 15g common sugar) with regard to changes in triglycerides (TGs) as well as other cardiometabolic parameters between baseline and 4 h after the meals. Methods: We studied 21 men [median age (interquartile range; IQR) = 65 (16) years] with wellcontrolled T2DM [median glycated haemoglobin (HbA1c) (IQR) = 6.6 (0.9) %]. All participants performed the meals with 1 week interval between the 2 meals. Results: Median (IQR) TG differences in mg/dl were 86 (100) and 46 (60) for LIPOLD and LIPOTEST meals, respectively, whereas the % differences in TGs were 105 (105) and 48 (55), respectively. The differences (in mg/dl and %) between TGs before ingesting the test meal and after 4h were significant for both LIPOLD and LIPOTEST meals (p = 0.003 for mg/dl differences and p = 0.005 for % differences). Patients who had a positive response to the LIPOLD meal (i.e. TGs > 220 mg/dl at 4 h) also had increased postprandial TGs with LIPOTEST. The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) correlated with TG differences (in mg/dl) following the LIPOLD meal consumption (Spearman's rho = (+) 0.527, p = 0.02). C-peptide correlated with TG differences (in mg/dl) following the LIPOTEST meal consumption (Spearman's rho = (+) 0.538, p = 0.032). There were no differences in TGs and glucose response postprandially in both testing meals according to body mass index (except for TGs between tertile 21.3-24.5 and 25-26.8 kg/m2, p=0.046, in LPOTEST group) and body surface area. Conclusion: An oral fat tolerance test (OFTT), which contains 75g fat, and represents the everyday habits of Western societies, could provide additional information regarding the postprandial state of the individuals with well-controlled T2DM. The consumption of meals with very high fat content may lead to over diagnosing PPL. TG differences after the consumption of a high fat meal correlated with HOMA-IR. This may be useful to evaluate the role of HOMA-IR in T2DM patients. A standardized the OFTT will help clinicians to better define postprandial TG abnormalities, leading to more appropriate therapeutic options to improve postprandial dysmetabolism.

Objective: Arterial Stiffness (AS) and Non-Alcoholic Fatty Liver Diseases (NAFLD) are 2 related, prevalent, risk predictors of Cardiovascular Disease (CVD). We assessed the effect of low dose (5 mg/day) vs. high dose (20-40 mg/day) rosuvastatin on aortic elasticity and central haemodynamics as well as on NAFLD in patients with Arterial Hypertension (AH). Methods: Forty patients with optimally controlled AH were randomised to 2 rosuvastatin doses and followed for 6 months. 24h AS was assessed by Mobil-O-Graph, which calculates (adjusted for age and gender) Pulse Wave Velocity (PWV), adjusted for Heart Rate (HR) augmentation index (AIx75%) and central haemodynamics. The diagnosis of NAFLD was based on >5% liver steatosis on ultrasound and moderately elevated serum levels of liver enzymes. Results: Both doses of rosuvastatin reduced Central Pulse Pressure (cPP), PWV and AIx75% (adjusted for HR) to normal values (p = NS adjusted for age, gender and HR). Liver enzymes were reduced in those with NAFLD to normal, but steatosis was reduced more by the 20-40 mg/day rosuvastatin dose (p=0.01) compared with the 5 mg/day dose. Conclusion: Both doses of rosuvastatin had a beneficial effect on AS; the high dose was more efficient in reducing PWVs and central haemodynamics, and also the high dose was more effective in ameliorating NAFLD. Given that AH control was optimal and lipid values attained targets, 4 other CVD predictors were also addressed. Larger and longer term studies are needed to demonstrate the clinical benefit of such treatment preference.

Arterial stiffness, central haemodynamics and Non-Alcoholic Fatty Liver Disease (NAFLD) have been associated with increased risk for Cardiovascular (CV) morbidity and mortality. Antihypertensive, antidiabetic and hypolipidaemic drugs may affect these predictors of CV risk. Such associations should be taken into consideration when treating high-risk patients.

Background: Current European Guidelines suggest the use of cardiovascular risk categories and also recommend using high-intensity statins for patients with acute coronary syndromes (ACS). Objective: We examined the risk of ACS patients prior to the event, as well as the overall use and intensity of statins. Methods: We enrolled 687 ACS patients (mean age 63 years, 78% males). Low-density lipoprotein cholesterol (LDL-C) levels upon admission were used to assess attainment of LDL-C targets. Patients were categorized as very high, high, moderate and low risk based on their prior to admission cardiovascular (CV) risk. We examined statin use and dosage intensity among patients discharged from the hospital. Patients were followed for a median period of 189 days. Results: The majority of the patients (n=371, 54%) were at very high CV risk prior to admission, while 101 patients were at high risk (15%), 147 (21%) moderate risk and 68 (10%) low risk. Interestingly, LDL-C target attainment decreased as the risk increased (p<0.001). The majority (96%) of patients received statins at discharge; however, most of them (60.4%) received low/moderate intensity statins and just 35.9% received the suggested by the Guidelines high-intensity dose of statins. At follow-up, the rate of patients at high-intensity dose of statins remained similar (34.8%); 6% received no statins at all at follow-up. Conclusion: According to our study, the majority of ACS patients are already at high risk prior to their admission. Further, LDL-C targets are underachieved prior to the event and high-intensity statins are underutilized in ACS patients at, and post-discharge.