Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology.

The coexistence of type 2 diabetes mellitus (T2DM) and heart failure (HF), either with reduced (HFrEF) or preserved ejection fraction (HFpEF), is frequent (30-40% of patients) and associated with a higher risk of HF hospitalization, all-cause and cardiovascular (CV) mortality. The most important causes of HF in T2DM are coronary artery disease, arterial hypertension and a direct detrimental effect of T2DM on the myocardium. T2DM is often unrecognized in HF patients, and vice versa, which emphasizes the importance of an active search for both disorders in the clinical practice. There are no specific limitations to HF treatment in T2DM. Subanalyses of trials addressing HF treatment in the general population have shown that all HF therapies are similarly effective regardless of T2DM. Concerning T2DM treatment in HF patients, most guidelines currently recommend metformin as the first-line choice. Sulphonylureas and insulin have been the traditional second- and third-line therapies although their safety in HF is equivocal. Neither glucagon-like preptide-1 (GLP-1) receptor agonists, nor dipeptidyl peptidase-4 (DPP4) inhibitors reduce the risk for HF hospitalization. Indeed, a DPP4 inhibitor, saxagliptin, has been associated with a higher risk of HF hospitalization. Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in patients with (or at risk of) HF. In recent trials, sodium-glucose co-transporter-2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have both shown a significant reduction in HF hospitalization in patients with established CV disease or at risk of CV disease. Several ongoing trials should provide an insight into the effectiveness of SGLT2 inhibitors in patients with HFrEF and HFpEF in the absence of T2DM.

Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The effect of the α-glucosidase inhibitor acarbose on cardiovascular outcomes in patients with coronary heart disease and impaired glucose tolerance is unknown. We aimed to assess whether acarbose could reduce the frequency of cardiovascular events in Chinese patients with established coronary heart disease and impaired glucose tolerance, and whether the incidence of type 2 diabetes could be reduced. METHODS: The Acarbose Cardiovascular Evaluation (ACE) trial was a randomised, double-blind, placebo-controlled, phase 4 trial, with patients recruited from 176 hospital outpatient clinics in China. Chinese patients with coronary heart disease and impaired glucose tolerance were randomly assigned (1:1), in blocks by site, by a centralised computer system to receive oral acarbose (50 mg three times a day) or matched placebo, which was added to standardised cardiovascular secondary prevention therapy. All study staff and patients were masked to treatment group allocation. The primary outcome was a five-point composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure, analysed in the intention-to-treat population (all participants randomly assigned to treatment who provided written informed consent). The secondary outcomes were a three-point composite outcome (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, development of diabetes, and development of impaired renal function. The safety population comprised all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513. FINDINGS: Between March 20, 2009, and Oct 23, 2015, 6522 patients were randomly assigned and included in the intention-to-treat population, 3272 assigned to acarbose and 3250 to placebo. Patients were followed up for a median of 5·0 years (IQR 3·4-6·0) in both groups. The primary five-point composite outcome occurred in 470 (14%; 3·33 per 100 person-years) of 3272 acarbose group participants and in 479 (15%; 3·41 per 100 person-years) of 3250 placebo group participants (hazard ratio 0·98; 95% CI 0·86-1·11, p=0·73). No significant differences were seen between treatment groups for the secondary three-point composite outcome, death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, or impaired renal function. Diabetes developed less frequently in the acarbose group (436 [13%] of 3272; 3·17 per 100 person-years) compared with the placebo group (513 [16%] of 3250; 3·84 per 100 person-years; rate ratio 0·82, 95% CI 0·71-0·94, p=0·005). Gastrointestinal disorders were the most common adverse event associated with drug discontinuation or dose changes (215 [7%] of 3263 patients in the acarbose group vs 150 [5%] of 3241 in the placebo group [p=0·0007]; safety population). Numbers of non-cardiovascular deaths (71 [2%] of 3272 vs 56 [2%] of 3250, p=0·19) and cancer deaths (ten [<1%] of 3272 vs 12 [<1%] of 3250, p=0·08) did not differ between groups. INTERPRETATION: In Chinese patients with coronary heart disease and impaired glucose tolerance, acarbose did not reduce the risk of major adverse cardiovascular events, but did reduce the incidence of diabetes. FUNDING: Bayer AG.

Sodium-glucose Cotransporter 2 Inhibitors (SGLT2i): Their Role in Cardiometabolic Risk Management.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel category of oral antidiabetic drugs that inhibit renal glucose reabsorption and increase renal glucose excretion, thus lowering plasma glucose levels. This unique mechanism of SGLT2i action is insulin independent, thus improving glycemic control without promoting hypoglycemia in the absence of exogenously administered insulin. METHODS: The present narrative review addresses the putative associations between SGLT2i and several cardiovascular (CV) and microvascular risk factors, as well as their effects on cardiac and renal function. RESULTS: SGLT2i improve several CV risk factors, including fasting and postprandial plasma glucose levels, lipids, blood pressure, body weight, serum uric acid and arterial stiffness. These drugs may also favorably modulate cardiac and renal function via their effects on inflammation, oxidative stress, diuresis, fluid and sodium retention, myocardial function, vascular resistance and 'fuel' metabolism. In the EMPA-REG OUTCOME study, the first published large CV outcome SGLT2i trial, empagliflozin significantly reduced the primary composite outcome (i.e. CV death, nonfatal myocardial infarction or stroke) and all-cause death as well as hospitalization for heart failure. In addition, empagliflozin was associated with a slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care in patients at high CV risk. CONCLUSION: Multiple metabolic benefits may account for the positive clinical outcomes in the EMPA-REG OUTCOME study. Ongoing CV outcome trials involving other SGLT2i will help establish whether the reported CV and microvascular risk benefits are compound-specific or drug class effects.

Modeling the oral glucose tolerance test in normal and impaired glucose tolerant states: a population approach.

OBJECTIVE: The conventional approach to analyzing data from oral glucose tolerance testing (OGTT) requires model identification in each individual separately (standard two stage, STS), ignoring knowledge about the population as a whole. In practice, however, the OGTT is sparsely sampled and individual estimates are often not resolvable from available data. This weakness is often encountered in large scale trials or epidemiological studies, leading to either multiple imputations or simply much less data available for analysis. METHODS: We have applied a population approach, nonlinear mixed effects modeling, to plasma glucose, insulin and C-peptide data obtained from a 120 minute OGTT undertaken by 106 subjects with varying glucose tolerance. This method provides estimates of population means, variances and covariances of model parameters and empirical Bayes estimates of individual parameter values, as well as measures of intra-individual (within-subject) and inter-individual (between-subject) variability. The recently developed oral glucose minimal model was used to evaluate insulin sensitivity, and a combined model approach was used to assess ß-cell secretion. RESULTS: Applying these models allowed for the reconstruction of insulin secretion and glucose absorption profiles and gave population indexes of insulin sensitivity (SI = 6.51 ± 1.20 × 10-4 min-1·µU-1·ml), fractional hepatic extraction of insulin (F = 0.522 ± 0.291) and fractional insulin clearance (kI = 0.258 ± 0.151 min-1). Whereas the traditional approach to parameter estimation failed to recover estimates in more than one third of the population, the population approach provided individual estimates in all subjects. Examination of the empirical Bayes estimates showed that individual parameter estimates were able to differentiate well between individuals at glucose tolerant states ranging from euglycemia to overt type 2 diabetes. CONCLUSIONS: Our findings suggest that population analysis is a powerful tool for obtaining accurate assessments of indexes of insulin sensitivity and ß-cell function from the OGTT, especially in epidemiological studies with large numbers of sparsely sampled subjects.

Insulin dose adjustments with add-on glucagon-like peptide-1 receptor (GLP-1R) agonists in clinical practice.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are gaining ground as therapeutic modalities in combination with insulin in patients with type 2 diabetes mellitus. Exploiting the multiple benefits of incretin-based therapies in certain patient populations, especially in those who would benefit most from potential weight loss or prevention of body weight gain, has provided a valuable add-on option in diabetes management. However, caution needs to be exercised when initiating such a double injectable therapy, as evidence indicates that, in most instances, the insulin dose needs to be re-adjusted. The majority of published studies suggest reduction of insulin dose, especially related to the 'bolus' component; however, some have also recommended that insulin dose should actually be increased, but we found no credible evidence to support the latter. An important determinant of the titration process is the insulin formulation already in use at baseline. As more potent and long-acting GLP-1RAs are introduced, optimal insulin dose scaling is a major challenge, especially in a primary setting. We provide an overview of the current knowledge in this rapidly changing field. Based on currently reported evidence, a reduction of basal insulin by 10% and a decrease of prandial insulin by 30 - 40% is recommended on addition of GLP-1RAs.

Rationale for and design of the Acarbose Cardiovascular Evaluation (ACE) trial.

Patients with cardiovascular disease and impaired glucose tolerance are at increased risk of cardiovascular events and type 2 diabetes mellitus (T2DM). Lifestyle modification or pharmacological intervention can delay progression to T2DM, but there is no clear evidence that they reduce cardiovascular risk in this population. Acarbose, an α-glucosidase inhibitor that lowers postprandial blood glucose, has been shown to reduce T2DM risk by 25%, and possibly cardiovascular risk in impaired glucose tolerance subjects without cardiovascular disease.

On the potential of acarbose to reduce cardiovascular disease.

In the emerging landscape of cardiovascular (CV) outcome trials evaluating the effects of blood glucose lowering drugs in individuals with type 2 diabetes, it is becoming increasingly apparent that since the promising signals coming from the United Kingdom Prospective Diabetes Study (UKPDS) no unequivocal benefits have been established for any single therapy thus far. There is an unmet need for introducing an effective pharmacological agent which could target both correlates of glycaemic regulation and CV risk factors, to ameliorate the enormous burden of fatal and non-fatal CV events in diabetic patients. Acarbose, like other alpha-glucosidase inhibitors (AGIs), has been proven to be an effective antidiabetic treatment for decades, but the overall significant impact of this class of drugs on modulating CV risk has only recently been appreciated. Accumulating evidence has shown that apart from its multiple effects on primarily postprandial glucose dysmetabolism, a key component of mechanisms linked to increased incidence of CV events, acarbose therapy also associates with a favorable impact on an array of surrogate markers of CV disease. Data stemming from in vitro testing of human cell lines as well as from preliminary trials in diabetic populations, like the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial, have highlighted - though not undisputed - the potential beneficial effects of the drug on CV morbidity. Large scale trials, like the ongoing Acarbose Cardiovascular Evaluation (ACE) trial, aim at conclusively establishing such a positive effect in patients with coronary heart disease and impaired glucose tolerance. In view of its usually acceptable level of side effects that are, if they occur, mostly limited to transient gastrointestinal symptoms, acarbose could well be a strong future player in CV disease secondary prevention. Current discouraging results from many trials of antidiabetic medications to significantly lower CV event rates in diabetic patients, should only draw further attention on alternative glucose lowering agents, among which acarbose is indeed promising.

Nutritional clinical studies in dermatology.

BACKGROUND & AIMS: Nutrition has long been associated with skin health, beauty, integrity and aging through multiple pathways and cofactors implicated in skin biology. The onset and clinical course of various common skin diseases, especially acne, psoriasis, atopic dermatitis, and hair loss, have been suggested to be critically affected by nutrition patterns and habits. The relationship between acne and diet, predominantly the role of high glycemic load diets and dairy consumption have recently gained increased interest. Abnormal nutritional conditions such as obesity or malnutrition often manifest themselves by specific cutaneous features and altered skin function. Skin photoprotection, rendered by various nutrients, is well documented and appropriate nutritional supplementation has been shown to exert beneficial effects upon impaired skin integrity, restore its appearance and promote skin health. It is our intention to provide a comprehensive review of the most recent information on the role of nutrition for common skin diseases and regulation of skin biology. METHODS: Nutritional clinical studies in dermatology have been reviewed using the MedLine literature source and the terms "diet" or "nutrition" and "skin". RESULTS & CONCLUSIONS: The data on the relationship between nutrition and skin are until now controversial and much more work is needed to be done to clarify possible etiological correlations.

Diurnal correlation of ambulatory blood pressure and interstitial glucose in patients with normal glucose tolerance.

OBJECTIVE: Among the physiological variables whose diurnal profile is governed by circadian rhythmicity, plasma glucose concentrations, and arterial blood pressure constitute key elements of the physiological regulation of energy homeostasis. Evidence on their diurnal association derived from frequent measurements of both variables is, however, lacking in humans. METHODS: We investigated the relationship between blood pressure levels recorded by an ambulatory device and interstitial glucose concentrations on an outpatient basis, in patients with normal glucose tolerance (N=20), either normotensive (group A; N=10), or newly diagnosed with essential hypertension (group B; N=10). RESULTS: In the population throughout the 24-h monitoring period, there was a significant positive correlation between interstitial glucose concentrations and systolic, diastolic, and mean 24-h blood pressure levels, which was retained in patients with hypertension compared with normotensive patients. In patients with newly diagnosed hypertension, interstitial glucose concentrations exhibit significant correlation to systolic blood pressure levels during the 24-h period, but no association with diastolic and mean blood pressure during the night, whereas the reverse is the case in patients with normal glucose tolerance and normal blood pressure. CONCLUSION: Diurnal variations of continuously monitored interstitial glucose concentrations significantly associate with blood pressure levels in both normotensive and hypertensive humans, indicating a common pathway of circadian autoregulation, probably stemming from both central mechanisms and peripheral inputs. Such a pathway might underlie similar pathophysiological aberration in disease states such as the metabolic syndrome.

The association between glycemia and endothelial function in nondiabetic individuals: the importance of body weight.

The aim of this study was to examine the association between glycemia and markers of early atherosclerosis in healthy nondiabetic individuals. In 309 individuals without diabetes or symptomatic cardiovascular disease, we assessed long-term glycemia by glycosylated hemoglobin (HbA1c) and endothelial function by flow-mediated dilatation (FMD) in the brachial artery. HbA1c was negatively associated with FMD (r = -0.162, P = 0.004). Multivariate linear regression analysis after adjusting for common risk factors of cardiovascular disease showed that BMI was an effect modifier of the association between HbA1c and FMD (P = 0.034 for the HbA1c x BMI interaction). We stratified the FMD outcome data into two groups separated by the median BMI (group 1: BMI < or = 26.1 kg/m(2) and group 2: BMI > 26.1 kg/m(2)). In the lower BMI group, HbA1c was an independent predictor of FMD even when adjusted for confounding factors associated with impaired glucose metabolism (r = -0.215, P = 0.009), but in the higher BMI group HbA1c was not associated with FMD (r = -0.051, P = 0.5). In a nondiabetic population, long-term glycemia was associated with endothelial dysfunction only in lean individuals. In the overweight individuals, this association was not apparent, possibly because some of the mechanisms that mediate the effect of glycemia on vascular function are shared by obesity.

Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1.

Glucagon-like peptide-1 (GLP-1), released from gut endocrine L cells in response to glucose, regulates appetite, insulin secretion, and gut motility. How glucose given orally, but not systemically, induces GLP-1 secretion is unknown. We show that human duodenal L cells express sweet taste receptors, the taste G protein gustducin, and several other taste transduction elements. Mouse intestinal L cells also express alpha-gustducin. Ingestion of glucose by alpha-gustducin null mice revealed deficiencies in secretion of GLP-1 and the regulation of plasma insulin and glucose. Isolated small bowel and intestinal villi from alpha-gustducin null mice showed markedly defective GLP-1 secretion in response to glucose. The human L cell line NCI-H716 expresses alpha-gustducin, taste receptors, and several other taste signaling elements. GLP-1 release from NCI-H716 cells was promoted by sugars and the noncaloric sweetener sucralose, and blocked by the sweet receptor antagonist lactisole or siRNA for alpha-gustducin. We conclude that L cells of the gut "taste" glucose through the same mechanisms used by taste cells of the tongue. Modulating GLP-1 secretion in gut "taste cells" may provide an important treatment for obesity, diabetes and abnormal gut motility.

Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP.

Among the products of enteroendocrine cells are the incretins glucagon-like peptide-1 (GLP-1, secreted by L cells) and glucose-dependent insulinotropic peptide (GIP, secreted by K cells). These are key modulators of insulin secretion, glucose homeostasis, and gastric emptying. Because of the rapid early rise of GLP-1 in plasma after oral glucose, we wished to definitively establish the absence or presence of L cells, as well as the relative distribution of the incretin cell types in human duodenum. We confirmed the presence of proglucagon and pro-GIP genes, their products, and glucosensory molecules by tissue immunohistochemistry and RT-PCR of laser-captured, single duodenal cells. We also assayed plasma glucose, incretin, and insulin levels in subjects with normal glucose tolerance and type 2 diabetes for 120 min after they ingested 75 g of glucose. Subjects with normal glucose tolerance (n=14) had as many L cells (15+/-1), expressed per 1,000 gut epithelial cells, as K cells (13+/-1), with some containing both hormones (L/K cells, 5+/-1). In type 2 diabetes, the number of L and L/K cells was increased (26+/-2; P<0.001 and 9+/-1; P < 0.001, respectively). Both L and K cells contained glucokinase and glucose transporter-1, -2, and -3. Newly diagnosed type 2 diabetic subjects had increased plasma GLP-1 levels between 20 and 80 min, concurrently with rising plasma insulin levels. Significant coexpression of the main incretin peptides occurs in human duodenum. L and K cells are present in equal numbers. New onset type 2 diabetes is associated with a shift to the L phenotype.

In vivo biological activity of exendin (1-30).

Activation of the glucagon-like peptide-1 (GLP-1) receptor on pancreatic beta cells by GLP-1 and exendin-4 increases insulin secretion. Exendin-4 is 39 amino acids long, unlike GLP-1 which has 30 amino acids. Because of its non-mammalian (lizard) origin and unique C-terminal sequence, exendin-4 may be immunogenic in humans. We showed previously that the C terminally truncated exendin peptide exendin (1-30) has a reduced affinity for the GLP-1 receptor and a diminished ability to increase intracellular cAMP in insulinoma cells. Here we show that daily intraperitoneal injection of exendin (1-30) (1 nmol/kg) for 20 d followed by 31 d twice daily to Lepr(db)/Lepr(db) (db/db) mice significantly reduced the amount of visceral fat relative to saline-treated controls and improved HbA1C (control 9.5 +/- 0.2% vs treated 7.9 +/- 0.2%, p = 0.001) but was not as effective as exendin-4. To examine the ability of exendin (1-30) to stimulate beta-cell growth, we injected one group of 3-mo-old Fisher rats with exendin (1-30) (1 nmol/kg) and another group with saline for 8 d. We observed no change in beta-cell area, but did see a change in the number of islets with nuclei positive for BrdU [10.7 +/- 1.8% exendin (1-30) vs 6.5 +/- 0.5% control].

Elevated plasma glucose-dependent insulinotropic polypeptide associates with hyperinsulinemia in impaired glucose tolerance.

OBJECTIVE: The role of gut-derived incretin, glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory peptide [GIP]), in compensatory beta-cell hypersecretion during insulin-resistant states and in transition to beta-cell failure in type 2 diabetes is unknown. RESEARCH DESIGN AND METHODS: We carried out oral glucose tolerance testing followed by blood sampling 10 times for 2 h on 68 age- and BMI-matched participants of the Baltimore Longitudinal Study on Aging (BLSA) with normal glucose tolerance (34 subjects), impaired glucose tolerance (IGT) (18 subjects with both impaired fasting and 2-h plasma glucose levels), and type 2 diabetes (16 subjects with both diabetic fasting and 2-h plasma glucose levels). We assayed plasma glucose, insulin, C-peptide, glucagon, and intact and total GIP levels and quantitated glucose and hormone responses to the oral glucose tolerance test. We also compared GIP and insulin release and sensitivity indexes between groups. RESULTS: After glucose ingestion, subjects with IGT had both hyperinsulinemia and hyperemia, while subjects with type 2 diabetes had both beta- and GIP-cell deficiency. In the former group, there was also a significant positive correlation between the augmented plasma intact and total GIP levels and both fasting and post-oral glucose load plasma insulin levels. CONCLUSIONS: Elevated plasma GIP levels are correlated with hyperinsulinemia in the impaired glucose-tolerant state, whereas type 2 diabetes is associated with a failure to secrete adequate amounts of both GIP and insulin, indicating a common pathway of resistance to and eventually failure of glucose responsiveness in beta- and GIP-cells.

The importance of the nine-amino acid C-terminal sequence of exendin-4 for binding to the GLP-1 receptor and for biological activity.

Exendin-4, a 39-amino acid (AA) peptide, is a long-acting agonist at the glucagon-like peptide-1 (GLP-1) receptor. Consequently, it may be preferable to GLP-1 as a long-term treatment for type 2 diabetes mellitus. Exendin-4 (Ex-4), unlike GLP-1, is not degraded by dipeptidyl peptidase IV (DPP IV), is less susceptible to degradation by neutral endopeptidase, and possesses a nine-AA C-terminal sequence absent from GLP-1. Here we examine the importance of these nine AAs for biological activity of Ex-4, a sequence of truncated Ex-4 analogs, and native GLP-1 and GLP-1 analogs to which all or parts of the C-terminal sequence have been added. We found that removing these AAs from Ex-4 to produce Ex (1-30) reduced the affinity for the GLP-1 receptor (GLP-1R) relative to Ex-4 (IC50: Ex-4, 3.22+/-0.9 nM; Ex (1-30), 32+/-5.8 nM) but made it comparable to that of GLP-1 (IC50: 44.9+/-3.2 nM). The addition of this nine-AA sequence to GLP-1 improved the affinity of both GLP-1 and the DPP IV resistant analog GLP-1 8-glycine for the GLP-1 receptor (IC50: GLP-1 Gly8 [GG], 220+/-23 nM; GLP-1 Gly8 Ex (31-39), 74+/-11 nM). Observations of the cAMP response in an insulinoma cell line show a similar trend for biological activity.

Is there a place for inhaled nitric oxide in the therapy of acute pulmonary embolism?

Acute pulmonary embolism (PE) is a serious complication resulting from the migration of emboli to the lungs. Although deep venous thrombi are the most common source of emboli to the lungs, other important sources include air, amniotic fluid, fat and bone marrow. Regardless of the specific source of the emboli, very little progress has been made in the pharmacological management of this high mortality condition. Because the prognosis is linked to the degree of elevation of pulmonary vascular resistance, any therapeutic intervention to improve the hemodynamics would probably increase the low survival rate of this critical condition. Inhaled nitric oxide (iNO) has been widely tested and used in cases of pulmonary hypertension of different causes. In the last few years some authors have described beneficial effects of iNO in animal models of acute PE and in anecdotal cases of massive PE. The primary cause of death in massive PE that is caused by deep venous thrombi, gas or amniotic fluid, is acute right heart failure and circulatory shock. Increased pulmonary vascular resistance following acute PE is the cumulative result of mechanical obstruction of pulmonary vessels and pulmonary arteriolar constriction (attributable to a neurogenic reflex and to the release of vasoconstrictors). As such, the vasodilator effects of iNO could actively oppose the pulmonary hypertension following PE. This hypothesis is consistently supported by experimental studies in different animal models of PE, which demonstrated that iNO decreased (by 10 to 20%) the pulmonary artery pressure without improving pulmonary gas exchange. Although maximal vasodilatory effects are probably achieved by less than 5 parts per million iNO, which is a relatively low concentration, no dose-response study has been published so far. In addition to the animal studies, a few anecdotal reports in the literature suggest that iNO may improve the hemodynamics during acute PE. However, no prospective, controlled, randomized clinical trial addressing this issue has been conducted to date. Future investigations addressing the effects of iNO combined with other drugs such as vasoconstrictors and inhibitors of phosphodiesterase III or V, may increase the responsiveness to iNO in acute PE.