High mortality and morbidity among adults with congenital heart disease and type 2 diabetes.

OBJECTIVES: With improving prognosis the prevalence of adult congenital heart disease (ACHD) is increasing. Patients with type 2 diabetes mellitus (T2DM) have a shorter life expectancy compared with the general population. We investigated, in a large national diabetes registry, the prevalence of ACHD in combination with T2DM to estimate the associated clinical risk, outcome and patient characteristics. DESIGN: Data from the Swedish National Diabetes Register (NDR) were linked with the Swedish National Patient Register (NPR) and the Cause of Death Register. RESULTS: 833 ACHD patients were matched with 5 controls each. ACHD patients had significantly lower body mass index or BMI, higher creatinine and were more sedentary as compared with patients with T2DM but without congenital heart disease. The overall mortality was 26.2% for ACHD patients as compared with 19.9% (P < 0.001) for the control group, and five-year mortality rates were 5.2 versus 3.4%, P = 0.014. CONCLUSIONS: Congenital heart disease and secondary risk factors for cardiovascular disease frequently coexist and the development of T2DM also in the ACHD population is not uncommon with an estimated prevalence of between 4 and 8%. Treatment of conventional cardiovascular risk factors in patients with congenital heart disease could be considered secondary prevention given the relatively high morbidity and high risk for mortality observed in patients with the combination of ACHD and T2DM.

Mediterranean-inspired diet lowers the ratio of serum phospholipid n-6 to n-3 fatty acids, the number of leukocytes and platelets, and vascular endothelial growth factor in healthy subjects.

BACKGROUND: Reduced cardiovascular mortality and morbidity have been shown in persons adhering to Mediterranean-inspired diets (MIDs). Although the underlying mechanisms of this association are poorly understood, the importance of increasing dietary amounts of polyunsaturated fatty acids of the n-3 series has been emphasized. OBJECTIVE: We investigated whether a MID provided to healthy subjects would affect 1) the inflammatory process and endothelial indexes such as vasoregulation and vascular endothelial growth factor (VEGF) and 2) serum phospholipid fatty acid composition. DESIGN: A total of 22 subjects (10 women) received a MID or an ordinary Swedish diet (OSD) for 4 wk in a crossover fashion. Concentrations of lipids and fatty acids, high-sensitivity C-reactive protein, and interleukin 6, both before and after lipopolysaccharide stimulation; the number of leukocytes and platelets; and VEGF and monocyte chemoattractant protein 1 were analyzed. RESULTS: The plasma ratio of n-6 to n-3 fatty acids was substantially lower after the MID than after the OSD (x +/- SEM: 4.72 +/- 0.19 and 2.60 +/- 0.17, respectively; P < 0.0001). Neither C-reactive protein nor interleukin 6 concentrations changed significantly after the MID compared with the OSD. The total number of leukocytes and platelets was 10% (P < 0.05) and 15% (P < 0.001) lower, respectively, after the MID than after the OSD. Serum VEGF concentrations were lower after the MID than after the OSD (237 +/- 30 and 206 +/- 25 pg/mL, respectively; P = 0.0014). CONCLUSIONS: A MID reduces the number of platelets and leukocytes and VEGF concentrations in healthy subjects. This may be linked to higher serum concentrations of n-3 fatty acids, which promote a favorable composition of phospholipids.

Blunted vascular response to endothelin-a receptor blockade in cyclosporine-treated lung transplant recipients.

BACKGROUND: The majority of cyclosporine-treated transplant recipients develop hypertension. Endothelin-1 (ET-1) has been suggested to mediate cyclosporine-induced vasoconstriction when binding to ET-A receptors. We hypothesized that cyclosporine-treated lung transplant recipients have an increased basal vascular resistance and an augmented response to ET-A receptor blockade. METHODS: The selective ET-A receptor blocker BQ-123 (10 and 50 nmol/min) was infused into the brachial artery, alone or in combination with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) (2 and 4 micromol/min) in 10 lung transplant recipients without pharmacologically treated hypertension and 8 healthy controls. Forearm blood flow (FBF) was measured by venous occlusion plethysmography and plasma levels of ET-1 were analyzed. RESULTS: Baseline forearm vascular resistance did not differ between recipients and controls (32 +/- 4 vs 42 +/- 7 mmHg/ml/min, p = 0.32). BQ-123 increased FBF in controls but not in recipients (26% +/- 9% vs 5% +/- 11% at 10 nmol/min, p = 0.043 between groups). Coinfusion of BQ-123 and L-NMMA caused a comparable decrease in FBF in recipients and controls (-26% +/- 11%, vs -34% +/- 7%). Baseline ET-1 was higher in recipients (17.2 +/- 1.1 vs 14.7 +/- 0.8 pg/ml, p = 0.038). BQ-123 infusion increased plasma ET-1 in controls but not in recipients (+24% +/- 11% vs -0.4% +/- 6.2%, p = 0.029 between groups). CONCLUSIONS: The results demonstrate that cyclosporine-treated lung transplant recipients have increased plasma levels of ET-1 and a blunted response to ET-A receptor blockade compared with healthy subjects. In contrast, we found no evidence for an increased basal vascular resistance in transplant recipients. These alterations in endothelin handling may contribute to the development of transplant-associated hypertension.

Treatment with sorafenib and sunitinib in renal cell cancer: a Swedish register-based study.

Sorafenib and sunitinib are used for renal cell carcinoma (RCC). The objective was to study the treatment duration and time to death in Swedish RCC patients on sorafenib or sunitinib as first-line or monotherapy or as sequential therapy. Patients with an RCC diagnosis were identified in the Swedish Cancer Register. Information on treatment with sorafenib and sunitinib was collected from the Swedish Prescribed Drug Register, and time of death from the Cause of Death Register. Outcome measures were duration of treatment and time to death on sorafenib or sunitinib as first-line or monotherapy and sequential therapy (sorafenib-sunitinib versus sunitinib-sorafenib). Poisson regression models were used to estimate hazard ratios (HR) with 95 % confidence intervals (CI). No difference was observed for sorafenib (n = 123 patients) versus sunitinib (n = 261 patients) in treatment duration (HR 1.00; CI 0.80-1.24) or risk for death (HR 1.30; CI 0.91-1.85) when used as first-line or monotherapy. The same applied for sequential therapy with sorafenib-sunitinib (n = 43 patients) versus sunitinib-sorafenib (n = 54 patients), HR 1.47 (CI 0.71-3.02) and HR 2.01 (CI 0.86-4.68), respectively. There was a difference between the two treatments in how the duration of first-line treatment influenced the duration of second-line treatment and time to death, in favor of starting with sorafenib. In conclusion, no difference was detected between sorafenib and sunitinib in the duration of treatment or time to death when used as first-line or monotherapy. The impact of the duration of first-line treatment differed between the two sequences, and the results indicated that sorafenib as first-line treatment is a favorable choice.

Opioid rotation in patients initiated on oxycodone or morphine: a register study.

PURPOSE: Strong opioids are recommended for the treatment of moderate to severe pain. However, some patients do not achieve a successful treatment outcome due to intolerable adverse events and/or inadequate analgesia, thus may benefit from switching to another opioid, a procedure known as "opioid rotation." The type of opioid at treatment initiation may influence the risk of opioid rotation and the objective of this study was to assess such rotation after treatment initiation with two alternative treatments, controlled-release (CR) oxycodone versus CR morphine in patients suffering from non-cancer pain. METHOD: The study reported here was a real-life study based on Swedish register data: the Prescribed Drug, National Patient, and Cause of Death registers. The captured data cover the entire Swedish population treated in specialist care. A statistical analysis plan was agreed and signed before data were accessed. RESULTS: Data from 50,223 cases were included in the analyses. The risk of rotation was 19% higher in patients initiating treatment with morphine compared with oxycodone (hazard ratio 1.19; 95% confidence interval 1.11-1.27; P < 0.001), after adjusting for such baseline variables that were both significantly correlated with the outcome variable (time to rotation) and significantly different between the groups; age at index date, osteoarthritis and number of pain-related drugs. CONCLUSION: Patients with non-cancer pain who initiated treatment with CR morphine had a higher risk of opioid rotation than patients initiated with CR oxycodone.

Vascular resistance and endothelial function in cyclosporine-treated lung transplant recipients.

The majority of patients undergoing solid organ transplantation develop hypertension, to which vasoconstriction and impaired endothelial function have been suggested to contribute. We compared basal vascular resistance and nitric oxide-mediated endothelial-dependent and independent vasoreactivity between cyclosporine-treated lung transplant recipients and healthy subjects. Forearm blood flow was measured by venous occlusion plethysmography at rest and during acetylcholine, glyceryltrinitrate and N(G)-monomethyl-L-arginine acetate (L-NMMA) infusion in 11 lung transplant recipients 3-5 years after transplantation and in eight healthy subjects. Forearm vascular resistance (FVR) was calculated. Plasma levels of endothelin-1 (ET-1) and von Willebrand factor (vWf) were analysed. Basal vascular resistance was 40% lower in transplant recipients than in healthy subjects (P = 0.021). Endothelial-dependent and independent vasodilation did not differ. Plasma levels of ET-1 and vWf were higher in transplant recipients (P = 0.009 and P < 0.001 respectively). There was a significant correlation between ET-1 levels and FVR in healthy subjects (r = 0.83, P = 0.042), but not in transplant recipients (r = -0.14, P = 0.70). The findings oppose the theory of generalized vasoconstriction and impaired endothelial function in the pathogenesis of hypertension after transplantation. Increased plasma levels of ET-1 do not cause increased FVR in lung transplant recipients.

Autonomic control of the heart and renal vascular bed during autonomic dysreflexia in high spinal cord injury.

Autonomic function and hemodynamics were studied in nine spinal cord injured (SCI) subjects, at rest and during peripheral afferent stimulation, bladder percussion. Nine able-bodied subjects were studied for comparison during unstimulated conditions. Spontaneous baroreceptor reflex sensitivity was calculated from recordings of ECG and intraarterial blood pressure. An index of sympathetic activity was provided by measuring total body noradrenaline (NA) spillover by isotope dilution technique. Renal vascular resistance was calculated from PAH-clearance.SCI subjects had lower total body NA spillover (1011 +/- 193 vs 2261 +/- 328 pmol/min, P < 0.01), but similar baroreceptor reflex sensitivity and hemodynamics compared to able-bodied subjects at rest. In SCI group, during bladder percussion, mean arterial pressure increased (79 +/- 5 vs 113 +/- 8 mm Hg, P < 0.01), whereas heart rate was reduced during the first minute of the manoeuvre (62 +/- 2 vs 56 +/- 2 bpm, P < 0.05). Baroreceptor reflex sensitivity remained unchanged. Total body NA spillover and renal vascular resistance increased by 332 % (from 1004 +/- 218 pmol/min, P < 0.05) and 55 % (from 0.078 +/- 0.011 mmHg/ml/min, P < 0.05), respectively.SCI subjects demonstrated lower total body sympathetic outflow but normal baroreceptor reflex sensitivity at rest, suggesting a balanced autonomic output to the heart. Bladder percussion caused a substantial increase in renal vascular resistance and blood pressure, which was partly due to marked generalised sympathetic activation. This activation was counterbalanced by an increased vagal activity as evidenced by reduction of the heart rate.

Increased arterial stiffness in cyclosporine-treated lung transplant recipients early after transplantation.

BACKGROUND: The majority of patients undergoing solid organ transplantation develop hypertension, to which cyclosporine (CsA)-induced peripheral vasoconstriction may contribute. We hypothesized that CsA-treated transplant recipients have an increased basal vascular tone and an altered response to nitric oxide. To test this hypothesis arterial resistance, non-endothelial dependent relaxation and arterial stiffness were investigated in CsA-treated lung transplant recipients within 18 months after transplantation. METHODS: In study 1, forearm blood flow (FBF) was measured by venous occlusion plethysmography at baseline and during glyceryl trinitrate (GTN) and N(G)-monomethyl-l-arginine acetate (l-NMMA) infusion in seven lung transplant recipients and nine healthy subjects. In study 2, arterial stiffness in carotid (CCA) and radial artery (RA) was measured by ultrasound (echo-tracking) in 10 lung transplant recipients, 12 healthy subjects and six patients waiting for lung transplantation. RESULTS: Basal FBF (3.1 +/- 0.2 vs. 3.0 +/- 0.3 mL/min, p = 0.79) and forearm arterial resistance (36 +/- 3 vs. 33 +/- 3 mmHg/mL/min, p = 0.60) did not differ between transplant recipients and controls. GTN infusion increased and l-NMMA decreased blood flow equally in both groups. Transplant recipients had increased arterial stiffness compared to both pre-transplant patients and healthy subjects (CCA stiffness index 11.7 +/- 1.1 vs. 8.5 +/- 0.2 and 8.6 +/- 0.6, p < 0.05 both; RA stiffness index 14.7 +/- 1.5 vs. 8.9 +/- 1.3 and 10.6 +/- 0.7, p < 0.05 both). CONCLUSIONS: Forearm blood flow and arterial resistance did not differ between healthy subjects and cyclosporine-treated lung transplant recipients early after transplantation. Increased arterial stiffness was demonstrated in transplant recipients, which may have implications for future development of transplant hypertension.

Effects of a Mediterranean-inspired diet on blood lipids, vascular function and oxidative stress in healthy subjects.

Mediterranean-inspired diets have been shown to decrease cholesterol levels in patients with hypercholesterolaemia, who frequently exhibit endothelial dysfunction. The aims of the present study are to improve endothelial function by dietary intervention in healthy subjects with lipid levels representative of a Western population. Twenty-two healthy subjects (mean total cholesterol, 5.6 mmol/l) were given a Mediterranean-inspired diet rich in omega-3 fatty acids and sterol esters, but low in saturated fat, or an ordinary Swedish diet, for 4 weeks in a randomized cross-over study. The composition of the diets were: in the Swedish diet, 2090 kcal (where 1 kcal=4.184 kJ; 48% of energy from carbohydrate, 15% from protein and 36% from fat) and 19 g of fibre; in the Mediterranean-inspired diet, 1869 kcal (48% of energy from carbohydrate, 16% from protein, 34% from fat) and 40 g of fibre. After each dietary period, fasting blood lipids, insulin and glucose levels, as well as apo B (apolipoprotein B) and LDL (low-density lipoprotein) particle size, were analysed. Endothelial-dependent and -independent vasodilation was measured invasively by venous occlusion plethysmography, and arterial distensibility was assessed by echocardiography tracking. Fibrinolytic capacity across the forearm, as well as oxidative stress measured through urinary F(2)-isoprostane, were evaluated. Total, LDL- and apo B-cholesterol and triacylglycerol (triglyceride) concentrations were decreased by 17%, 22%, 16% and 17% respectively, after the Mediterranean-inspired diet compared with the Swedish diet ( P <0.05 for all). However, no differences in plasma concentrations of insulin and glucose and LDL particle size, endothelial function, arterial distensibility, fibrinolytic capacity or oxidative stress were detected. Treatment for 4 weeks with a Mediterranean-inspired diet decreased blood lipids in healthy individuals with a low-risk profile for cardiovascular disease. This beneficial effect was not mirrored in vascular function or oxidative stress evaluation.