Henrik M. Reims

Sodium accumulation promotes diastolic dysfunction in end-stage heart failure following Serca2 knockout

Alterations in trans‐sarcolemmal and sarcoplasmic reticulum (SR) Ca2+ fluxes may contribute to impaired cardiomyocyte contraction and relaxation in heart failure. We investigated the mechanisms underlying heart failure progression in mice with conditional, cardiomyocyte‐specific excision of the SR Ca2+‐ATPase (SERCA) gene. At 4 weeks following gene deletion (4‐week KO) cardiac function remained near normal values. However, end‐stage heart failure developed by 7 weeks (7‐week KO) as systolic and diastolic performance declined. Contractions in isolated myocytes were reduced between 4‐ and 7‐week KO, and relaxation was slowed. Ca2+ transients were similarly altered. Reduction in Ca2+ transient magnitude resulted from complete loss of SR Ca2+ release between 4‐ and 7‐week KO, due to loss of a small remaining pool of SERCA2. Declining SR Ca2+ release was partly offset by increased L‐type Ca2+ current, which was facilitated by AP prolongation in 7‐week KO. Ca2+ entry via reverse‐mode Na+–Ca2+ exchange (NCX) was also enhanced. Up‐regulation of NCX and plasma membrane Ca2+‐ATPase increased Ca2+ extrusion rates in 4‐week KO. Diastolic dysfunction in 7‐week KO resulted from further SERCA2 loss, but also impaired NCX‐mediated Ca2+ extrusion following Na+ accumulation. Reduced Na+‐K+‐ATPase activity contributed to the Na+ gain. Normalizing [Na+] by dialysis increased the Ca2+ decline rate in 7‐week KO beyond 4‐week values. Thus, while SERCA2 loss promotes both systolic and diastolic dysfunction, Na+ accumulation additionally impairs relaxation in this model. Our observations indicate that if cytosolic Na+ gain is prevented, up‐regulated Ca2+ extrusion mechanisms can maintain near‐normal diastolic function in the absence of SERCA2.

Improved insulin sensitivity with the angiotensin II-receptor blocker losartan in patients with hypertension and other cardiovascular risk factors

We aimed to compare the effects of two different vasodilating principles, angiotensin II-receptor blockade and calcium channel blockade, on peripheral insulin-mediated glucose uptake in patients with hypertension and other cardiovascular risk factors. Twenty-one hypertensive patients (11 women and 10 men) with mean age 58.6 years (range 46–75 years), body mass index 29.2±1.0 kg/m2 and blood pressure 160±3/96±2 mm Hg entered a 4-week run-in period with open-label amlodipine 5 mg. Thereafter they were randomized double-blindly to additional treatment with amlodipine 5 mg or losartan 100 mg. After 8 weeks of treatment, all patients underwent clinical examination and laboratory testing, and 17 of them underwent a hyperinsulinaemic isoglycaemic glucose clamp. After a 4-week open-label wash-out phase, the participants crossed over to the opposite treatment regimen and final examinations with hyperinsulinaemic isoglycaemic glucose clamp after another 8 weeks. Blood pressure was lowered to the same level in both treatment periods. The glucose disposal rate was significantly higher after treatment with losartan 100 mg+amlodipine 5 mg compared to amlodipine 10 mg (4.9±0.4 vs 4.2±0.5 mg/kg/min, P=0.039). Thus our data suggest that angiotensin II-receptor blockade with losartan improves glucose metabolism at the cellular level beyond what can be expected by the vasodilatation and blood pressure reduction alone.

Relations between insulin sensitivity, fitness and autonomic cardiac regulation in healthy, young men.

Objectives We hypothesized that insulin sensitivity and vagal cardiac control are independently related in young men after adjustment for fitness and other confounding variables. Design Male volunteers aged 21–24 years with high (borderline hypertensive; n = 20) and low–normal (normotensive; n = 21) screening blood pressure (BP) were studied cross-sectionally. Methods Mean R–R interval (RR) and heart rate variability (HRV) were computed from 30-min ECGs, and baroreflex sensitivity (BRS) and latency (phase shift) from 15-min beat-to-beat finger blood pressure (BP) and heart rate recordings. Insulin-adjusted glucose disposal rate (GDR/I) was measured with a 90-min hyperinsulinaemic glucose clamp and fitness by peak oxygen uptake (VO2peak) during a treadmill test. Results HRV, baroreflex function, GDR/I, and VO2peak did not differ between the groups. GDR/I correlated positively with time and frequency domain HRV, including high-frequency power (HF) (r = 0.40, P = 0.01) and root-mean squared successive differences (RMSSD) (r = 0.43, P = 0.005), but not BRS or phase shift. GDR/I correlated with VO2peak (r = 0.70, P < 0.0001) and was explained (R2 = 0.56) by VO2peak (β = 0.57, P < 0.0001) and RR (β = 0.29, P = 0.03), independently of HRV and measures of obesity. Conversely, RR (β = 0.55, P = 0.0004) and HRV, including HF (β = 0.44, P = 0.006) and RMSSD (β = 0.46, P = 0.004) were explained by GDR/I, independently of VO2peak. Conclusions Insulin sensitivity and autonomic cardiac control are related independently of physical fitness in young men.

Gender specific sympathetic and hemorrheological responses to mental stress in healthy young subjects

Objective - Activation of the sympathetic nervous system may increase hematocrit (Hct), whole blood viscosity (WBV), and possibly cardiovascular risk. The aim was to study gender specific differences of mental stress on sympathetic reactivity and blood rheology. Methods - Responses in blood pressure, heart rate (HR), Hct, WBV (Bohlin rotational viscosimeter), and plasma catecholamines to a mental arithmetic stress test (MST) were measured in male ( n = 10, 23 - 3 years, BMI 23 - 2 kg/m2) and female ( n = 10, 21 - 4 years, BMI 24 - 2 kg/m2) students. Results - Systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR increased during MST in men and women, and declined to baseline levels after 15 min of recovery. In men, plasma adrenaline increased by 217% during MST ( p < 0.01, ANOVA), and plasma noradrenaline increased by 68% ( p < 0.05). Hct and WBV at low shear rates (0.5 and 1.1 l/s) increased as well ( p < 0.01, p < 0.05, and p < 0.05, respectively). In women, the increase in plasma adrenaline averaged 118% during MST ( p < 0.05) while plasma noradrenaline (-3%, p = 0.38), Hct, and WBV at all shear rates remained unchanged. Men and women differed in j adrenaline ( p < 0.05), j noradrenaline ( p = 0.01), j Hct ( p < 0.05), and j WBV ( p < 0.05). j Hct tended to correlate with j SBP ( r = 0.60, p = 0.07), j DBP ( r = 0.57, p = 0.09), and j HR ( r = 0.50, p = 0.14), and correlated significantly with j noradrenaline ( r = 0.66, p < 0.05) in men only. Multiple regression analysis showed that gender independently explained 22% of the change in Hct during mental stress. Conclusion - Data suggest gender specific differences in sympathetic and hemorrheological responses to mental stress in healthy young subjects. In men, sympathetic responses were related to hemorrheological responses, but not in women. It may be speculated whether such differences in stress responses may contribute to lower cardiovascular risk in premenopausal women than in men.OBJECTIVE Activation of the sympathetic nervous system may increase hematocrit (Hct), whole blood viscosity (WBV), and possibly cardiovascular risk. The aim was to study gender specific differences of mental stress on sympathetic reactivity and blood rheology. METHODS Responses in blood pressure, heart rate (HR), Hct, WBV (Bohlin rotational viscosimeter), and plasma catecholamines to a mental arithmetic stress test (MST) were measured in male (n = 10, 23 +/- 3 years, BMI 23 +/- 2 kg/m2) and female (n = 10, 21 +/- 4 years, BMI 24 +/- 2 kg/m2) students. RESULTS Systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR increased during MST in men and women, and declined to baseline levels after 15 min of recovery. In men, plasma adrenaline increased by 217% during MST (p < 0.01, ANOVA). and plasma noradrenaline increased by 68% (p < 0.05). Hct and WBV at low shear rates (0.5 and 1.1 l/s) increased as well (p < 0.001, p < 0.05, and p < 0.05, respectively). In women, the increase in plasma adrenaline averaged 118% during MST (p < 0.05) while plasma noradrenaline (-3%, p = 0.38), Hct, and WBV at all shear rates remained unchanged. Men and women differed in A adrenaline (p < 0.05), A noradrenaline (p = 0.01), delta Hct (p < 0.05), and delta WBV (p < 0.05). A Hct tended to correlate with delta SBP (r= 0.60, p = 0.07), A DBP (r = 0.57. p = 0.09). and delta HR (r = 0.50, p = 0.14), and correlated significantly with A noradrenaline (r = 0.66, p < 0.05) in men only. Multiple regression analysis showed that gender independently explained 22% of the change in Hct during mental stress. CONCLUSION Data suggest gender specific differences in sympathetic and hemorrheological responses to mental stress in healthy young subjects. In men, sympathetic responses were related to hemorrheological responses, but not in women. It may be speculated whether such differences in stress responses may contribute to lower cardiovascular risk in premenopausal women than in men.

Alcohol consumption and cardiovascular risk in hypertensives with left ventricular hypertrophy: the LIFE study.

The Losartan Intervention For End point reduction in hypertension (LIFE) study showed superiority of losartan over atenolol for reduction of composite risk of cardiovascular death, stroke, and myocardial infarction in hypertensives with left ventricular hypertrophy. We compared hazard ratios (HR) in 4287 and 685 participants who reported intakes of 1–7 and >8 drinks/week at baseline, respectively, with those in 4216 abstainers, adjusting for gender, age, smoking, exercise, and race. Within categories, clinical baseline characteristics, numbers randomized to losartan and atenolol, and blood pressure (BP) lowering were similar on the drug regimens. Overall BP control (<140/90 mmHg) at end of follow-up was similar in the categories. Composite end point rate was lower with 1–7 (24/1000 years; HR 0.87, P<0.05) and >8 drinks/week (26/1000 years; HR 0.80, NS) than in abstainers (27/1000 years). Myocardial infarction risk was reduced in both drinking categories (HR 0.76, P<0.05 and HR 0.29, P<0.001, respectively), while stroke risk tended to increase with >8 drinks/week (HR 1.21, NS). Composite risk was significantly reduced with losartan compared to atenolol only in abstainers (HR 0.81 95% confidence interval, CI (0.68, 0.96), P<0.05), while benefits for stroke risk reduction were similar among participants consuming 1–7 drinks/week (HR 0.73, P<0.05) and abstainers (HR 0.72, P<0.01). Despite different treatment benefits, alcohol-treatment interactions were nonsignificant. In conclusion, moderate alcohol consumption does not change the marked stroke risk reduction with losartan compared to atenolol in high-risk hypertensives. Alcohol reduces the risk of myocardial infarction, while the risk of stroke tends to increase with high intake.

Plasma catecholamines, blood pressure responses and perceived stress during mental arithmetic stress in young men

We assessed plasma noradrenaline (NA) and adrenaline (A) at rest during a hyperinsulinaemic glucose clamp and responses to a mental arithmetic stress test (MST) in relation to blood pressure (BP) responses (Finapres) and distress in 20 men with high (≥140/90 mmHg) and 21 men with normal (≤⃒115/75 mmHg) screening BP, 21-24 years of age. Perceived stress, effort and overall discomfort were scored 1-10. Catecholamines and BP increased in both groups, change in diastolic BP (ΔDBP; 9.9 vs. 3.8 mmHg, p < 0.05) and ΔDBP carryover (recovery period minus baseline) (7.2 vs. 2.2 mmHg, p < 0.01) being greater in men with high screening BP. Independently of BP status, change in systolic BP (ΔSBP) and ΔSBP carryover were related to A (both p < 0.001), and ΔDBP and ΔDBP carryover to ΔNA (both p < 0.001). The subjective score sum correlated with maximal NA (r [Formula: See Text] = 0.40) and A (r [Formula: See Text] = 0.37) (both p < 0.05). Maximal NA was independently related to stress (p < 0.05) and the subjective score sum (p < 0.01). ΔA% was greater in the high- (score ≥6) than in the low-stress category, independently of BP status (p < 0.05). High screening BP is associated with impaired BP recovery after mental stress. Plasma catecholamine responses are related to BP responses and carryover effects, and reflect perceived stress in young men.

High screening blood pressure is related to sympathetic nervous system activity and insulin resistance in healthy young men

The cardiovascular metabolic syndrome is characterized by the presence of several cardiovascular risk factors, including blood pressure (BP) elevation. We aimed to study the relation between mental stress, plasma catecholamines, BP and BP responses to mental stress in healthy young Caucasian men selected from different levels of screening BP. We included 98 men with high and 22 men with normal screening BP. They were examined at baseline in the laboratory, during a hyperinsulinemic, isoglycemic glucose clamp and during mental stress. At baseline in the laboratory, the men with high screening BP were characterized by elevated BP (p < 0.005) and plasma catecholamines (p < 0.05), but unaltered serum lipid levels compared to men with normal screening BP. After 2 h rest the differences almost disappeared, but could be reproduced during a mental arithmetic stress test. The men with elevated screening BP had significantly higher fasting glucose (p = 0.01) and lower insulin sensitivity (p < 0.005). In a multiple regression model, norepinephrine during mental stress (R 2  = 0.10, p < 0.05) was the main variable to retrospectively explain allocation to the normal or high screening BP group. In conclusion, young healthy men with elevated screening BP are characterized by increased sympathetic activity and insulin resistance. Norepinephrine during mental stress is the main variable to explain allocation to the normal or elevated screening BP group. We have shown that one single screening BP measurement predicts insulin resistance and elevated fasting glucose in this cohort.

Lack of Chemokine Signaling through CXCR5 Causes Increased Mortality, Ventricular Dilatation and Deranged Matrix during Cardiac Pressure Overload

Rationale Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. Objective We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. Methods and Results Mice harboring a systemic knockout of the CXCR5 (CXCR5−/−) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5−/− developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5−/− compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5−/− mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. Conclusions Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly.

Blood viscosity: Effects of mental stress and relations to autonomic nervous system function and insulin sensitivity

We studied effects of mental stress on whole‐blood viscosity (WBV) and blood pressure (BP), and relations between WBV and autonomic nervous system activity and insulin sensitivity. We measured WBV (rotational rheometer), plasma noradrenaline (NA), finger BP, heart rate variability (HRV) and baroreflex sensitivity (BRS; transfer technique) during hyperinsulinaemic glucose clamp and mental arithmetic stress test (MST) in 20 men with high (⩾140/90 mmHg) and 21 men with normal (⩽115/75 mmHg) screening BP, and 10 women regardless of screening BP (all normotensive). WBV and NA increased during the MST, while HRV and BRS decreased. During the MST, WBV (all shear rates) and the response (ΔWBV) (low shear) were higher in men with high compared to normal screening BP (p<0.05). In men, WBV correlated positively with NA and negatively with HRV, BRS and insulin sensitivity. The diastolic BP response (ΔDBP) was independently explained by high‐shear ΔWBV (p<0.05) and ΔNA (p<0.0001), and ΔWBV independently by ΔDBP (p<0.05). WBV is related to increased sympathetic activity, impaired vagal cardiac control and low insulin sensitivity in young adults. The haemorheological effect of mental stress is increased in young men with high screening BP and may be mediated by the acute increase in BP.

The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation

BACKGROUND & AIMS A strong association between human inflammatory biliary diseases and gut inflammation has led to the hypothesis that gut microbes and lymphocytes activated in the intestine play a role in biliary inflammation. The NOD.c3c4 mouse model develops spontaneous biliary inflammation in extra- and intrahepatic bile ducts. We aimed to clarify the role of the gut microbiota in the biliary disease of NOD.c3c4 mice. METHODS We sampled cecal content and mucosa from conventionally raised (CONV-R) NOD.c3c4 and NOD control mice, extracted DNA and performed 16S rRNA sequencing. NOD.c3c4 mice were rederived into a germ free (GF) facility and compared with CONV-R NOD.c3c4 mice. NOD.c3c4 mice were also co-housed with NOD mice and received antibiotics from weaning. RESULTS The gut microbial profiles of mice with and without biliary disease were different both before and after rederivation (unweighted UniFrac-distance). GF NOD.c3c4 mice had less distended extra-hepatic bile ducts than CONV-R NOD.c3c4 mice, while antibiotic treated mice showed reduction of biliary infarcts. GF animals also showed a reduction in liver weight compared with CONV-R NOD.c3c4 mice, and this was also observed in antibiotic treated NOD.c3c4 mice. Co-housing of NOD and NOD.c3c4 mice indicated that the biliary phenotype was neither transmissible nor treatable by co-housing with healthy mice. CONCLUSIONS NOD.c3c4 and NOD control mice show marked differences in the gut microbiota. GF NOD.c3c4 mice develop a milder biliary affection compared with conventionally raised NOD.c3c4 mice. Our findings suggest that the intestinal microbiota contributes to disease in this murine model of biliary inflammation. LAY SUMMARY Mice with liver disease have a gut microflora (microbiota) that differs substantially from normal mice. In a normal environment, these mice spontaneously develop disease in their bile ducts. However, when these mice, are raised in an environment devoid of bacteria, the disease in the bile ducts diminishes. Overall this clearly indicates that the bacteria in the gut (the gut microbiota) influences the liver disease in these mice.