Reduction Of Extracellular Volume Research Articles

Myocardial Fibrosis Improves in Young Patients with Sickle Cell Disease after Hematopoietic Cell Transplantation

Introduction: Cardiovascular complications are a leading cause of early mortality in patients with sickle cell disease (SCD). Chronic anemia, iron overload and repeated microvascular ischemic insults with reperfusion injury often result in progressive myocardial injury and maladaptive remodeling in SCD patients. Patients with SCD develop diffuse myocardial fibrosis, which can be detected by quantifying the myocardial extracellular volume (ECV) using cardiovascular magnetic resonance (CMR) imaging. Our group and others have previously shown that diffuse myocardial fibrosis is highly prevalent in both children and young adults with SCD, including those who have normal ventricular size and function by echocardiography. Additionally, we have shown that the disease modifying therapies (DMT) such as hydroxyurea or chronic transfusions do not appear to be protective against development of diffuse myocardial fibrosis. In a retrospective study, we found no difference in the myocardial ECV in patients who began DMT early (less than 6 years of age) versus later in life (at least 6 years or after) (Morin CE and Sharma A et al. Blood 2023.). Hematopoietic cell transplantation (HCT) can cure SCD, but myocardial effects of the therapy are unknown. Our goal was to evaluate cardiovascular parameters of function and injury, especially the progression of diffuse myocardial fibrosis, by comparing serial CMR studies performed before and after HCT in patients with SCD. Methods: We performed prospective CMR evaluation of children and young adults with SCD who received a matched sibling donor (MSD) or haploidentical donor (HAPLO) HCT following a reduced toxicity conditioning on a clinical trial (NCT04362293). CMR was performed pre-HCT, and at 1 month, and 12 months post-HCT. CMR-derived ventricular and atrial volumes were calculated. ECV was measured from T1 maps with a modified Look-Locker inversion recovery (MOLLI) sequence in short-axis. T2 and T2* maps were obtained. Regions of interest in the mid-ventricular septum were identified for analysis. We report descriptive statistics for CMR measures along with paired t-tests comparing patient ECV levels at 1-month and 12-months post-HCT to their respective baseline ECV. Results: Our study cohort consisted of 14 patients with SCD who underwent HCT and had serial CMR evaluations available. Thirteen patients had HbSS genotype and one had HbSC genotype. All patients were receiving DMT, either with hydroxyurea or chronic transfusions prior to HCT. Participants were majority male (57%) with median age of 15.2 years (range 6.8-21.3) at the pre-HCT CMR. Six received an MSD HCT and 8 received a HAPLO HCT. Ten patients each had follow up CMR evaluations performed at 1 month, and 12 months post-HCT. At 1 and 12 months post-HCT ejection fraction was preserved while biventricular volume and cardiac index decreased (Table 1). Compared to pre-HCT, ECV decreased from median 29% [range 27-38] to 28% (range 21-35, P= 0.061) at 1 month and 27% (range 24-31, P= 0.043) at 12 months post-HCT. There was no difference in the cardiac chamber sizes or the ECV measurements of those who received a MSD versus HAPLO HCT. Conclusions: We observed an improvement in cardiac chamber sizes with preservation of cardiac function as early as one month after HCT in patients with SCD. We further noted a reduction in ECV indicating a decrease in diffuse myocardial fibrosis in these young patients with SCD. To our knowledge, this is the first study to show that diffuse myocardial fibrosis can improve in patients with SCD after HCT. In addition to further corroborating the organ function protective effects of HCT in patients with SCD, these data further demonstrate the use of CMR as an essential non-invasive tool to assess the effects of therapeutic interventions on SCD-cardiac injury.

Rosuvastatin, but not atorvastatin, enhances the antihypertensive effect of cilostazol in an acute model of hypertension

PurposeHypertensive emergency, a sudden and severe increase in blood pressure, necessitates immediate intervention to avoid end-organ damage. Cilostazol, a selective phosphodiesterase-III inhibitor, has vasodilator effect. Here, we investigated the effect of two commonly used statins, atorvastatin or rosuvastatin, on cilostazol antihypertensive activity in acute model of hypertension.MethodsHypertensive emergency was induced via angiotensin II intravenous infusion (120 ng.kg−1.min−1). Rats were subjected to real-time arterial hemodynamics and electrocardiogram recording while investigated drugs were injected slowly at cumulative doses 0.5, 1, and 2 mg.kg−1, individually or in combination, followed by baroreflex sensitivity (BRS) analysis and serum electrolytes (Na+ and K+) and vasomodulators (norepinephrine (NE), and nitric oxide (NO)) assessment.ResultsCilostazol reduced systolic blood pressure (SBP), while co-injection with rosuvastatin augmented cilostazol SBP-reduction up to 30 mmHg. Compared to atorvastatin, rosuvastatin boosted the cilostazol-associated reduction in peripheral resistance, as evidenced by further decrease in diastolic, pulse, and dicrotic-notch pressures. Rosuvastatin co-injection prevented cilostazol-induced changes of ejection and non-ejection durations. Additionally, rosuvastatin coadministration produced better restoration of BRS, with an observed augmented increase in BRS indexes from spectral analysis. Greater reduction in sympathetic/parasympathetic ratio and serum NE upon rosuvastatin coadministration indicates further shift in sympathovagal balance towards parasympathetic dominance. Additionally, rosuvastatin coinjection caused a greater decrease in serum sodium, while more increase in NO indicating augmented reduction of extracellular volume and endothelial dysfunction.ConclusionRosuvastatin boosted cilostazol’s antihypertensive actions through effects on peripheral resistance, BRS, sympathovagal balance, endothelial dysfunction, and electrolytes balance, while atorvastatin did not demonstrate a comparable impact.

Call to action for drug interactions between tirzepatide and heart failure guideline-directed medical therapy

BackgroundNo drug interaction between the guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF) and glucose-dependent insulinotropic polypeptide (GIP)-glucagon-like peptide-1 (GLP-1) agonists is currently indexed in available drug interaction databases or package inserts for tirzepatide, the first dual GIP/GLP-1 agonist. The objective of our case series is to present 3 patients with HF who required modification in GDMT regimens for HFrEF or loop diuretic therapy after tirzepatide initiation. Case summaryThree patients older than 60 years with HFrEF receiving GDMT agents (angiotensin receptor neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors) were initiated on tirzepatide for weight loss management. After initiating tirzepatide therapy, all 3 patients developed symptomatic hypotension. Two cases had acute kidney injury owing to tirzepatide’s direct vasodilation, natriuresis, reduction in extracellular volume, and weight loss. GDMT regimens and diuretic therapy were significantly modified to improve these adverse reactions. Practice implicationsClinicians must closely monitor vital signs and volume status after initiating tirzepatide for potential need to modify GDMT regimens. Authors request a call to action to index the drug interaction between GDMT agents and tirzepatide in major drug interaction databases for a potential hypotension or dehydration risk.

Tafamidis decreased cardiac amyloidosis deposition in patients with Ala97Ser hereditary transthyretin cardiomyopathy: a 12-month follow-up cohort study

BackgroundTransthyretin cardiac cardiomyopathy (ATTR-CM) is a rare but life-threatening disease. Tafamidis is an effective treatment for patients with ATTR-CM, however its long-term effects on cardiac remodeling and cardiac amyloid deposition are unknown. This study aimed to used cardiac magnetic resonance (CMR) to investigate the effects of tafamidis on patients with hereditary A97S ATTR-CM.MethodsWe retrospectively analyzed a prospective cohort of ATTR-CM patients, including 14 with hereditary A97S ATTR-CM and 17 healthy controls with baseline CMR data. All ATTR-CM patients received tafamidis treatment and received CMR with extracellular volume (ECV) at baseline and after 1 year of follow-up.ResultsBaseline N-terminal pro-B-type natriuretic peptide, left ventricular (LV) mass, LV ejection fraction, global radial, circumferential and longitudinal strain, T1 mapping and ECV were significantly worse in the patients with ATTR-CM compared with the healthy controls. After 1 year of tafamidis treatment, ECV decreased from 51.5 ± 8.9% to 49.0 ± 9.4% (P = 0.041), however there were no significant changes in LV mass, LV ejection fraction, global radial strain, global circumferential strain, global longitudinal strain and T1 mapping.ConclusionsAfter a one-year treatment period, tafamidis exhibited subtle but statistically significant reductions in ECV, potentially indicating a decrease in amyloid deposition among patients diagnosed with hereditary A97S ATTR-CM.

Cerebral salt wasting syndrome: A case report

Introduction: The development of extracellular volume reduction due to decreased renal sodium transport in individuals with the intracranial illness and normal adrenal and thyroid function is known as a cerebral salt wasting syndrome (CSWS). Complications of cerebral salt-wasting syndrome include symptomatic hyponatremia and dehydration. We reported and discussed the diagnostic approach and the management of a 66-year-old woman who experienced severe hyponatremia with a history of head trauma and was treated at Udayana University Hospital. Case Description: A 66-year-old female patient complained of decreased consciousness. According to family information, the patient complained of having decreased consciousness one hour before admission and was accompanied by vomiting one time. Two weeks before admission, the patient had fallen, and the back of the patient's head had hit the table. The patient also had time to experience stiffness in the right and left hands and stomping. Urine collected 24 hours as much as 3880 ml on the first day of treatment. Conclusion: In cerebral salt wasting syndrome (CSWS) the management mainly focuses on the correction of intravascular volume depletion using 0.9% sodium chloride and hyponatremia, as well as on the replacement of ongoing urinary sodium loss, usually with iv hypertonic saline solutions, Fludrocortisone/mineralocorticoid that directly acts on the renal tubules to increase sodium reabsorption showed a favorable response in CSWS.

Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study

ObjectivesThe goal of this study was to evaluate the effect of empagliflozin, in addition to optimal medical treatment, on epicardial adipose tissue (EAT), interstitial myocardial fibrosis, and aortic stiffness in nondiabetic patients with heart failure with reduced ejection fraction (HFrEF). BackgroundSeveral randomized clinical trials have established the benefits of the inhibitors of the sodium-glucose cotransporter-2 receptor (SGLT2-i) in HFrEF, independent of their hypoglycemic effects. The mechanisms of the benefits of SGLT2-i in HFrEF have not been well defined. MethodsThis study was a secondary analysis of patients enrolled in the EMPA-TROPISM [ATRU-4] (Are the cardiac benefits of Empagliflozin independent of its hypoglycemic activity?) clinical trial. It was a double-blind, placebo-controlled randomized clinical trial investigating the effect of empagliflozin in nondiabetic patients with HFrEF. Patients underwent cardiac magnetic resonance at baseline and after 6 months. Interstitial myocardial fibrosis was calculated by using T1 mapping (extracellular volume). Aortic stiffness was calculated by using pulsed wave velocity, and EAT was measured from the cine sequences. ResultsEmpagliflozin is associated with significant reductions in EAT volume (–5.14 mL; 95% CI: –8.36 to –1.92) compared with placebo (–0.75 mL; 95% CI: –3.57 to 2.06; P < 0.05); this finding was paralleled by reductions in subcutaneous adipose tissue area (–5.33 cm2 [95% CI: –12.61 to 1.95] vs 9.13 cm2 [95% CI: –2.72 to 20.99]; P < 0.05). Empagliflozin-treated patients reported a reduction in extracellular volume (–1.25% [±0.56 95% CI] vs 0.24% [±0.57 95% CI]; (P < 0.01)]; specifically, empagliflozin reduced both matrix volume (–7.24 mL [95% CI: –11.59 to –2.91] vs 0.70 mL [95% CI: –0.89 to 2.29]; P < 0.001) and cardiomyocyte volume (–11.08 mL [95% CI: –19.62 to –2.55] vs 0.80 mL [95% CI: –1.96 to 3.55]; P < 0.05). Pulsed wave velocity was also significantly reduced in the empagliflozin group (–0.58 cm/s [95% CI: –0.92 to –0.25] vs 0.60 cm/s [95% CI: 0.14 to 1.06]; P < 0.01). Using proteomics, empagliflozin was associated with a significant reduction in inflammatory biomarkers. ConclusionsEmpagliflozin significantly improved adiposity, interstitial myocardial fibrosis, aortic stiffness, and inflammatory markers in nondiabetic patients with HFrEF. These results shed new light on the mechanisms of action of the benefits of SGLT2-i. (Are the “Cardiac Benefits” of Empagliflozin Independent of Its Hypoglycemic Activity [ATRU-4] [EMPA-TROPISM]; NCT03485222)

Reduction of extracellular volume and reverse cardiac remodeling during sacubitril/valsartan therapy assessed by cardiac magnetic resonance in patients with heart failure (REMODELING CMR-HF)

Abstract Funding Acknowledgements Type of funding sources: None. OnBehalf REMODELING HF Background/Introduction: Extracellular volume (ECV) expansion is a major determinant of cardiac remodeling in heart failure. Cardiac magnetic resonance (CMR) T1 mapping has been developed as a noninvasive technique to estimate ECV. Purpose The objective of this study is to assess the response to Sacubitril/Valsartan by measuring changes in myocardial ECV and their association with reverse cardiac remodeling in patients with heart failure with reduced ejection fraction (HFrEF). Methods Prospective, single-center, open-label study of two hundred-four HFrEF patients underwent CMR T1 mapping using the modified Look-Locker inversion recovery (MOLLI) sequence for ECV calculation, and initiated with sacubitril-valsartan treatment according to Guideline-Directed Medical Therapy. Absolute change in myocardial ECV, serum levels of procollagen type I amino-terminal peptide (PINP) and procollagen type III amino-terminal peptide (PIIINP), left ventricular end-diastolic volume index, left ventricular end-systolic volume index and left ventricle ejection fraction (LVEF) were analyzed from baseline to 12-month follow-up. Results Baseline MOLLI-ECV was 48.2% ± 2.4 in 106 patients with ischemic cardiomyopathy (ICM) and 38.7% ± 2.7 in 98 with idiopathic dilated cardiomyopathy (DCM), decreasing to 34% ± 2.4 for ICM and 29.5% ± 2.7 for DCM (P &amp;lt; 0.001), at 12 months with sacubitril-valsartan therapy. These changes were correlated with a reduction of -36 μg/L for PINP (CI 95% 78-93, P &amp;lt; 0.001), and -3.0 μg/L for PIIINP (CI 95% 73-91, P &amp;lt; 0.001), -20 ml/m² in left ventricle end-diastolic and -18 ml/m² in end-systolic volumes, and an improvement in LVEF from 29% to 36% in both groups (P &amp;lt; 0.001). Conclusions For the first time, we observe that changes in extracellular volume induced by sacubitril-valsartan therapy are related to reverse cardiac remodeling in patients with in HFrEF. These findings suggest that there may be an opportunity to decrease adverse remodeling with the use of a CMR-guided therapeutic approach aimed at decreasing fibrogenic activity and modulate the remodeling process.

Abstract 17157: The SGLT2 Inhibitor Empagliflozin Ameliorates Interstitial Myocardial Fibrosis and Aortic Stiffness in Non-Diabetic Patients With Heart Failure With Reduced Ejection Fraction: A Secondary Analysis of the EMPATROPISM Trial

Background: SGLT2 inhibitors (SGLT2i) improve prognosis in HFrEF patients. We recently demonstrated in a porcine model of non-diabetic HFrEF that empagliflozin (EMPA) ameliorates adverse cardiac remodeling and improves LV systolic function. However, the effect of EMPA on interstitial myocardial fibrosis (IMF) and aortic stiffness has not yet been studied Hypothesis: Empagliflozin ameliorates IMF and aortic stiffness in non-diabetic HFrEF patients Methods: The EMPATROPISM clinical trial (NCT 03485222) investigated the efficacy and safety of EMPA in non-diabetic HFrEF patients. 84 patients were randomized to EMPA 10mg daily for 6 months or placebo on top of optimal medical treatment, and were evaluated with cardiac magnetic resonance (CMR). IMF was assessed by CMR using extracellular volume (ECV) by T1 mapping. Aortic stiffness was quantified by pulse wave velocity (PWV) by CMR. The primary endpoint was change in LVEDV. Prespecified secondary endpoints were changes in ECV (ΔECV) and PWV (ΔPWV) at 6 months between both arms Results: 80 patients completed the follow up period. There were no differences at baseline in LVEDV (220±75 vs 209±68mL for EMPA vs placebo, p=0.5) or LVEF (36±8 vs 37±8%, p=0.7). There were no differences at baseline in both groups in either ECV or PWV (Table). In the primary endpoint, EMPA-treated patients showed decrease in LVEDV and increase in LVEF (ΔLVEDV -25±25 vs -1±25mL, p&lt;0.001; and ΔLVEF 6±4 vs 0±4%, p&lt;0.001 for EMPA vs placebo). EMPA-treated patients exhibited a reduction in ECV (ΔECV -1.25±1.5 vs 0.3±1.4% for EMPA vs placebo, p&lt;0.001), which demonstrates IMF regression with SGLT2i. EMPA-treated patients exhibited a reduction in PWV (ΔECV -0.6±1 vs 0.6±1.4 m/s for EMPA vs control, p&lt;0.001), which indicates amelioration of aortic stiffness with SGLT2i Conclusions: In HFrEF patients without diabetes, treatment with empagliflozin ameliorates IMF and aortic stiffness. This may explain the benefits of SGLT2i in HFrEF even in the absence of diabetes

Regression of cardiac amyloid deposits with novel therapeutics: reaching new frontiers in cardiac ATTR amyloidosis

Abstract Background Cardiac involvement is the main driver of outcome in ATTR amyloidosis. Advances in therapeutics hold potential in transforming the course of the disease but the impact on cardiac amyloid load is unknown. The aim of this study was to evaluate the impact of patisiran, a new double stranded RNA based gene silencing therapy and a stabilizer, diflunisal, on cardiac amyloid load as measured by CMR and T1 mapping, in patients with ATTR amyloidosis. Methods and results Thirty-two patients with hereditary cardiac amyloidosis were studied. Sixteen patients received treatment with patisiran, and sixteen control subjects did not receive any disease modifying treatment. Patients were assessed with echocardiogram, CMR, NT-proBNP and six-minute walk time measurements at baseline and at 1 year (Mean interval 11.45±3.08 months in treatment group, mean interval 12.82±5.06 months in the control group). CMR analysis comprised LV volumes, T1 mapping to measure the extracellular volume (ECV) occupied by amyloid, T2 mapping and late gadolinium enhancement imaging. At 1-year follow-up, there was a substantial reduction in cardiac amyloid burden, in keeping with cardiac amyloid regression in 45% of patients on treatment. Overall the treatment group showed a reduction in ECV at 1 year follow up compared to an increase in ECV at 1 year in the control group (−1.37%, 95% CI: −3.43 to 0.68% versus 5.02%, 95% CI: 2.86% to 7.18% respectively, p&amp;lt;0.001). The treatment group also showed an improvement in change in 6MWT at 1 year follow up compared to 6MWT at 1 year in the control group (−8.12 meters, 95% CI: −50.8 to 34.6 meters in the treatment group versus −132.27 meters, 95% CI: −216 to −48.6 meters in the control group, p=0.002). The treatment group showed a reduction in BNP at 1 year follow up compared to an increase in the control group (−567.87, 95% CI: −1288.90 to 153.15 in the treatment group versus 2004, 95% CI: 12.82 to 3995.45 in the control group, p&amp;lt;0.001). There was no significant difference from baseline and 1-year data between the control and treatment groups for the difference in echocardiographic parameters, native T1, T2. There was a significant reduction in the percentage of injected dose by 99Tc-DPD scintigraphy in treated patients at 1 year compared to baseline. Conclusions These findings provide the first compelling evidence of substantial cardiac amyloid regression in ATTR amyloidosis, as well as the potential for CMR to be used to track response in treated patients with ATTR cardiac amyloidosis. Combination therapy with transthyretin knock down and stabilizing agents may well be synergistic given enhanced stoichiometry of stabilizers in the face of much reduced plasma transthyretin concentration. Funding Acknowledgement Type of funding source: None

Interplay of volume, blood pressure, organ ischemia, residual renal function, and diet: certainties and uncertainties with dialytic management.

Extracellular fluid volume overload and its inevitable consequence, hypertension, increases cardiovascular mortality in the long term by leading to left ventricular hypertrophy, heart failure, and ischemic heart disease in dialysis patients. Unlike antihypertensive medications, a strict volume control strategy provides optimal blood pressure control without need for antihypertensive drugs. However, utilization of this strategy has remained limited because of several factors, including the absence of a gold standard method to assess volume status, difficulties in reducing extracellular fluid volume, and safety concerns associated with reduction of extracellular volume. These include intradialytic hypotension; ischemia of heart, brain, and gut; loss of residual renal function; and vascular access thrombosis. Comprehensibly, physicians are hesitant to follow strict volume control policy because of these safety concerns. Current data, however, suggest that a high ultrafiltration rate rather than the reduction in excess volume is related to these complications. Restriction of dietary salt intake, increased frequency, and/or duration of hemodialysis sessions or addition of temporary extra sessions during the process of gradually reducing postdialysis body weight in conventional hemodialysis and discontinuation of antihypertensive medications may prevent these complications. We believe that even if an unwanted effect occurs while gradually reaching euvolemia, this is likely to be counterbalanced by favorable cardiovascular outcomes such as regression of left ventricular hypertrophy, prevention of heart failure, and, ultimately, cardiovascular mortality as a result of the eventual achievement of normal extracellular fluid volume and blood pressure over the long term.

Phase I trial to investigate the effect of renal impairment on isavuconazole pharmacokinetics

PurposeThe purpose of the study is to evaluate the effect of renal impairment (RI) and end-stage renal disease (ESRD) on the pharmacokinetics (PK) of isavuconazole and the inactive cleavage product, BAL8728.MethodsA single intravenous dose of the prodrug isavuconazonium sulfate (372 mg, equivalent to 200 mg isavuconazole and 75 mg of BAL8728 cleavage product) was administered to healthy controls (parts 1 and 2) and participants with mild, moderate, or severe RI (part 2) or ESRD (part 1); ESRD participants received two doses of 200 mg isavuconazole, 1 h post-dialysis (day 1) and prior to dialysis (day 15). Plasma PK parameters for isavuconazole included maximum concentration (Cmax), area under the concentration–time curve (AUC) from time of dose to 72 h (AUC72), AUC extrapolated to infinity (AUC∞), AUC to last measurable concentration (AUClast), half-life (t½ h), volume of distribution (Vz), and total clearance (CL), for the healthy control group versus those with mild, moderate, or severe RI or ESRD.ResultsIsavuconazole Cmax values were 4% higher in mild RI and 7, 14, and 21% lower in participants with moderate RI, severe RI, or ESRD versus the healthy control group, respectively. When hemodialysis occurred post-dose (day 15), participants with ESRD had a 30% increase in AUC72 for isavuconazole in parallel with reduction of extracellular volume induced by dialysis. Exposure (AUC∞ and AUClast) was not significantly different for participants with mild, moderate, or severe RI versus healthy controls although there was considerable variability. The t1/2 (day 1) was 125.5 ± 63.6 h (healthy control group), 204.5 ± 82.6 h (ESRD group) in part 1, and 140.5 ± 77.7 h (healthy control group), 117.0 ± 66.2 h (mild RI), 158.5 ± 56.4 h (moderate RI), and 145.8 ± 65.8 L/h (severe RI) in part 2. CL was 2.4 ± 0.8 L/h (healthy control group) and 2.9 ± 1.3 L/h (ESRD group) in part 1 and 2.4 ± 1.2 L/h (healthy control group), 2.5 ± 1.0 L/h (mild RI), 2.2 ± 0.8 L/h (moderate RI), and 2.4 ± 0.8 L/h (severe RI) in part 2. The Vz was 382.6 ± 150.6 L in the healthy control group and 735.6 ± 277.3 L in ESRD patients on day 1 in part 1 of the study. In part 2 of the study, Vz was 410.8 ± 89.7 L in the healthy control group, 341.6 ± 72.3 L in mild RI, 509.1 ± 262.2 L in moderate RI, and 439.4 L in severe RI.ConclusionsBased on the findings of this study, dose adjustments of isavuconazole are unlikely to be required in individuals with RI or in those with ESRD who receive hemodialysis.

Time course and mechanisms of the anti‐hypertensive and renal effects of liraglutide treatment

Glucagon-like peptide-1 receptor agonist studies have revealed clinically significant reductions in systolic blood pressure (SBP). The aim was to investigate the time course of the anti-hypertensive effect of liraglutide treatment and potential underlying mechanisms. We used an open-label, single-centre trial; 31 participants with Type 2 diabetes and hypertension completed the study. All participants were treated with liraglutide escalated to a maximum dose of 1.8mg/day for 7weeks, followed by a 21-day washout period. The primary outcome was a change in 24-h SBP. Twenty-four-h SBP increased by 10mmHg on day 3 (P=0.008) and 7mmHg on day 7 (P=0.033, 0.6mg/day). On day 29, (1.8mg/day), 24-h SBP was 7mmHg lower compared with baseline (P=0.11). Following the treatment period (day 49) and after washout (day 70), 24-h BP was equivalent to baseline. In addition, extracellular volume (ECV) was reduced by 2.0l [95% confidence interval (CI)=1.0-3.1l, P<0.001] and midregional-pro-atrial natriuretic peptide (MR-proANP) was reduced by 20% (95% CI=12-28%, P<0.001). Also, urinary albumin excretion declined by 30% (95% CI=12-44%, P=0.003), GFR by 11ml/min/1.73m(2) (95% CI=7.2-14.4ml/min/1.73m(2) , P<0.001) and fractional albumin excretion by 29% (95% CI=3-48%, P=0.032). Liraglutide treatment was associated with an initial increase in 24-h SBP, followed by a 7mmHg reduction after escalation to 1.8mg/day. This effect subsided after 4weeks of maximum dose. Reductions in ECV and MR-proANP may explain the anti-hypertensive potential. Liraglutide treatment was associated with reversible reductions in albuminuria and GFR, which has to be confirmed in randomized trials.

Effects of insulin detemir and NPH insulin on renal handling of sodium, fluid retention and weight in type 2 diabetic patients

In type 2 diabetic patients, insulin detemir (B29Lys(ε-tetradecanoyl),desB30 human insulin) induces less weight gain than NPH insulin. Due to the proposed reduction of tubular action by insulin detemir, type 2 diabetic patients should have increased urinary sodium excretion, thereby reducing extracellular volume and body weight when changed from NPH insulin to insulin detemir. In a randomised, open-labelled, two-way crossover study of 24 patients with type 2 diabetes, patients were first treated with NPH insulin or insulin detemir for 8 weeks. Thereafter, they were changed to the other insulin for 8 weeks. In a third 1 week period, they were changed back to the first insulin. At the end of 8 weeks, body weight was reduced by 0.8 ± 0.2 kg (mean ± SEM) on insulin detemir compared with NPH insulin (p < 0.01). After insulin detemir treatment, we also observed a significant reduction of lean body mass (0.8 ± 0.2 kg, p < 0.05) and a non-significant reduction of extracellular volume (0.8 ± 0.5 l/1.73 m², p = 0.14). The weight loss occurred after as early as 1 week (0.8 ± 0.2 kg, p < 0.001), with a simultaneous and transient increase of urinary sodium excretion (p = 0.07). Insulin detemir induces significant and sustained weight loss, which is first observed at 1 week after changing from NPH insulin. The initial weight loss seems to be related to changes in fluid volume and may reflect changed insulin action in the kidneys.

New Approaches to Pathogenesis and Management of Hypertension

New Approaches to Pathogenesis and Management of Hypertension

Sodium, hypertension, and an explanation of the “lag phenomenon” in hemodialysis patients

Sodium balance is precisely regulated by intake and output. The kidneys are responsible for adjusting sodium excretion to maintain balance at varying intakes. Our distant ancestors were herbivores. Their diet contained little sodium, so they developed powerful mechanisms for conserving sodium and achieving low urinary excretion. About 10,000 years ago, early humans became villagers and discovered that food could be preserved in brine. This led to increased consumption of salt. High salt intake increases extracellular volume (ECV), blood volume, and cardiac output resulting in elevation of blood pressure. High ECV induces release of a digitalis-like immunoreactive substance and other inhibitors of Na(+)-K(+)-ATPase. As a consequence, intracellular sodium and calcium concentrations increase in vascular smooth muscles predisposing them to contraction. Moreover, high ECV increases synthesis and decreases clearance of asymmetrical dimethyl-l-arginine leading to inhibition of nitric oxide (NO) synthase. High concentration of sodium and calcium in vascular smooth muscles, and decreased synthesis of NO lead to an increase in total peripheral resistance. Restoration of normal ECV and blood pressure are attained by increased glomerular filtration and decreased sodium reabsorption. In some individuals, the kidneys have difficulty in excreting sodium, so the equilibrium is achieved at the expense of elevated blood pressure. There is some lag time between reduction of ECV and normalization of blood pressure because the normal levels of Na(+)-K(+)-ATPase inhibitors and asymmetrical dimethyl-l-arginine are restored slowly. In dialysis patients, all mechanisms intended to increase renal sodium removal are futile but they still operate and elevate blood pressure. The sodium balance must be achieved via dialysis and ultrafiltration. Blood pressure is normalized a few weeks after ECV is returned to normal, i.e., when the patient reaches dry body weight. This is called the "lag phenomenon."

Extracellular Volume Changes and Blood Pressure Levels in Hemodialysis Patients

Despite the use of highly efficient antihypertensive drugs (AHD), blood pressure (BP) is poorly controlled in the vast majority of hemodialysis (HD) patients. Many of them show no reduction in nocturnal BP, a finding that is associated with left ventricular hypertrophy. The aim of the study was to investigate the effect of the removal of a fluid overload on BP by monitoring the ambulatory BP during 48 hours in 16 hypertensive HD patients treated with AHD. Our aim was to obtain a gradual reduction in post-HD body weight (BW) over a period of 3 to 4 months. During a period of 3-4 months, the postdialysis BW was reduced as the minimal tolerable BW was gradually achieved by slightly increasing the ultrafiltration volume. The Na concentration in the dialysate was reduced from 143-141 mmol/L to 139-138 mmol/L. Extracellular volume (ECV) was measured with a multiple-frequency bioimpedance analyzer (Xitron 4000B, Xitron Technologies Inc., San Diego, CA, USA). Based on the change in ECV, the patients were subdivided into two groups: group 1 with a reduction in ECV (n = 10), and group 2 with no reduction (n = 6). At the start of the study, BW, BP, and AHD in group 1 and group 2 were virtually identical. Group 1 showed a significant reduction during the entire 48-hour period in systolic (156 +/- 16 mmHg vs. 140 +/- 14 mmHg, P = 0.030) and diastolic BP (97 +/- 12 mmHg vs. 87 +/- 9 mmHg, P = 0.026) as well as in mean arterial pressure (MAP, 117 +/- 13 vs. 105 +/- 10 mmHg, P = 0.027). This reduction was more marked during the night (systolic BP 156 +/- 15 mmHg vs. 138 +/- 14 mmHg, P = 0.007; diastolic BP 97 +/- 12 mmHg vs. 85 +/- 9 mmHg, P = 0.009) than during the day (157 +/- 18 mmHg vs. 142 +/- 15 mmHg, P = 0.067; diastolic BP 97 +/- 13 mmHg vs. 90 +/- 9 mmHg, P = 0.126). A significant reduction in systolic load also occurred during the entire 48-hour period (76 +/- 24% vs. 46 +/- 28%, P = 0.043) as well as in night systolic load (75 +/- 21% vs. 41 +/- 30%, P = 0.015) and night diastolic load (67 +/- 32% vs. 39 +/- 31%, P = 0.030). AHD were stopped in eight and reduced in two patients. There were no significant reductions in BP and AHD in group 2. The removal of excess fluid is necessary for adequate BP control and especially for the reduction in elevated BP during the night.

Mechanistic investigation of extracellular K+ accumulation during acute myocardial ischemia: a simulation study.

In this study, we have used computer simulations to study the mechanisms of extracellular K+ accumulation during acute ischemia. A modified version of the Luo-Rudy phase II action potential model was used to simulate the electrical behavior of one ventricular myocyte during 14 min of simulated ischemia. Our results show the following: 1) only the integrated effect of activation of ATP-dependent K+ current, an ischemic Na+ inward current, and inhibition of Na(+)-K(+) pump activity in the absence of coronary flow replicates the biphasic time course of extracellular K+ concentration observed during acute ischemia; 2) the time to onset of the plateau phase and the plateau level value are determined by the rate of stimulation and by the rate of alteration of the three mechanisms. However, acidosis and reduction of extracellular volume produce only a slight anticipation of the plateau phase; and 3) cellular K+ loss is mainly due to an increase of K+ efflux via the time-independent K+ current and ATP-dependent K+ current rather than to a decrease of K+ influx.

Development of brain damage as measured by brain impedance recordings, and changes in heart rate, and blood pressure induced by different stunning and killing methods

Poultry are electrically stunned before slaughter to induce unconsciousness and to immobilize the chickens for easier killing. From a welfare point of view, electrical stunning should induce immediate and lasting unconsciousness in the chicken. As an alternative to electroencephalography, which measures brain electrical activity, this study used brain impedance recordings, which measure brain metabolic activity, to determine the onset and development of brain damage. Fifty-six chickens were surgically equipped with brain electrodes and a canula in the wing artery and were subjected to one of seven stunning and killing methods: whole body electrical stunning; head-only electrical stunning at 50, 100 or 150 V; or an i.v. injection with MgCl2. After 30 s, the chickens were exsanguinated. Brain impedance and blood pressure were measured. Extracellular volume was determined from the brain impedance data and heart rate from the blood pressure data. An immediate and progressive reduction in extracellular volume in all chickens was found only with whole body stunning at 150 V. This treatment also caused cardiac fibrillation or arrest in all chickens. With all other electrical stunning treatments, extracellular volume was immediately reduced in some but not all birds, and cardiac fibrillation or arrest was not often found. Ischemic conditions, caused by cessation of the circulation, stimulated this epileptic effect. A stunner setting of 150 V is therefore recommended to ensure immediate and lasting unconsciousness, which is a requirement for humane slaughter.

Angiotensin II AT(1A) receptor antisense lowers blood pressure in acute 2-kidney, 1-clip hypertension.

To test the effectiveness of antisense oligonucleotides targeted to the angiotensin type 1A (AT(1A)) receptor mRNA on blood pressure reduction, the 2-kidney, 1-clip (2K1C) Goldblatt model of hypertension was studied in the acute phase of hypertension, when the peripheral renin-angiotensin system is overactive. A single injection of AT(1A) receptor antisense oligodeoxynucleotides significantly reduced systolic blood pressure for a period of 8 days in 2K1C rats after clipping, from 157.5+/-5 mm Hg on day 7 to 141.3+/-3.0 mm Hg on day 15 after clipping (P<0.01). The AT(1A) receptor antisense oligonucleotide labeled with fluorescein shows that the antisense oligonucleotide at 24 hours was taken up into aorta, mesenteric artery, liver, kidney glomeruli, and medulla, remaining up to 6 days. The AT(1A) receptor number in fmol/g tissue was significantly decreased after AT(1A) receptor antisense oligonucleotide treatment in the dorsal aorta, mesenteric artery, renal cortex, and renal medulla (P<0.05) compared with that of the AT(1A) receptor-scrambled antisense oligonucleotide control-treated group. The data clearly demonstrate a prolonged antihypertensive effect of AT(1A) receptor antisense oligonucleotide in the 2K1C renovascular model of hypertension when it is administered intravenously in a single low dose (0.33 mg/kg(-1)). It also shows that the AT(1A) receptor antisense oligonucleotide is actively taken up by AT(1A) target tissues and that there is a significant decrease in receptor density. We conclude that in the acute phase of 2K1C hypertension, antisense to AT(1A) receptor decreases AT(1A) receptor density, which attenuates the vascular vasoconstrictive effects of high plasma angiotensin II levels and in the kidney elicits natriuresis. The decrease in renal AT(1A) receptor density may also lead to sodium loss and reduction of extracellular volume.

Advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in conjunction with omapatrilat, a vasopeptidase inhibitor.

The preferred initial agents for the treatment of high blood pressure are low-dose thiazide diuretics, beta blockers, calcium antagonists, and angiotensin-converting enzyme (ACE) inhibitors. In high-risk patients, including those with diabetes, renal insufficiency, left ventricular dysfunction, and atherosclerosis, ACE inhibitors may have specific benefit in reducing cardiovascular morbidity and mortality. Omapatrilat, the prototypical vasopeptidase inhibitor, inhibits not only ACE but also neutral endopeptidase. Like conventional ACE inhibitors, omapatrilat causes extracellular volume reduction and vasodilatation; moreover, it increases levels of atrial and brain natriuretic peptides and bradykinin. Effective blood pressure control, especially in the high-risk patient, usually necessitates combination therapy. A recent study randomized 274 subjects with mild to severe hypertension (stages 1-3 diastolic blood pressure elevation) and confirmed the benefits of omapatrilat combined with hydrochlorothiazide in patients not controlled on hydrochlorothiazide alone. The frequencies of adverse events, serious adverse events, and discontinuation attributed to adverse events were similar for omapatrilat and placebo. Furthermore, there were no clinically significant changes in serum creatinine, potassium, or other laboratory parameters. Adding omapatrilat to the background of hydrochlorothiazide treatment produced statistically significant additional reductions in trough diastolic and systolic blood pressures at weeks 4 and 8.