Extracellular Volume Expansion Research Articles

Deoxycorticosterone-acetate salt-sensitive hypertension initiates with intracellular K+ and water loss

Background: Textbook teaching pretends that Na+-driven extracellular fluid and blood volume expansion may cause hypertension. We tested the alternative hypothesis, namely that K+ loss-driven intracellular volume contraction causes hypertension. Methods: We tested the effect of deoxycorticosterone acetate (DOCA; 25 mg pellet) in mice on low Na+ diet (0.02-0.03%) without (tap water), or with Na+ in their drinking water (1% NaCl or 1.44% NaHCO3). We measured BP with radio-telemetry, and analysed body Na+, K+, and water content 2, 6, and 12 days after initiation of DOCA treatment. We monitored food intake, solute and water excretion in urine and stool, and quantified renal and cutaneous blood flow by pulse-wave/laser Doppler spectroscopy. Results: DOCA NaCl treatment initially reduced intracellular K+ and water content, and elevated BP without accompanying Na+ retention. To re-hydrate the intracellular volume space, hypertensive DOCA NaCl−treated mice secondarily replaced lost intracellular K+ by Na+ solutes, increased fluid intake, reduced renal solute-free water clearance, constricted renal blood vessels, and reduced dermal blood flow. Normotensive DOCA NaHCO3-treated mice similarly lost intracellular K+, but immediately compensated by intracellular Na+ accumulation, and therefore experienced no intracellular volume contraction. Without prolonged under-hydration of their K+-space, DOCA NaHCO3-treated mice neither showed augmentation of renal or dermal water conservation, nor vasoconstriction and blood flow reduction, and their BP remained normal despite body Na+ excess. Conclusions: DOCA salt-sensitive hypertension is caused by K+-driven under-hydration, and not by Na+-driven over-hydration. The BP increase is explainable by secondary-adaptive multi-organ water conservation physiology, but not by Na+-driven water excretion physiology. National Medical Research Council (NMRC) of Singapore to the Duke-NUS Medical School, the German Federal Ministry for Economics and Technology/DLR Forschung unter Weltraumbedingungen (Mars500-III; 50WB2024). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

SGLT2 Inhibitors Decrease Overhydration and Proteasuria in Patients with Chronic Kidney Disease: A Longitudinal Observational Study.

SGLT2 inhibitors are used to reduce the risk of progression of chronic kidney disease (CKD). In patients with type 2 diabetes, they have been found to reduce extracellular volume. Given the high prevalence of extracellular volume expansion and overhydration (OH) in CKD, we investigated whether SGLT2 inhibitors might correct these disturbances in CKD patients. CKD patients who started treatment with an SGLT2 inhibitor were investigated in this prospective observational study for 6 months. Body composition and fluid status were measured by bioimpedance spectroscopy. In addition, spot urine samples were analyzed for albuminuria, glucosuria, and urinary aprotinin-sensitive serine protease activity. Forty-two patients (29% with diabetic/hypertensive CKD, 31% with IgA nephropathy; 88% dapagliflozin 10 mg, 10% dapagliflozin 5 mg, 2% empagliflozin 20 mg; median eGFR 46 mL/min/1.73 m2 and albuminuria 1,911 mg/g creatinine) participated in the study. Median glucosuria increased to 14 (10-19) g/g creatinine. At baseline, patients displayed OH with +0.4 (-0.2 to 2.2) L/1.73 m2, which decreased by 0.5 (0.1-1.2) L/1.73 m2 after 6 months. Decrease of OH correlated with higher OH at BL, decrease of albuminuria, glucosuria, and urinary aprotinin-sensitive protease activity. Adipose tissue mass was not significantly reduced after 6 months. SGLT2 inhibitors reduce OH in patients with CKD, which is pronounced in the presence of high albuminuria, glucosuria, and urinary aprotinin-sensitive protease activity.

Kiosk 6R-TC-06 - Extracellular Volume Expansion Has Distinct Patterns in Morphological Subgroups of the HCMR Cohort

Kiosk 6R-TC-06 - Extracellular Volume Expansion Has Distinct Patterns in Morphological Subgroups of the HCMR Cohort

Quantification of extracellular volume with cardiac computed tomography in patients with left ventricle dysfunction

Abstract Background Myocardial fibrosis (MF) is a common endpoint in the majority of pathological mechanisms affecting cardiac muscle, ultimately resulting in cardiac failure. Cardiovascular magnetic resonance (CMR) with gadolinium-based contrast agent and T1 mapping technique is able to deliver a non-invasive quantification of the extracellular volume (ECV) expansion. Recently, ECV estimation with cardiac computed tomography (ECV-CCT) has been validated in the setting of cardiac amyloidosis, showing good agreement with ECV-CMR. However, no evidence is available with last generation single source single energy CT scanner in the clinical context of newly diagnosed left ventricular dysfunction. Therefore, the aim of this study is to test the diagnostic accuracy of ECV-CCT for the detection of MF in patients with recent diagnosis of reduced left ventricle ejection fraction (LVEF), having ECV-CMR as reference technique. Methods A consecutive cohort of 41 patients with newly diagnosed left ventricle dysfunction (LVEF < 50%) was enrolled. Time interval of maximum 30 days was present between CCT and CMR. Myocardial segment evaluability with each technique, agreement between ECV-CMR and ECV-CCT, regression analysis and Bland-Altman analysis were performed. Results Age of enrolled patients was 62 ± 11 years, and mean LVEF at CMR was 35.2 ± 10.7%. Mean total amount of administrated iodinated contrast was 112.6 ± 22.2 ml, while overall radiation exposure for ECV estimation was2.1 ± 1.1 mSv. Out of 656 myocardial segments available, 656 (100%) segments were evaluable at CCT while 640 (97.6%) were evaluable at CMR. ECV-CCT demonstrated slightly lower values compared to ECV-CMR both at global and region-based comparison (all segments, 33.1 ± 8.5% vs 35.5 ± 10.7%, p < 0.001). At regression analysis, strong correlations were described both at global and region-based analysis (all segments, r = 0.877, 95% CI: 0.840 to 0.914). On Bland-Altman analysis, bias between ECV-CMR and ECV-CCT for global analysis was 2.4 (95% CI: -7.8 to 12.7). Conclusions ECV estimation with last-generation single source single energy CT scanner is feasible and accurate. Integration of ECV measurement in comprehensive CCT evaluation of patients with newly diagnosed left ventricular dysfunction can be performed with a small increase in overall radiation exposure.

Abstract 11373: Suppression of Plasma Angiotensin II by GLP-1 in Humans is Independent of Changes in Plasma Angiotensinogen

Introduction: In humans, the natriuretic effect of GLP-1 depends on GLP-1 receptor interaction, is independent of changes in renal blood flow, renin, ANP, and aldosterone but is accompanied by suppression of angiotensin II (ANGII). The mechanism by which GLP-1 reduces ANGII independently of changes in renin is not clarified. Hypothesis: It was hypothesized that GLP-1 suppresses renin substrate, angiotensinogen, in plasma. Methods: To test this proposal, we measured arterial angiotensinogen concentration in biobanked plasma samples from healthy males during a 3-hour GLP-1 infusion that induced natriuresis (1). Samples were from a study with fixed sodium intake where eight healthy men were examined twice in random order during a 3-hour infusion of either GLP-1(1.5 pmol kg -1 min -1 ) or vehicle together with an intravenous infusion of 0.9% NaCl (750 mL/hour). Arterial plasma angiotensinogen was measured in plasma by dilution (1:200) and addition of excess exogenous human renin (Inst. Of Biological Standards UK). After prolonged incubation, ANGI was quantified by radioimmunoassay. Intraassay variation was 9-12%. Results: Arterial plasma angiotensinogen and renin levels decreased similarly and modestly (~15 and ~30%, respectively) after NaCl infusion during both studies whereas ANGII levels decreased significantly (~25%) only during GLP-1 infusion. Conclusions: Suppression of plasma angiotensinogen is less likely to account for GLP-1-mediated ANGII suppression in healthy young males. In perspective, GLP-1 could enhance pathways of ANGII degradation rather than inhibit its formation. 1. Asmar A et al. Extracellular fluid volume expansion uncovers a natriuretic action of GLP-1: a functional GLP-1-renal axis in man. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2509-2519.

Exercise-Induced Fluid Retention, Cardiac Volume Overload, and Peripheral Edema in Ultra-Distance Cyclists

IntroductionUltracyclists expose themselves to extreme physical challenges. This study aimed to elucidate the effects of ultracycling on electrolyte and fluid balance and investigate the potential occurrence of peripheral edema. MethodsSerial laboratory analyses of blood and urine, bioelectrical impedance analyses and echocardiography were performed at four time points during a six-day bicycle ride in 13 ultracyclists (5 female, 8 male). Throughout the ride, participants continuously tracked fluid intake, measured extremity circumferences daily, and self-tested urinary electrolytes using a point-of-care testing device. Portrait photos were judged by 20 physicians for occurrence of facial and eyelid edema. ResultsParticipants covered a mean distance of 1,205 km and 19,417 vertical meters. From baseline to day 6, body weight remained stable (p = 0.479), but body composition changed with increasing total body water (+1.98 L ± 1.37, p = 0.003) and plasma volume (+18.86 % ± 10.7, p < 0.001). A significant increase in NT-proBNP (+297.99 ng/L ± 190.42, p < 0.001) until day 6 indicates concomitant cardiac volume overload. Swelling of face and eyelids peaked on day 5 (both p ≤ 0.033). On recovery, changes partly resolved. While urinary sodium concentration showed a nadir on day 4 (-32.18 mmol/L ± 23.88, p = 0.022), plasma osmolality (+5.69 mmosmol/kg ± 5.88, p = 0.004) and copeptin (+38.28 pg/mL ± 18.90, p < 0.001) increased steadily until day 6. ConclusionUltracycling over multiple days induces extracellular volume expansion, peripheral edema and cardiac volume overload. Renal sodium and water retention is likely contributing to this condition.

Chemotherapy effect on myocardial fibrosis markers in patients with gynecologic cancer and low cardiovascular risk.

Patients with gynecologic cancers experience side effects of chemotherapy cardiotoxicity. We aimed to quantify cardiac magnetic resonance (CMR) markers of myocardial fibrosis in patients with gynecologic cancer and low cardiovascular risk who undergo chemotherapy. This study is part of a registered clinical research. CMR T1 mapping was performed in patients with gynecologic cancer and low cardiovascular risk undergoing chemotherapy. The results were compared with those of age-matched healthy control subjects. 68 patients (median age = 50 years) and 30 control subjects were included. The median number of chemotherapy cycles of patients was 9.0 (interquartile range [IQR] 3.3-17.0). Extracellular volume fraction (ECV) (27.2% ± 2.7% vs. 24.5% ± 1.7%, P < 0.001) and global longitudinal strain (-16.2% ± 2.8% vs. -17.4% ± 2.0%, P = 0.040) were higher in patients compared with controls. Patients with higher chemotherapy cycles (>6 cycles) (n=41) had significantly lower intracellular mass indexed (ICMi) compared with both patients with lower chemotherapy cycles (≤6 cycles) (n=27) (median 27.44 g/m2 [IQR 24.03-31.15 g/m2] vs. median 34.30 g/m2 [IQR 29.93-39.79 g/m2]; P = 0.002) and the control group (median 27.44 g/m2 [IQR 24.03-31.15 g/m2] vs. median 32.79 g/m2 [IQR 27.74-35.76 g/m2]; P = 0.002). Patients with two or more chemotherapy regimens had significantly lower ICMi compared with both patients with one chemotherapy regimen (27.45 ± 5.16 g/m2 vs. 33.32 ± 6.42 g/m2; P< 0.001) and the control group (27.45 ± 5.16 g/m2 vs. 33.02 ± 5.52 g/m2; P < 0.001). The number of chemotherapy cycles was associated with an increase in the ECV (Standard regression coefficient [β] = 0.383, P = 0.014) and a decrease in the ICMi (β = -0.349, P = 0.009). Patients with gynecologic cancer and low cardiovascular risk who undergo chemotherapy have diffuse extracellular volume expansion, which is obvious with the increase of chemotherapy cycles. Myocyte loss may be part of the mechanism in patients with a higher chemotherapy load. http://www.chictr.org.cn, identifier ChiCTR-DDD-17013450.

1652-P: Suppression of Plasma Angiotensin II by GLP-1 in Humans Is Independent of Changes in Plasma Angiotensinogen

In humans, the natriuretic effect of GLP-1 depends on GLP-1 receptor interaction, is independent of changes in renal blood flow, renin, ANP, and aldosterone but is accompanied by suppression of angiotensin II (ANGII). The mechanism by which GLP-1 reduces ANGII independently of changes in renin is not clarified. It was hypothesized that GLP-1 suppresses renin substrate, angiotensinogen, in plasma. To test this proposal, we measured arterial angiotensinogen concentration in biobanked plasma samples from healthy males during a 3-hour GLP-1 infusion that induced natriuresis (1). Samples were from a study with fixed sodium intake where eight healthy men were examined twice in random order during a 3-hour infusion of either GLP-1(1.5 pmol kg-1 min-1) or vehicle together with an intravenous infusion of 0.9% NaCl (750 mL/hour). Arterial plasma angiotensinogen was measured in plasma by dilution (1:200) and addition of excess exogenous human renin (Inst. of Biological Standards UK). After prolonged incubation, ANGI was quantified by radioimmunoassay. Intraassay variation was 9-12%. Arterial plasma angiotensinogen and renin levels decreased similarly and modestly (~15 and ~30%, respectively) after NaCl infusion during both studies whereas ANGII levels decreased significantly (~25%) only during GLP-1 infusion. Suppression of plasma angiotensinogen is less likely to account for GLP-1-mediated ANGII suppression in healthy young males. In perspective, GLP-1 could enhance pathways of ANGII degradation rather than inhibit its formation. 1. Asmar A et al. Extracellular fluid volume expansion uncovers a natriuretic action of GLP-1: a functional GLP-1-renal axis in man. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2509-2519. Disclosure B.L.Jensen: None. A.Asmar: Research Support; Novo Nordisk A/S.

Quantification of extracellular volume with cardiac computed tomography in patients with left ventricle dysfunction

Abstract Funding Acknowledgements Type of funding sources: None. Background Myocardial fibrosis (MF) is a common endpoint in the majority of pathological mechanisms affecting cardiac muscle, ultimately resulting in cardiac failure. Cardiovascular magnetic resonance (CMR) with gadolinium-based contrast agent and T1 mapping technique is able to deliver a non-invasive quantification of the extracellular volume (ECV) expansion. Recently, ECV estimation with cardiac computed tomography (ECV-CCT) has been validated in the setting of cardiac amyloidosis, showing good agreement with ECV-CMR. However, no evidence is available with last generation single source single energy CT scanner in the clinical context of newly diagnosed left ventricular dysfunction. Therefore, the aim of this study is to test the diagnostic accuracy of ECV-CCT for the detection of MF in patients with recent diagnosis of reduced left ventricle ejection fraction (LVEF), having ECV-CMR as reference technique. Methods A consecutive cohort of 41 patients with newly diagnosed left ventricle dysfunction (LVEF &amp;lt; 50%) was enrolled. Time interval of maximum 30 days was present between CCT and CMR. Myocardial segment evaluability with each technique, agreement between ECV-CMR and ECV-CCT, regression analysis and Bland-Altman analysis were performed. Results Age of enrolled patients was 62 ± 11 years, and mean LVEF at CMR was 35.2 ± 10.7%. Mean total amount of administrated iodinated contrast was 112.6 ± 22.2 ml, while overall radiation exposure for ECV estimation was 2.1 ± 1.1 mSv. Out of 656 myocardial segments available, 656 (100%) segments were evaluable at CCT while 640 (97.6%) were evaluable at CMR. ECV-CCT demonstrated slightly lower values compared to ECV-CMR both at global and region-based comparison (all segments, 33.1 ± 8.5% vs 35.5 ± 10.7%, p &amp;lt; 0.001). At regression analysis, strong correlations were described both at global and region-based analysis (all segments, r = 0.877, 95%CI: 0.840 to 0.914). On Bland-Altman analysis, bias between ECV-CMR and ECV-CCT for global analysis was 2.4 (95%CI: −7.8 to 12.7). Conclusions ECV estimation with last-generation single source single energy CT scanner is feasible and accurate. Integration of ECV measurement in comprehensive CCT evaluation of patients with newly diagnosed left ventricular dysfunction can be performed with a small increase in overall radiation exposure.

Abstract 10265: Association of Myocardial Mechanical Markers of Extracellular Volume Expansion With Heart Failure and All-Cause Mortality: The Multi-Ethnic Study of Atherosclerosis

Introduction: Characteristic myocardial deformation indices have been proposed to be associated with extracellular volume (ECV) expansion and differentiate cardiac pathologies that induce cardiac remodeling. Hypothesis: Our hypothesis was that such mechanical markers are associated with (1) pathologic ECV expansion and cardiac remodeling and (2) clinical outcomes of heart failure and mortality. Methods: Our analysis included 2778 participants who underwent cardiac MRI at the Multi-Ethnic Study of Atherosclerosis Exam 5 (2010-2012). The following deformation indices were calculated: relative apical strain ratio (RAS), septal apical basal ratio (SAB) and ejection fraction circumferential strain ratios (EFSR). We used linear regression to analyze the associations of these deformation indices with cardiac remodeling and ECV expansion. We used Cox proportional models to investigate the associations of mechanical deformation indices with incident HF and all-cause mortality. Results: The mean (SD) age of the cohort at Exam 5 was 69.1 (9.3) years; 53% were female. MRI tagging and T1 mapping analyses showed that higher levels of EFSR were associated with 0.2% greater ECV and 4.4ms higher native T1. In addition, EFSR was associated with 3.59ml lower LV end-diastolic volume, 1.98g higher LV mass and 0.13 ⃘ higher torsion. EFSR was associated with greater LA volume, decreased total emptying fraction and reduced maximal strain (Table 1). During a follow-up period of 7.5 years (Figure 1), there were 101 incident heart failure events, and 228 all-cause deaths. In the multivariable cox regression analysis, hazard ratios (95% CI) of incident HF and all-cause mortality for each unit increase of EFSR were 1.36 (1.04,1.78) and 1.31 (1.05,1.64) (Table 2), respectively. Conclusion: Mechanical markers of extracellular expansion are associated with adverse cardiac remodeling, incident HF and all-cause mortality.

PSUN68 Finerenone for Primary Aldosteronism: A Novel Mineralocorticoid Receptor Antagonist

Abstract Background In primary aldosteronism (PA), aldosterone is inappropriately released into the systemic circulation and binds to the mineralocorticoid receptor (MR) in the distal tubule and collecting duct of the kidney. As a result, there is sodium reabsorption and potassium wasting leading to extracellular volume expansion, hypertension, hypokalemia, and, ultimately, suppressed renin. For medication management of aldosterone-producing adenomas with MR antagonists, spironolactone or eplerenone, are recommended. Finerenone is a novel, selective, non-steroidal MR antagonist approved July 2021 to reduce the risk of kidney and heart complications in patients with diabetic kidney disease. Interestingly, finerenone is at least as potent as spironolactone, and more selective for the MR (at least 500-fold) than eplerenone (1). We present a case using finerenone for the treatment of PA. Clinical Case OA 62-year-old male with CKD Stage G4/A3, T2DM, obesity, refractory hypertension and persistent hypokalemia underwent two radiofrequency ablations of a left adrenal nodule for the management of PA. Because of biochemical evidence for persistent hyperaldosteronism, pharmacologic therapy was initiated with eplerenone, which was chosen over spironolactone based on tolerability profile. Other antihypertensives included labetalol and nifedipine. Eplerenone was gradually titrated to 150 mg twice daily along with potassium replacement, but PRA remained below goal at 0.35 ng/mL/h with average BP 164/97 mmHg lying, 169/92 mmHg sitting, and 139/90 mmHg standing. Other pertinent labs included average SCr 4.62 mg/dL and eGFR 15 mL/min/1.73m2. A joint decision was made to replace eplerenone with finerenone 10 mg once daily. Two weeks after starting finerenone, PRA increased to 0.59 ng/mL/h, and SCr, eGFR, and potassium were 4.79 mg/dL, 14 mL/min/1.73m2, and 4.2 mEq/L, respectively. BP was 165/92 mmHg lying, 154/92 mmHg sitting, and 118/82 mmHg standing. Finerenone was increased to 20 mg once daily with close follow-up monitoring revealing an average PRA 0.42 ng/mL/h, SCr 4.28 mg/dL, eGFR 16 mL/min/1.73m2, potassium 3.5 mEq/L, and average BP 163/90 mmHg lying, 164/94 mmHg sitting, and 149/84 mmHg standing. Finerenone was well-tolerated and no changes were made to potassium replacement during this time. Conclusion Current MR antagonists, spironolactone and eplerenone, have concerns with tolerability due to minimal selectivity and efficacy, respectively. A new generation of MR antagonists, such as finerenone, with high potency and selectivity may lead to practice changes for management of PA. Based on our patient, finerenone increased PRA and similarly controlled BP compared to eplerenone. Further research will be required to evaluate finerenone for PA as a safe, effective, and convenient alternative MR antagonist, specifically with evaluation of dose-dependent effects beyond 20 mg daily as currently described in the literature. Reference 1. Kolkhof P, Bärfacker L. 30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development. J Endocrinol. 2017;234(1): T125-T140. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Myocardial Extracellular Volume Expansion in Type 2 Diabetes Is Associated With Ischemic Heart Disease, Autonomic Neuropathy, and Active Smoking.

Myocardial interstitial fibrosis expands the extracellular volume (ECV) and in patients with type 2 diabetes is implicated in development of heart failure. ECV can be determined with gadolinium contrast MRI. We investigated which known risk factors for cardiovascular disease were associated with increased ECV in patients with type 2 diabetes. A total of 296 patients with type 2 diabetes and 25 sex and age-matched control subjects were included in a cross-sectional MRI study. The influence of risk factors on ECV was investigated with multiple regression analysis. Control subjects and patients with type 2 diabetes without complications had similar ECV (mean ± SD 27.4 ± 2.1% vs. 27.9 ± 2.6%, P = 0.4). Compared with patients without, ECV was significantly increased in patients with one or more complications (29.0 ± 3.3%, P = 0.02). Both in univariable analysis and after multivariable adjustment, ischemic heart disease, autonomic neuropathy, and active smoking were associated with increased levels of ECV. Active smoking exhibited the largest effect size (β = 2.0 percentage points, 95% CI 0.7-3.3). Former smokers ECV similar to that of never smokers. Albuminuria and systolic blood pressure were inversely associated with ECV in multivariable analysis, but after adjustment for medication suspected to affect ECV, the association with albuminuria was no longer significant (P = 0.1). Sodium-glucose cotransporter 2 inhibitor treatment was not significantly associated with reduced ECV (-0.8%, 95% CI -1.7 to 0.06, P = 0.067). Patients with complications of diabetes have increased ECV, not seen in patients without complications. Ischemic heart disease, autonomic neuropathy, and active but not former smoking were highly associated with increased ECV.

Cardiac pressure overload exposes hidden anthracycline-induced cardiotoxicity: results from a preclinical large-animal trial

Abstract Aim The purpose of this work is to elucidate if low cumulative doxorubicin doses has a differential cardiac impact in pigs with or without pre-existing LV pressure overload. Impact of interventions on LV anatomy, function and tissue composition was evaluated by serial cardiac magnetic resonance (CMR). At the end of the in vivo protocol, hearts were processed to evaluate differential molecular pathways in both groups. Methods A total of 95 pigs were included. 52 animals underwent supravalvular aortic banding to generate LV hypertrophy, while another did not. 4 months after banding (a time where LV hypertrophy is prominent), animals in both groups were randomized to receive intravenous doxorubicin (1 mg/kg once per week, for 5 weeks) or saline. Thus, 4 study groups (N=15–22 per group) comprised the study population (banding yes/no, doxorubicin yes/no). All individuals underwent to serial Cardiac Magnetic Resonance exams every month and were sacrificed fo ex vivo analysisat 4 months after doxorubicin injections. To discriminate between doxorubicin effect in banding/no banding groups but also the effect of banding in doxorubicin protocols, t-test was used for two-group comparisons after two-way ANOVA test. Differences were considered statistically significant at p&amp;lt;0.05. Logrank test was performed to compare survival curves. Results Pigs receiving doxorubicin after cardiac pressure overload showed an increased mortality compared with the other groups (p=0.006). Only this group developed a progressive cardiotoxicity phenotype, characterized as a significant decline in cardiac function compared with control operated animals (49.7% ± 8.1 vs 79.6% ± 6.7, p&amp;lt;0.001), but also with non-operated pigs receiving the same anthracycline regime (vs 63.9% ± 4, p&amp;lt;0.001). Cardiac deterioration was based mainly on systolic dysfunction compared with control operated animals (38.2 ml indexed ± 3.5 vs 13.6±6.6, p=0.01) and non-operated pigs treated with doxorubicin (vs 26.6 ml indexed ± 6.6, p&amp;lt;0.001). In-vivo CMR tissue characterization revealed elevation on T2 relaxation times compared with Control animals (46.2 ms ± 3.5 vs 41.8±2.7, p=0.04) with no Extracellular Volume expansion. Ex-vivo histological analyses showed presence of intra-cardiomyocyte vacuolization in the Banding + DOXO group (p=0.01). Regarding mitochondrial phenotype, animals with Banding + DOXO exhibited a fragmented phenotype with extremely damaged mitochondria. Animals with only aortic banding exhibit increasing cardiac hyperkinesia and cardiac hypertrophy at the end of the study. Conclusion(s) We demonstrated that a very low dosage of doxorubicin is enough to exert cardiotoxicity in a pressure overload scenario. Characterized as a deterioration in cardiac function, myocardial edema, classical histological lesions and mitochondrial damage. Providing preclinical evidence that modest anthracycline protocols may be harmful for patients with cardiac comorbidities. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ERC MATRIX

Diffuse myocardial fibrosis precedes subclinical functional myocardial impairment and provides prognostic information in systemic sclerosis.

Myocardial involvement is common in patients with systemic sclerosis (SSc) and causes myocardial fibrosis and subtle ventricular dysfunction. However, the temporal onset of myocardial involvement during the progression of the disease and its prognostic value are yet unknown. We used cardiovascular magnetic resonance (CMR) to investigate subclinical functional impairment and diffuse myocardial fibrosis in patients with very early diagnosis of SSc (VEDOSS) and established SSc and examined whether this was associated with mortality. One hundred and ten SSc patients (86 established SSc, 24 VEDOSS) and 15 healthy controls were prospectively recruited. The patients were followed-up for a median duration of 7.0 years (interquartile range 6.0-7.3 years). Study subjects underwent CMR including assessment of myocardial fibrosis [native T1 and extracellular volume (ECV)] and measurement of global longitudinal (GLS) and circumferential (GCS) myocardial strain. Native T1 values and ECV were elevated in VEDOSS and SSc patients compared with controls (P < 0.001). GLS was similar in VEDOSS and controls but significantly impaired in patients with established SSc (P < 0.001). GCS was similar over all groups (P = 0.88). There were 12 deaths during follow-up. Elevated native T1 [hazard ratio (HR) 5.8, 95% confidence interval (CI): 1.7-20.4; P = 0.006] and reduced GLS (HR 6.1, 95% CI: 1.3-29.9; P = 0.038) identified subjects with increased risk of death. Only native T1 was predictive for cardiovascular mortality (P < 0.001). Subclinical myocardial involvement first manifests as diffuse myocardial fibrosis identified by the expansion of ECV and increased native T1 in VEDOSS patients while subtle functional impairment only occurs in established SSc. Native T1 and GLS have prognostic value for all-cause mortality in SSc patients.

Primary hyperaldosteronism without suppressed renin

Primary Hyperaldosteronism characterizes elevated plasma and urinary aldosterone with suppression of plasma renin activity. Suppression can be due to sodium retention which is aldosterone dependent and extracellular volume expansion. Here a 29 year old male presented with uncontrolled hypertension, on work up he was diagnosed to have primary Hyperaldosteronism with normal plasma renin level. So with the available medical data on the patient as well as the publications on aldosterone/renin association in primary hyperaldosteronism was reviewed here to explain the rare finding.

Volume-Independent Sodium Toxicity in Peritoneal Dialysis: New Insights from Bench to Bed

Sodium overload is common in end-stage kidney disease (ESKD) and is associated with increased cardiovascular mortality that is traditionally considered a result of extracellular volume expansion. Recently, sodium storage was detected by Na23 magnetic resonance imaging in the interstitial tissue of the skin and other tissues. This amount of sodium is osmotically active, regulated by immune cells and the lymphatic system, escapes renal control, and, more importantly, is associated with salt-sensitive hypertension. In chronic kidney disease, the interstitial sodium storage increases as the glomerular filtration rate declines and is related to cardiovascular damage, regardless of the fluid overload. This sodium accumulation in the interstitial tissues becomes more significant in ESKD, especially in older and African American patients. The possible negative effects of interstitial sodium are still under study, though a higher sodium intake might induce abnormal structural and functional changes in the peritoneal wall. Interestingly, sodium stored in the interstial tissue is not unmodifiable, since it is removable by dialysis. Nevertheless, the sodium removal by peritoneal dialysis (PD) remains challenging, and new PD solutions are desirable. In this narrative review, we carried out an update on the pathophysiological mechanisms of volume-independent sodium toxicity and possible future strategies to improve sodium removal by PD.

Abstract 14147: Septal Native T1 is Higher in Patients With Pre-Capillary Pulmonary Hypertension Compared to Post-Capillary Pulmonary Hypertension

Introduction: Right heart catheterization (RHC) is used to diagnose and classify pulmonary hypertension (PH). Because RHC is invasive, there is growing interest in non-invasive PH evaluation techniques, such as cardiac magnetic resonance (CMR). Hypothesis: CMR-derived fibrosis indices [native T1 (NT1) and extracellular volume (ECV)] differ between pre-capillary PH (PRE-PH), post-capillary PH (POST-PH) and controls. Methods: RHC-defined PH patients and healthy controls (N=25, age=52+/-13 years) underwent CMR. A cardiologist classified patients into PRE-PH (N=29, age=55+/-8 years) and POST-PH (N=19, age=66+/-13 years) based on RHC measurements and clinical history. T1 maps of the left ventricle were acquired using a Modified Look-Locker Inversion Recovery sequence before and after administration of gadolinium contrast. T1 maps were manually segmented using the AHA 16 segment model to obtain segmental native and post-contrast T1. Segmental ECV was calculated using NT1, post-contrast T1, and hematocrit. Global ECV and NT1 were calculated by averaging all segments. Results: PRE-PH had higher NT1 than POST-PH in segments 8 (1077+/-39 vs 1046+/-36 ms, p=.01), 9 (1082+/-47 vs 1051+/-44 ms, p=.03), and 14 (1080+/-74 vs 1028+/-53 ms, p=.01). Global ECV and NT1 were higher in PRE-PH (31+/-4% and 1056+/-36 ms) than controls (28+/-4% and 1013+/-29 ms) (p=.017 and p=.000, respectively). Conclusions: NT1 was different between PRE-PH and POST-PH in mid- and apical-septal segments, however segmental ECV and global measures were not. NT1 may reflect more than just ECV expansion, providing additional insight into the myocardium. Regional NT1 may complement RHC for classifying PH.

Abstract 10884: B-Cell-Mediated Sodium and Water Retention Contributes to Heart Failure Pathogenesis

Background: B-cells have been shown to serve pathogenic roles in heart failure through cardiac-specific monocyte mobilization and autoantibody deposition. Beyond this, we recently showed that mice with hypomorphic c-Myb activity ( c-myb h/h ) have reduced B-cells and that B-cell deficiency is associated with increased sodium- and water-excretion and reduced blood pressure. Here, we determine the relevance of these responses in an experimental model of heart failure. Methods &amp; Results: C57BL/6J wild-type (WT) and B-cell deficient c-myb h/h mice (male and female; aged 10-12 weeks) underwent either: (i) permanent LAD ligation to induce myocardial infarction (MI); or (ii) sham surgery. Echocardiography showed that B-cell deficiency preserved ejection fraction (53±2 vs. 44±2 %; N=6-7/group; P&lt;0.01) and limited pathologic remodeling with reduced LVID (end-diastolic: 4.9±0.1 vs. 5.5±0.1 mm; N=6-7/group; P&lt;0.01; end-systolic: 3.8±0.2 vs. 4.5±0.1 mm; N=6-7/group; P&lt;0.001) at 4-weeks post-MI compared to WT. Heart weight/tibia length and right lung weight/tibia length ratios (g/mm; P&lt;0.01), as well as pleural effusion volumes (μl; P&lt;0.05) were increased post-MI in WT, rather than c-myb h/h mice. Indeed, mice with B-cell deficiency manifest reduced right lung weight/tibia length ratio (0.005±0.000 vs. 0.009±0.001 g/mm; N=5-6/group; P&lt;0.01) and pleural effusion volume (17±6 vs. 55±18 μl; N=6-7/group; P&lt;0.06) post-MI compared to WT. Underlying this decongestion, metabolic cage studies revealed that B-cell deficient mice had sustained increases in 24-h urine volume/body weight and 24-h sodium excretion/body weight ratios, which correlated with ejection fraction 4-weeks post-MI (r=0.53; N=13 pairs; P&lt;0.05; and r=0.50; N=13 pairs; P&lt;0.05, respectively). Conclusion: Together, these data show that B-cells play a role in sodium- and water-retention, and consequently, extracellular fluid volume expansion and congestion post-MI, and suggest that B-cells may represent a therapeutic target in heart failure.

Amyloid deposits and fibrosis on left ventricular endomyocardial biopsy correlate with extracellular volume in cardiac amyloidosis

Abstract Background The relative contribution of amyloid and fibrosis to extracellular volume expansion in cardiac amyloidosis (CA) has never been defined. Methods We included all patients diagnosed with amyloid light-chain or transthyretin (AL/ATTR) CA at a tertiary referral center between 2014 to 2020 and undergoing a left ventricular (LV) endomyocardial biopsy (EMB). Results Patients (n=37) were more often male (92%), with a median age of 72 years (68–81). Lambda+ AL was found in 14/19 AL cases (38%) and kappa+ AL in 5/19 (14%), while TTR was detected in the other 18 cases (48%). Amyloid deposits accounted for 15% of tissue sample area (10–30%), without significant differences between AL and ATTR. All patients displayed myocardial fibrosis, with a median extent of 15% of tissue samples (10–23%, range 5–60%), in the absence of spatial overlap with amyloid deposits. Interstitial fibrosis was often associated with mild and focal subendocardial fibrosis. The extent of fibrosis or the combination of amyloidosis and fibrosis did not differ significantly between ATTR and AL subgroups. In 20 patients with myocardial T1 mapping at cardiac magnetic resonance (CMR), the combined amyloid and fibrosis extent displayed a modest correlation with extracellular volume (ECV; r=0.661, p=0.001). The combined amyloid and fibrosis extent correlated with high-sensitivity troponin T (p=0.035) and N-terminal pro-B-type natriuretic peptide (p=0.002) serum levels. Conclusions Extracellular spaces in CA are enlarged to a similar extent by amyloid deposits and fibrotic tissue. Their combination can better explain the increased ECV at CMR and circulating biomarkers than amyloid extent alone. Funding Acknowledgement Type of funding sources: None.

Amyloid Deposits and Fibrosis on Left Ventricular Endomyocardial Biopsy Correlate With Extracellular Volume in Cardiac Amyloidosis.

BackgroundThe relative contribution of amyloid and fibrosis to extracellular volume expansion in cardiac amyloidosis (CA) has never been defined.Methods and ResultsWe included all patients diagnosed with amyloid light‐chain (AL) or transthyretin cardiac amyloidosis at a tertiary referral center between 2014 to 2020 and undergoing a left ventricular endomyocardial biopsy. Patients (n=37) were more often men (92%), with a median age of 72 years (interquartile range, 68–81). Lambda‐positive AL was found in 14 of 19 AL cases (38%) and kappa‐positive AL in 5 of 19 (14%), while transthyretin was detected in the other 18 cases (48%). Amyloid deposits accounted for 15% of tissue sample area (10%–30%), without significant differences between AL and transthyretin amyloidosis. All patients displayed myocardial fibrosis, with a median extent of 15% of tissue samples (10%–23%; range, 5%–60%), in the absence of spatial overlap with amyloid deposits. Interstitial fibrosis was often associated with mild and focal subendocardial fibrosis. The extent of fibrosis or the combination of amyloidosis and fibrosis did not differ significantly between transthyretin amyloidosis and AL subgroups. In 20 patients with myocardial T1 mapping at cardiac magnetic resonance, the combined amyloid and fibrosis extent displayed a modest correlation with extracellular volume (r=0.661, P=0.001). The combined amyloid and fibrosis extent correlated with high‐sensitivity troponin T (P=0.035) and N‐terminal pro‐B‐type natriuretic peptide (P=0.002) serum levels.ConclusionsExtracellular spaces in cardiac amyloidosis are enlarged to a similar extent by amyloid deposits and fibrotic tissue. Their combination can better explain the increased extracellular volume at cardiac magnetic resonance and circulating biomarkers than amyloid extent alone.