Miller, Wayne L.

The relationship of blood volume (BV) to systemic blood pressure (BP) is not well defined in resistant hypertension (RH). The goal of this study was to examine the extent to which systemic BP stratified by patient sex would impact BV phenotypes. A retrospective analysis of clinical and quantitative BV data was undertaken in a cohort of ambulatory patients with a history of controlled and uncontrolled RH. We analyzed 253 unique BVs with 54% of patients above goal BP of <150 mmHg. BV phenotypes were highly variable but no correlation of systolic BP to absolute BV or percentage deviation from normal volume was identified in either sex. Males demonstrated overall larger absolute BVs with higher prevalence of large plasma volume (PV) expansion; females were overall more hypovolemic by total BV but with a higher frequency of normal PV than males. Females trended towards more RBC mass deficit (true anemia) (49% vs. 38%. P = 0.084) while more males demonstrated RBC mass excess (erythrocythemia) (21% vs. 11%, P = 0.029). Importantly, a significant portion (52%) of patients with true anemia identified by BVA would go undetected by hemoglobin measurement alone. BV phenotypes are highly diverse in patients with RH. However, absolute BV or variability in BV phenotypes even when stratified by patient sex did not demonstrate an association with systemic BP. BV phenotyping provides a key to optimizing clinical management by identifying RBC mass profiles particularly distinguishing true anemia, dilutional anemia, and erythrocythemia and the contribution of PV expansion. Findings support the clinical utility of BV phenotyping in RH.

Abstract Background/Introduction Hypertension (HTN) and metabolic syndrome (MetS) are both leading risk factors for major cardiovascular diseases, which frequently coexist as a complicated cardiometabolic disorder. The cardiac hormone atrial natriuretic peptide (ANP) plays a key role in both blood pressure and metabolic regulation through activation of the guanylyl cyclase-A receptor (GC-A) and the second messenger 3’,5’ cyclic guanosine monophosphate (cGMP). Indeed, ANP decreases blood pressure, induces lipolysis by increasing plasma levels of non-esterified fatty acids (NEFA) and improves insulin-sensitivity. MANP is a new Mayo Clinic designed natriuretic peptide consisting of the native ANP with a 12-amino-acid C-terminus extension and its biological actions are mediated by the GC-A/cGMP pathway. MANP is less susceptible to neprilysin degradation and exert more sustained cGMP dependent biological actions than ANP. Purpose In a proof-of-principle human study, for the first time we aimed to determine the cardiovascular and metabolic properties of MANP, a novel ANP analog, in the clinical setting of HTN with MetS. Methods We conducted a double-blind, placebo-controlled trial in 22 patients (17 receiving MANP) with HTN and MetS involving single subcutaneous injection of MANP (2.5 µg/kg) or placebo (NCT03781739). Blood pressure (BP) and circulating cGMP were monitored for 24 hours post treatment. Circulating metabolic parameters including insulin, glucose, non-esterified fatty acids (NEFA) and insulin resistance (HOMA-IR) and insulin sensitivity (HOMA-IS) indexes were assessed for the first 4 hours post treatment. Results Compared to baseline, MANP increased plasma cGMP at 30 minutes (delta: 4.8 ± 2.0 pmol/mL, P = 0.02) and 1 hour (delta: 2.9 ± 1.3 pmol/mL, P = 0.03) post injection. At 6 hours, systolic BP decreased by 5.7 ± 2.9 mmHg (P = 0.06) in the MANP group, whereas no reduction in BP was observed in placebo group. Among the 17 subjects receiving MANP, lower baseline cGMP levels were associated with greater mean reductions in systolic BP (ρ = 0.66, P = 0.005). After MANP injection, glucose levels decreased at 2 (delta: -4.7 ± 2.1 mg/mL, P = 0.04) and 4 hours (delta: -13.1 ± 3.9 mg/mL, P = 0.003) compared to baseline while insulin levels remained stable. During the first 4 hours post injection, we also observed a trend of increase in insulin sensitivity index (HOMA2-IS) and decrease in insulin resistance index (HOMA2-IR) with MANP, both were opposite to the trends in placebo. At 1 hour post MANP administration, NEFA increased by 108.2 ± 37.4 µM compared to baseline (P = 0.01). Conclusion(s) Our findings support the favorable cardiovascular and metabolic actions of MANP as a potential therapeutic strategy for HTN with MetS.

The novel findings of this study demonstrate that blood volume profiles while highly variable in clinically compensated patients with HF on stable medical therapy do not change substantially over a 6-mo period regardless of baseline expanded or normal blood volumes. This lack of change in volume profiles particularly from an expanded blood volume has implications for long-term volume management and also for how we understand the pathophysiology of volume homeostasis in chronic HF.

Abstract Funding Acknowledgements Type of funding sources: None. Background The impact of capacitance and blood volume redistribution on outcomes of patients with chronic heart failure is incompletely understood. Quantitative plasma volume (PV) measurements together with echocardiographic evaluation allow a comprehensive assessment of the interplay between volumetric overload, cardiac chamber remodelling and myocardial function. Purpose We hypothesize that PV expansion is associated with myocardial and renal dysfunction, right ventricular-pulmonary arterial uncoupling and unfavorable outcomes in HF patients with reduced ejection fraction (HFrEF). Methods Patients hospitalized at Mayo Clinic with decompensated HF and who had PV by the indicator-dilution nuclear methodology (Daxor BVA100) were included. Patients were considered hypervolemic if BV was ≥25% over expected. The primary endpoint was the composite of all-cause mortality or heart transplantation. The closest TTE to the time of PV was used to measure various indexes of myocardial performance (standard echo parameters and global chamber-specific strain parameters). Event-free survival was estimated using the Kaplan-Meier method. The relationship between PV and various parameters was evaluated with correlation coefficient (r²). Results A total of 65 patients were enrolled in the study. Reduced LVEF was present in 53 (81.6%) patients. There were 44 events (32 deaths, 12 heart transplants) after a median follow-up of 43 months (IQR 14–65). Results in patients with HFrEF are presented in the Table. Our main findings were: 1) PV expansion was associated with an increased risk of adverse events (Figure 1); 2) Volume redistribution correlated with various indexes of cardiac chamber function, suggesting that volume overload and associated cardiac remodeling may be responsible for altered myocardial mechanics in patients with HFrEF (Figure 2); 3) right ventricular-pulmonary arterial uncoupling was triggered by the plasma volume expansion, that causes postcapillary pulmonary hypertension; 4) PV redistribution was also associated with renal dysfunction and increasing the level of the protein catabolism (Table 1). Conclusion Expansion of plasma volume in HFrEF patients is associated with left atrium dilatation, abnormal filling of both atria and right ventricular dilatation / dysfunction. Plasma volume redistributions apparently became a trigger of right ventricular-pulmonary arterial uncoupling and stimulated postcapillary pulmonary hypertension, renal dysfunction with increasing the level of protein catabolism and unfavorable outcomes.

Introduction: Cardiac resynchronization therapy (CRT) has known benefit for heart failure (HF) with reduced left ventricular ejection fraction (LVEF) and dyssynchrony. However, very little is known about its benefit in infiltrative cardiomyopathies such as cardiac amyloidosis (CA) due to relative rarity of these conditions. Methods: This retrospective case series (2003-2021) comprised patients with HF due to transthyretin wild-type CA with (case) or without (control) CRT implant. Only controls with an indication for CRT or LVEF <40% were included. To further match disease severity, cases were 1:1 matched (propensity score tolerance 0.04) to controls for age, NYHA class, and CA stage (UK Staging). Primary outcome was MACE (major adverse cardiac events) which included stroke, myocardial infarction, HF hospitalization and cardiac mortality during a 3-year follow-up. Loss to follow-up was censored as per last visit date. LVEF and NYHA were noted closest to 1-year follow-up. Survival analysis for MACE was performed with Kaplan-Meier (KM) and multivariable cox regression models. Results: Study Cohort (n=160) had a mean age of 75.5 (SD 7.8) years and 97.5% were males. A majority had NYHA class 2 or 3 (92.3%) and CA stage 2 (42.2.%). Notably, median LVEF at baseline was lower in controls (33.5 vs 36.5; P = .001) and 77.5% of controls had an indication for CRT device. A total of 79 MACE events occurred, most frequent being HF hospitalization (n=45). KM curves were comparable for MACE events in the two groups (log-rank test; P = .059). Even after adjusting, as in table, CRT device was not associated with MACE events (adjusted HR 0.66; 95% CI 0.40-1.09; P = .106). Lastly, change in LVEF ( P = .84) and NYHA ( P = .86) at follow-up was similar in cases vs controls. Conclusions: The findings of this largest yet observational study to examine this question suggest that CRT in patients with transthyretin wild-type CA does not favorably impact outcomes for MACE events, improve LVEF or NYHA functional class.

Abstract Aims To identify different red blood cell mass (RBCM) profiles, separate from haemoglobin concentrations, and their impact on blood volume expansion and clinical outcomes in chronic heart failure. Methods and results RBCM was measured at hospital discharge using standardized nuclear medicine indicator-dilution methodology in patients following diuretic treatment for clinical congestion. Individual RBCM phenotypes were prospectively identified and analysed for heart failure-related mortality or first rehospitalization over 1 year. Of 132 patients, 42 (32%) demonstrated normal RBCM, 36 (27%) RBCM deficit (true anaemia), and 54 (41%) RBCM excess (erythrocythemia). Dilutional ‘anaemia’ defined by haemoglobin &lt;12 g/dL with normal or an excess in RBCM with plasma volume expansion was identified in 37 (28%) patients. There were 61 composite outcome events, which included 38 deaths (29% of cohort) occurring over the 1 year follow-up period [14/36 (39%) in RBCM deficit, 12/42 (29%) in normal RBCM, and 12/54 (22%) in RBCM excess subgroups]. By Kaplan–Meier and multivariate analyses, RBCM excess was independently associated with the best event-free survival while RBCM deficit (true anaemia) the poorest outcomes; both compared with normal RBCM (P &lt; 0.001). Dilutional ‘anaemia’ demonstrated a lower risk compared with true anaemia (P = 0.03). Conclusions Markedly different RBCM profiles are identifiable among comparably compensated heart failure patients, and this variability carries significant implications for post-hospital outcomes. Novel to this analysis and in contrast to RBCM deficit is the independent association of RBCM excess with better event-free survival compared with normal RBCM. The distinction of RBCM profiles to guide risk stratification and individualized patient management strategies warrants further study.

Abstract Funding Acknowledgements Type of funding sources: None. Background Right heart and renal dysfunction occurring due to volume fluid redistribution remain a front-line issue in the development of the syndrome of congestion in chronic heart failure (HF). Quantitative total blood volume (TBV) measurements and Speckle-tracking Echo (STE) provide complementary information on the myocardial function which allows for providing a more integrated assessment of clinical status and outcomes. Purpose We hypothesize adverse outcomes in patients with heart failure (HF) who have expansion of TBV, right ventricular (RV) and renal dysfunction. Methods This is a prospective study and a total of 66 participants NYHA class III&IV with chronic HF are enrolled from 2014-2022. TBV, right heart catheterization, TTE, TEE, and kidney function tests is performed. STE is calculated using TomTec software for all heart chambers. Patients is divided into 1-st group of the total participants, 2-nd group is patients adverse outcomes which are heart transplant (HT) or death, 3rd group is of alive patients. Simple, multivariable linear regression analyses is used to evaluate associations between TBV, cardiac and renal function. Statistical analyses is performed using JMP, BlueSky, and two-sided with P-values &lt;0.05 considered to be statistically. Results Of 66 patients, the 1-st group has 66 patients, the 2nd group has 44 patients out of which deceased are 32 patients (48.4%), HT has 12 patients (18.1%), and the 3rd group has 22 patients (33.3%). In the 2nd group, out of the 44 patients, 35 (79.5%) patients have HFrEF, and 9 (20.4%) patients presented HFpEF. In the 3rd group out of 22 patients, 15 (68.2%) have HFrEF, and 7 (31.8%) patients have HFpEF. RV dimensions are significantly related to TBV in all groups of participants (Table 1). In the total patients, TBV is directly correlated to a moderate degree with EDSRV (r = 0.51, P &lt; 0.001), ESSRV (r = 0.44, P &lt; 0.001) and FAC (r = 0.40, P &lt; 0.001). More significant moderate and strong relationships are observed in patients with adverse outcome between TVB and EDSRV (r = 0.54, P &lt; 0.001), ESSRV (r = 0.65, P &lt; 0.001) and FAC (r = 0.48, P &lt; 0.001). In group 1, weak and direct association of TBV and RV GLS, FW LS, FW LSR, and RA reservoir strain. In the 2nd group, TBV directly correlated to a moderate degree with FW LS (r = 0.41, P = 0.005) and FW LSR (r = 0.43, P = 0.002). Similar relationships in the 2nd group are observed between TBV and renal function parameters (TBV and eGFR (r = 0.53, P &lt; 0.001)). The direct and weak correlation obtained between TBV and BUN in both 1st and 2nd groups. In patients with adverse outcomes, TBV is directly proportional to LV Diastolic BP. Conclusion The association among intravascular volume and parameters of RV dilatation, myocardial and renal dysfunction in patients with chronic HF is associated with adverse outcomes. Understanding the impact of all these variables guide optimal and effective individualized HF management and therapy.

AbstractIntravascular volume is largely regulated by the kidneys but how differences in intravascular volume profiles interact with chronic kidney disease (CKD) to influence outcomes in chronic heart failure (HF) has not been explored. Our hypothesis was that a greater degree of volume expansion (VE) would moderate the impact of CKD on HF‐related clinical outcomes. Quantitative blood volume (BV) data were available in 137 patients at the time of hospital discharge using a nuclear medicine radiolabeled albumin indicator‐dilution technique. The study patients were stratified by the cohort median glomerular filtration rate (GFR, 44 ml/min/1.73 m2). An a priori cut‐point of ≥+25% above normal BV was then used to further stratify the two GFR subgroups and prospectively analyzed for 1‐year HF‐related mortality or 1st re‐hospitalization. Persistent BV expansions ≥+25% were present in 51% of the cohort. In the subgroup with GFR above the median (N = 68) greater or lesser BV expansion from +25% did not differentiate outcomes. However, in the subgroup with GFR below the median (N = 69), BV expansion‐stratified risk (log‐rank p = 0.022) with <+25% VE associated with poorer outcomes, while VE ≥ + 25% was associated with lower risk and comparable to GFR above the median. In patients with chronic HF, significant intravascular VE and CKD are common co‐existing conditions. The presence of larger VE, however, appears to be a factor mitigating the impact of declining renal function on clinical outcomes, and as an element of volume pathophysiology warrants further study.

Fluid volume homeostasis in health and heart failure (HF) requires a complex interaction of 2 systems, the intravascular and interstitial‐lymphatic circulations. With the development of HF both the intravascular and interstitial compartments undergo variable degrees of volume remodeling which can include significant expansion. This reflects the impact of multiple pathophysiologic mechanisms on both fluid compartments which initially play a compensatory role to stabilize intravascular circulatory integrity but with progression in HF can evolve to produce the various manifestations of volume overload and clinical HF congestion. The intent of this review is to help enhance recognition of the pathophysiologic and clinical importance of the interlinked roles of these 2 circulatory systems in volume regulation and chronic HF. It would also be hoped that a better understanding of the interacting functions of the intravascular and interstitial‐lymphatic fluid compartments can potentially aid development of novel management strategies particularly addressing the generally undertargeted interstitial‐lymphatic system and help bring such approaches forward through a more integrated view of these 2 circulatory systems.