Miller, Wayne L.

The novel findings of this study demonstrate that intravascular volume profiles among the patients with chronic heart failure (HF) vary substantially even with similar clinical compensation. Importantly, a profile of blood volume (BV) expansion (compared with a normal BV) is associated with lower HF mortality/morbidity. Furthermore, RBC polycythemia is common and independently associated with improved outcomes. These observations support BV expansion with RBC polycythemia as a compensatory mechanism in chronic HF.

The aim of this study was to determine if left ventricular (LV) diastolic function influences pulmonary function (PF) in healthy subjects and to determine if they are independently related after accounting for age, gender, BMI and blood pressure (BP). Echocardiograms and PF tests were performed in 103 healthy subjects (22‐76 yr). The ratio of peak early (E) and late (A) mitral inflow velocities and the ratio of peak early (E') and late (A') mitral annular velocities were obtained by pulsed wave Doppler and tissue Doppler imaging. The first stage of diastolic dysfunction, often observed in healthy aging, is characterized by reduced E and E', and greater A and A' resulting in a reversal of E/A and E'/A'. PF measures included forced vital capacity (FVC), carbon monoxide diffusing capacity (DL CO ) and forced mid‐expiratory flow (FEF 25‐75 ). Age, gender and BMI accounted for >60% of the interindividual variation between diastolic function and PF. After accounting for age, gender, BMI and BP, E' was positively associated with FVC (additional R 2 =0.03 , P <0.01). A was negatively and A' positively associated with DL CO (additional R 2 =0.03, R 2 =0.01, P <0.05) and FVC (additional R 2 =0.03, R 2 =0.03, P <0.01). E/A was positively associated with DL CO (additional R 2 =0.02, P <0.01). In conclusion, LV diastolic function may influence PF in healthy subjects, with the greatest interactions being observed in older males. NIH HL71478

Introduction: Atrial natriuretic peptide (ANP) plays an important role in blood pressure (BP) regulation via the second messenger cGMP. ANP also induces lipolysis by increasing plasma levels of non-esterified fatty acids (NEFA). MANP is a new Mayo Clinic designed ANP analog consisting of the native ANP with a novel 12-amino-acid C-terminus extension. In experimental models, MANP is more potent than ANP in reducing BP and inducing natriuresis. These actions are mediated by the activation of the pGC-A receptor and generation of cGMP. To date, the BP pressure lowering, cGMP generating and lipolytic actions of MANP remain unexplored along with its safety and tolerability in subjects with hypertension (HTN) associated with metabolic disease. Hypothesis: In subjects with HTN, obesity and metabolic syndrome (MS), MANP administration is safe, well tolerated, activates cGMP and exerts BP lowering and lipolytic properties. Methods: Double-blind, placebo-control clinical trial in 22 subjects (17 receiving MANP) with HTN, obesity and MS involving a single subcutaneous (SQ) injection of MANP (2.5 μg/Kg) or placebo. Subjects were monitored and cardiovascular, cGMP and metabolic parameters were collected during 24 hours after the injection. Results: In all subjects, MANP was safe and well-tolerated with no serious adverse side effects. MANP increased mean cGMP plasma levels after 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) when compared to baseline. Six hours after MANP injection systolic BP decreased by 5.7 ± 2.9 mmHg (p=0.06) whereas subjects receiving placebo had no decrease in blood pressure values compared to baseline. During fasting period, one hour after the administration of MANP, NEFA plasma levels increased by 108.2 ± 37.4 μM (p=0.01). Conclusions: In subjects with HTN, obesity and MS, SQ MANP is safe, well tolerated and activates the pGC-A receptor as measured by a significant increase in the second messenger cGMP. Subjects receiving MANP showed a borderline significant decrease in systolic BP and a significant increase in NEFA circulating levels supporting anti-hypertensive and lipolytic properties. Our findings support MANP as a potential novel therapy for HTN associated with metabolic disease.

Abstract Aims Elevated cardiac filling pressures producing clinical congestion in heart failure (HF) patients may be secondary to intravascular volume expansion or abnormalities in cardiac diastolic properties. The objective of this study was to assess the extent to which measures of myocardial function and intravascular volume correlate with haemodynamic abnormalities in chronic HF. Methods and results Subjects underwent invasive haemodynamic assessment, measurement of total blood volume (TBV) using radiolabel indicator‐dilution methodology, and echocardiography to evaluate cardiac structure and function. Patients were divided into those with hypervolaemia (defined as TBV > +8% above referenced normal volume) and normal volume (‘euvolaemia’) (TBV ≤ + 8%). Of 66 patients, 39 (59%) were hypervolaemic and 27 (41%) normal TBV. Central venous pressure (CVP, P = 0.01) and pulmonary capillary wedge pressure (PCWP, P < 0.001) were higher in hypervolaemic compared with euvolaemic patients; however, 15% of hypervolaemic patients displayed normal pressures. Of euvolaemic patients, 70% displayed elevated CVP and 63% elevated PCWP. PCWP was moderately correlated with TBV (r = 0.42), left ventricular diastolic function (e′ velocity, r = −0.44), and left atrial strain (r = −0.47). In multivariable regression TBV, left ventricular e′, and left atrial strain were independently associated with PCWP (all P < 0.05). Conclusions While hypervolaemic patients displayed elevations in filling pressures, a substantial proportion (15%) had normal pressures, and of all subjects with elevated filling pressures nearly one third had normal TBVs. Importantly, of patients with normal volumes, a majority (>60%) display elevated filling pressures. Combined analysis of volume, pressure, and cardiac function may be helpful to guide comprehensive assessments of HF status.

Abstract Background/Introduction Intravascular volume is regulated by the kidneys but the interconnection of the extent of volume expansion with renal function and outcomes in patients with chronic HF has not been assessed. Therefore, we evaluated how GFR-defined renal function and HF-related clinical outcomes are impacted by the relative extent of intravascular volume expansion. Our hypothesis was that greater rather than lesser volume expansion would be protective of worse renal function and contribute to better clinical outcomes than mild-moderate volume expansion. Purpose Assess the impact of quantitated intravascular volume expansion on heart failure (HF) outcomes in relation to renal function in post-hospital clinically determined “euvolemic” chronic HF patients. Methods Blood volume (BV) was prospectively measured in 87 HF patients considered clinically “euvolemic” post-diuresis at the time of hospital discharge using a standardized radiolabeled albumin indicator-dilution technique (Daxor Corp., NY, NY). A volume cut-point of ≥+25% above normal expected BV was used to define the greater degree of volume expansion from more mild-moderate expansion. These volume subgroups were then stratified by cohort median eGFR (46 mL/min/1.73m2) and analyzed for 1-year outcomes of HF-related mortality or 1st re-hospitalization using the Kaplan-Meier method. Results Volume expansion ≥+25% was demonstrated in 53% of the cohort at the time of hospital discharge despite hospital diuretic therapy. In this subgroup over 1.0 year of follow-up the risk for the composite outcome was significantly lower than in the group with mild-moderate volume expansion (Log-Rank p=0.017). Further, in the clinical setting of greater volume expansion, worse renal function with eGFR below the cohort median (<46 mL/min/1.73m2) was not associated with increased risk for the composite end-point (Figure). In contrast, low eGFR in the presence of mild-moderate volume expansion stratified risk and was associated with worse outcome relative to a higher eGFR above the median (Figure). Figure 1 Conclusions In post-hospital chronic HF patients significant intravascular volume expansion is common, and importantly the extent of BV expansion impacts outcomes including HF-related mortality. However, greater rather than lesser volume expansion appears to favorably mitigate the impact of worse renal function (low eGFR), while normal or mild-moderate expansion does not spare the impact of worse renal function on outcomes. Thus, a favorable degree of volume expansion appears to balance the risks of worse renal function. Volume-kidney interconnections are complex with volume status modulating the impact of impaired renal function on outcomes in chronic HF. Acknowledgement/Funding None

Background: Functional tricuspid regurgitation (FTR) is common in heart failure with reduced ejection fraction and mostly consequent to pulmonary hypertension. However, the intrinsic clinical implications of FTR are not fully understood. Methods: The cohort of all Mayo Clinic patients from 2003 to 2011 diagnosed with heart failure stage B-C and ejection fraction<50%, with FTR grading and systolic pulmonary artery pressure estimation by Doppler echocardiography was identified and outcomes were analyzed. Patients with pacemakers/defibrillators, organic valve disease, or previous valve surgery were excluded. The primary outcome measure was overall mortality (censored at implantation of a defibrillator, ventricular assist device, or cardiac transplantation), adjusting for clinical and echocardiographic associates with mortality and major comorbidities. Results: Among 13 026 patients meeting inclusion criteria, FTR was detected in 88% (N=11 507: 33% trivial, 32% mild, 17% moderate, and 6% severe), aged 68±14 years, 35% women, ejection fraction 36±10%, systolic pulmonary artery pressure 41±14 mm Hg with 20% atrial fibrillation. Covariates independently associated with FTR included elevated systolic pulmonary artery pressure, older age, female sex, lower ejection fraction, mitral regurgitation, and atrial fibrillation (all P <0.0001). FTR was independently associated with more dyspnea, impaired kidney function, and lower cardiac output ( P <0.003 for all). For long-term outcome, higher FTR degree compared with trivial tricuspid regurgitation was independently associated with higher mortality (adjusted hazard ratios 1.09 [1.01-1.17] for mild FTR, 1.21 [1.11-1.33] for moderate FTR and 1.57 [1.39-1.78] for severe FTR); hence, 5-year survival was substantially lower with increasing severity of functional FTR, 68±1% for trivial FTR, 58±2% for mild FTR, 45±2% for moderate FTR, and 34±4% for severe FTR. Conclusions: In this large cohort of patients with heart failure with reduced ejection fraction, FTR was common and independently associated with pulmonary hypertension, atrial fibrillation, and more severe heart failure presentation. Long-term, higher FTR severity is associated with considerably worse survival, independently of baseline characteristics. Given these untoward outcomes associated with FTR in patients with heart failure with reduced ejection fraction, clinical trials should be directed at testing FTR treatment.

Background: Patients with combined post- and precapillary pulmonary hypertension due to left heart disease have a worse prognosis compared with isolated postcapillary. However, it remains unclear whether increased mortality in combined post- and precapillary pulmonary hypertension is simply a result of higher total right ventricular load. Pulmonary effective arterial elastance (Ea) is a measure of total right ventricular afterload, reflecting both resistive and pulsatile components. We aimed to test whether pulmonary Ea discriminates survivors from nonsurvivors in patients with pulmonary hypertension due to left heart disease and if it does so better than other hemodynamic parameters associated with combined post- and precapillary pulmonary hypertension. Methods and Results: We combined 3 large heart failure patient cohorts (n=1036) from academic hospitals, including patients with pulmonary hypertension due to heart failure with preserved ejection fraction (n=232), reduced ejection fraction (n=335), and a mixed population (n=469). In unadjusted and 2 adjusted models, pulmonary Ea more robustly predicted mortality than pulmonary vascular resistance and the transpulmonary gradient. Along with pulmonary arterial compliance, pulmonary Ea remained predictive of survival in patients with normal pulmonary vascular resistance. The diastolic pulmonary gradient did not predict mortality. In addition, in a subset of patients with echocardiographic data, Ea and pulmonary arterial compliance were better discriminators of right ventricular dysfunction than the other parameters. Conclusions: Pulmonary Ea and pulmonary arterial compliance more consistently predicted mortality than pulmonary vascular resistance or transpulmonary gradient across a spectrum of left heart disease with pulmonary hypertension, including patients with heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and pulmonary hypertension with a normal pulmonary vascular resistance.

Volume regulation, assessment, and management remain basic issues in patients with heart failure. The discussion presented here is directed at opening a reassessment of the pathophysiology of congestion in congestive heart failure and the methods by which we determine volume overload status. Peer-reviewed historical and contemporary literatures are reviewed. Volume overload and fluid congestion remain primary issues for patients with chronic heart failure. The pathophysiology is complex, and the simple concept of intravascular fluid accumulation is not adequate. The dynamics of interstitial and intravascular fluid compartment interactions and fluid redistribution from venous splanchnic beds to central pulmonary circulation need to be taken into account in strategies of volume management. Clinical bedside evaluations and right heart hemodynamic assessments can alert clinicians of changes in volume status, but only the quantitative measurement of total blood volume can help identify the heterogeneity in plasma volume and red blood cell mass that are features of volume overload in patients with chronic heart failure and help guide individualized, appropriate therapy—not all volume overload is the same.