Micha T. Maeder

Myocardial and Systemic Iron Depletion in Heart Failure: Implications for Anemia Accompanying Heart Failure

OBJECTIVESnThis study sought to determine the potential pathophysiological link between anemia and disease severity, and adverse outcome in heart failure (HF).nnnBACKGROUNDnAnemia frequently accompanies advanced HF; however, the pathophysiological mechanism responsible for the association between anemia and more severe HF remains uncertain. We hypothesized that a depletion of myocardial iron content may provide the biological link.nnnMETHODSnComplementary clinical and basic studies were performed. Hemodynamic, biochemical, and echocardiographic investigations were performed in 9 healthy controls and 25 patients with advanced HF (left ventricular ejection fraction: 23 ± 10%). Tissue iron content and type 1 transferrin receptor (Tfr1) expression were assessed in human myocardial tissue, and the regulation of Tfr1 expression was studied in isolated cardiomyocytes.nnnRESULTSnHF patients displayed evidence of iron deficiency as measured by lower serum iron (p < 0.05) and transferrin saturation (TFS) (p < 0.05). When subclassified according to the presence of anemia, TFS was lower in anemic compared with nonanemic HF patients, whereas TFS in nonanemic HF patients was intermediate. In association, myocardial iron content was reduced in HF versus non-HF samples (0.49 ± 0.07 μg/g vs. 0.58 ± 0.09 μg/g, p < 0.05), and there was a significant reduction (p < 0.05) in the myocardial mRNA expression of Tfr1, which plays a key role in cellular iron transport. In the context of HF, catecholamines and aldosterone both down-regulated Tfr1 expression in isolated cardiomyocytes.nnnCONCLUSIONSnThis study suggests the presence of iron depletion in the failing human heart, providing a potential link for the association between anemia and adverse prognosis in HF.

Noninvasive assessment of pulmonary vascular resistance by Doppler echocardiography.

BACKGROUNDnThe ratio of tricuspid regurgitation velocity (TRV) to the time-velocity integral of the right ventricular outflow tract (TVIRVOT) has been studied as a reliable measure to distinguish elevated from normal pulmonary vascular resistance (PVR). The equation TRV/TVIRVOT × 10 + 0.16 (PVRecho) has been shown to provide a good noninvasive estimate of PVR. However, its role in patients with significantly elevated PVR (> 6 Wood units [WU]) has not been conclusively evaluated. The aim of this study was to establish the validity of the TRV/TVIRVOT ratio as a correlate of PVR. The role of TRV/TVIRVOT was also compared with that of a new ratio, TRV(2)/TVIRVOT, in patients with markedly elevated PVR (>6 WU).nnnMETHODSnData from five validation studies using TRV/TVIRVOT as an estimate of PVR were compared with invasive PVR measurements (PVRcath). Multiple linear regression analyses were generated between PVRcath and both TRV/TVIRVOT and TRV(2)/TVIRVOT. Both PVRecho and a new derived regression equation based on TRV(2)/TVIRVOT: 5.19 × TRV(2)/TVIRVOT - 0.4 (PVRecho2) were compared with PVRcath using Bland-Altman analysis. Logistic models were generated, and cutoff values for both TRV/TVIRVOT and TRV(2)/TVIRVOT were obtained to predict PVR > 6 WU.nnnRESULTSnOne hundred fifty patients remained in the final analysis. Linear regression analysis between PVRcath and TRV/TVIRVOT revealed a good correlation (r = 0.76, P < .0001, Z = 0.92). There was a better correlation between PVRcath and TRV(2)/TVIRVOT (r = 0.79, P < .0001, Z = -0.01) in the entire cohort as well as in patients with PVR > 6 WU. Moreover, PVRecho2 compared better with PVRcath than PVRecho using Bland-Altman analysis in the entire cohort and in patients with PVR > 6 WU. TRV(2)/TVIRVOT and TRV/TVIRVOT both predicted PVR > 6 WU with good sensitivity and specificity.nnnCONCLUSIONSnTRV/TVIRVOT is a reliable method to identify patients with elevated PVR. In patients with TRV/TVIRVOT > 0.275, PVR is likely > 6 WU, and PVRecho2 derived from TRV(2)/TVIRVOT provides an improved noninvasive estimate of PVR compared with PVRecho.

Changes in Right Ventricular Function During Continuous-low Left Ventricular Assist Device Support

BACKGROUNDnStudies in explanted hearts from patients supported with a left ventricular assist device (LVAD) suggest that no or a less pronounced reverse remodeling process occurs in the right ventricle (RV) during LVAD support. The intermediate-term functional changes in RV function in patients with refractory heart failure (HF) supported with a continuous LVAD are not well characterized.nnnMETHODSnSerial transthoracic echocardiograms and simultaneous measurements of biochemical surrogates of disease severity and organ perfusion were obtained in 20 patients (aged 57 +/- 17 years) with refractory HF before and after implantation of a continuous-flow LVAD (VentrAssist, Ventracor Ltd, Chatswood, Australia).nnnRESULTSnAfter a median (interquartile range) follow-up of 140 days (34-367 days), RV diameter was reduced (36 +/- 7 vs 33 +/- 4 mm; p = 0.04), as was right atrial area (27 +/- 5 vs 24 +/- 6 cm(2); p = .04). There was a trend toward a reduction in tricuspid annulus plane systolic excursion (14 +/- 6 vs 13 +/- 5 mm; p = .05). RV fractional area change (26% +/- 13% vs 27% +/- 10%; p = .53) and global RV dysfunction graded visually using a scale from 0 (absent) to 3 (severe dysfunction) did not change from pre-implant to follow-up (2 [1-2] vs 1.5 [0.5-2]; p = .18). The degree of global RV dysfunction at follow-up was closely related to the degree of RV dysfunction at the pre-implant study (r = 0.69; p = .001). Changes in global RV dysfunction were inversely related to changes in glomerular filtration rate (r = -0.49; p = .03).nnnCONCLUSIONSnDuring continuous-flow LVAD support, pre-existing RV dysfunction does not worsen in the intermediate term.

Hemodynamic Determinants of the Abnormal Cardiopulmonary Exercise Response in Heart Failure With Preserved Left Ventricular Ejection Fraction

BACKGROUNDnThe cardiopulmonary exercise testing (CPET) response in heart failure with preserved left ventricular ejection fraction (HFPEF) is incompletely understood. We aimed to describe the CPET response in HFPEF and to assess its invasive hemodynamic determinants.nnnMETHODS AND RESULTSnTen patients with HFPEF and 8 asymptomatic controls underwent resting and exercise right heart catheterization and maximal symptom-limited CPET. The slope of the minute ventilation/carbon dioxide production relationship (VE/VCO(2) slope; 34.3xa0±xa05.4 vs. 28.4xa0±xa03.4; Pxa0=xa0.02) was steeper, peak oxygen consumption (peak VO(2); 15.1xa0±xa04.9 vs. 26.6xa0±xa012.5 mL∗kg(-1)∗min(-1); Pxa0=xa0.02) was lower, and heart rate recovery 1 minute after exercise termination (HRR-1; 10xa0±xa05 vs. 27xa0±xa010 beats/min; Pxa0<xa0.001) was slower in HFPEF compared to controls. A steeper VE/VCO(2) slope (rxa0=xa00.67, Pxa0=xa0.002), lower peak VO(2) (rxa0=xa0-0.48, Pxa0=xa0.04), and slower HRR-1 (rxa0=xa0-0.58, Pxa0=xa0.02) were significantly related to a higher ratio of the change in pulmonary capillary wedge pressure per change in work rate as a measure of the left ventricular pressure volume relationship.nnnCONCLUSIONSnIn HFPEF patients, fundamental alterations in the CPET profile occur and these may, in part, result from the rapid rise in left ventricular filling pressures which accompanies exercise in these patients.

Differential impact of heart rate and blood pressure on outcome in patients with heart failure with reduced versus preserved left ventricular ejection fraction

BACKGROUNDnIn contrast to patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF; HFREF) the prognostic role of heart rate (HR) and blood pressure (BP) in patients with HF and preserved LVEF (HFPEF) is not well known. The aim of this study was to characterize the relationship between HR and BP and outcomes in HFPEF and to compare it to HFREF.nnnMETHODSnThe association between HR and BP and outcomes (median follow-up: 38 months) was analyzed in patients with HFREF (LVEF ≤ 45%; n=6792) and HFPEF (LVEF > 45%; n=988) from the Digitalis Investigator Group trial.nnnRESULTSnMortality (35% vs. 23%) and HF hospitalization rates (31% vs. 20%; p<0.001 for both) were higher in HFREF compared to HFPEF. In HFREF, higher HR and lower systolic and diastolic BP quartiles were associated with higher mortality and HF hospitalization rates. By contrast, there was no significant association between HR and BP respectively and mortality in HFPEF, and there was no significant association between systolic BP and hospitalization risk in HFPEF either. However, HF hospitalization rates were significantly related to increasing HR and decreasing diastolic BP quartile respectively (4.9, 6.8, 6.8, and 10.5 and 5.5, 8.1, 6.0, and 10.1 respectively events per 1000 person-years) in HFPEF. In HFPEF, there was also evidence of a significant J-shaped relationship between pulse pressure and mortality.nnnCONCLUSIONSnThe prognostic value of HR and BP differed substantially between HFREF and HFPEF. These data may provide a foundation for the design of novel interventions in HFPEF patients.

Accuracy of Doppler Echocardiography to Estimate Key Hemodynamic Variables in Subjects With Normal Left Ventricular Ejection Fraction

BACKGROUNDnThe accuracy of Doppler echocardiography to estimate key hemodynamic parameters in subjects with normal left ventricular ejection fraction (LVEF) has not been fully investigated.nnnMETHODS AND RESULTSnThirty-six subjects with LVEF >50% (median age 62 years), with a broad clinical profile, underwent Doppler echocardiography immediately followed by right heart catheterization. Correlation coefficients between invasive and noninvasive right atrial pressure (RAP), systolic (sPAP) and mean (mPAP) pulmonary artery pressure, cardiac output (CO), and pulmonary vascular resistance (PVR) were 0.39, 0.70, 0.72, 0.57, and 0.60 (P < .001 for all). There was no significant correlation between invasive and noninvasive (based on the peak early transmitral to peak early septal mitral annular velocity ratio) pulmonary capillary wedge pressure (PCWP; r = 0.23; P = .18). Bland-Altman plots revealed variable bias but with consistently large limits of agreement for all noninvasive parameters, particularly PCWP. Areas under the receiver operating characteristic curve for noninvasive sPAP, CO, PVR, and PCWP to predict an invasively assessed mPAP ≥25 mm Hg, cardiac index <2.5 L min(-1) m(-2), PVR >3 Wood units, and PCWP ≤15 mm Hg, respectively, were 0.92, 0.83, 0.70, and 0.58.nnnCONCLUSIONSnSingle Doppler echocardiography parameters are not accurate enough to reliably estimate key hemodynamic parameters, particularly PCWP, in subjects with normal LVEF.

Does hypoxemia have an impact on the cardiac release and circulating concentrations of natriuretic peptides in humans in vivo

A large number of experimental studies have suggested that hypoxia may be a potent stimulus for the myocardial synthesis and release of Atype natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) [1]. However, these studieshaveevaluatedeither theeffectofhypoxiaonANP and/orBNPproduction in isolated cardiomyocytes [2,3], isolatedperfused hearts [4,5], or animals [5,6], or on the circulating concentrations of ANP, BNP, and/or N-terminal pro-BNP (NT-proBNP) but not on the cardiac release of these peptides in humans [7–9]. Accordingly, we performed two complementary studies to assess the relationship between the partial pressure of arterial oxygen (PaO2) and i) the cardiac release and ii) the circulating concentrations of natriuretic peptides in humans. First, we measured PaO2 and the transcardiac gradients of BNP and NT-proBNP (i.e., the differences between concentrations in the coronary sinus [BNPCS, NT-proBNPCS] and arterial plasma [BNPA, NT-proBNPA]) in patients undergoing a detailed non-invasive and invasive hemodynamic International Journal of Cardiology 167 (2013) 1046–1087

Inverse Association Between Myocardial B-Type Natriuretic Peptide Release and Functional Capacity in Healthy Humans

BACKGROUNDnB-type natriuretic peptide (BNP) has been found to be inversely related to peak oxygen consumption (peak VO2) in various patient populations. However, in these studies, circulating plasma BNP, i.e. the net effect of release and elimination, rather than cardiac BNP release has been measured. We assessed the relationship between the transcardiac BNP gradient [ΔBNPCS-A, i.e. the difference between BNP in coronary sinus (BNPCS) and arterial (BNPA) plasma] and peak VO2 in healthy subjects with a view to better understanding the regulation of cardiac BNP release in humans.nnnMETHODSnWe studied 10 asymptomatic subjects (age 64±11 years, two females) with preserved left ventricular function (left ventricular ejection fraction 62±5%, averaged early diastolic mitral annular velocity 9±3cm/s) and low BNP (BNP in venous plasma [BNPV] <100ng/l). Subjects underwent measurement of BNPA and BNPCS for the calculation of ΔBNPCS-A, maximal cardiopulmonary exercise testing, echocardiography and resting and submaximal exercise right heart catheterisation.nnnRESULTSnThe median (range) BNPV, BNPA, BNPCS, and ΔBNPCS-A were 62 (14, 82), 60 (13, 79), 110 (25, 157), and 44 (1, 103) ng/l. The median peak VO2 during cardiopulmonary exercise testing was 21.5 (18, 54) ml/min/kg. There was an inverse correlation between higher ΔBNPCS-A and lower peak VO2 (r=-0.84; p=0.002) and oxygen pulse (r=-0.64, p=0.049). There was a trend towards an inverse correlation between ΔBNPCS-A and the exercise arteriovenous oxygen content difference (r=-0.58; p=0.08).nnnCONCLUSIONSnIn healthy humans, there is an inverse association between myocardial BNP release and peak VO2, which may be due to cardiac and non-cardiac mechanisms.

Transcardiac gradients of B-type natriuretic peptides are increased in human pulmonary arterial hypertension

In patients with pulmonary arterial hypertension (PAH), measurement of B-type natriuretic peptide (BNP) and the amino-terminal part of its precursor peptide N-terminal-pro-BNP (NT-proBNP) is recommended for risk stratification [1]. However, whilst the peripheral plasma concentrations of natriuretic peptides are often considered as being reflective of cardiac release, more correctly they represent the net balance between cardiac production and extra-cardiac elimination [2]. As such, it is currently unknown whether the elevation in plasma BNP and NT-proBNP concentration in PAH patients reflects an increased cardiac release. Accordingly, we compared the transcardiac gradients [i.e., the differences between coronary sinus (CS) and arterial plasma concentrations] of BNP (ΔCS-ABNP) and NT-proBNP (ΔCS-ANT-proBNP) as measures of cardiac release in PAH patients and controls. We studied 18 subjects with left ventricular (LV) ejection fraction N50%, normal sinus rhythm, and pulmonary capillary wedge pressure (PCWP) ≤15 mmHg. Nine patients with established PAH were studied during a clinically indicated repeat right heart catheterisation on established vasodilator therapy. In one patient a previously unknown large atrial septal defect was detected. All other patients had idiopathic PAH. Nine healthy subjects served as controls. All subjects underwent transthoracic echocardiography immediately followed by cardiac catheterisation. Echocardiograms were obtained by one single experienced echocardiographer. Measurements were performed off-line by a single reader. A 3 F arterial line (Cook, Brisbane, QLD, Australia) was placed in a radial or brachial artery. A 6 F CS catheter (Cordis, Auburn, NSW, Australia) was inserted via an introducer sheath placed in the right internal jugular or a brachial vein and positioned under fluoroscopic control. The tip of the catheter was positioned at least 2 cm proximal to the CS orifice confirmed by contrast injection. Blood samples were simultaneously taken from the arterial line and the CS catheter. Right heart catheterisation was performed using a balloon-tipped 7 F thermodilution catheter (Edwards Lifesciences, Irvine, CA, USA). Concentrations of BNP and NT-proBNP in arterial and CS ethylene-diamine-tetra-acetate plasma were measured using the ARCHITECT BNP (Abbott, Abbott Park, Illinois, USA) [3] and Roche Elecsys proBNP II [4] respectively assays on the E170 analyzer (Roche, Basel, Switzerland). We calculated ΔCS-ABNP and ΔCS-ANT-proBNP as concentration in CS plasma — concentration in arterial plasma. Comparisons between PAH patients and controls were

AGE SPECIFIC HEMODYNAMIC FEATURES IN HFPEF: IMPLICATIONS FOR THERAPY

Background: Heart failure is a clinical diagnosis in which a stratification based on left ventricular ejection fraction (LVEF) has been applied to identify more homogeneous groups for the purpose of diagnosis and treatment. Within the group with HF with preserved ejection fraction (HFpEF), a range