Baroreflex activation therapy for the treatment of heart failure with reduced ejection fraction in patients with and without coronary artery disease.

BACKGROUND: In a randomized trial, baroreflex activation therapy (BAT) improved exercise capacity, quality of life and NT-proBNP in patients with heart failure with reduced ejection fraction (HFrEF). In view of different mechanisms underlying HFrEF, we performed a post-hoc subgroup analysis of efficacy and safety of BAT in patients with and without coronary artery disease (CAD). METHODS AND RESULTS: Patients with left ventricular ejection fraction <35% and NYHA Class III were randomized 1:1 to guideline-directed medical and device therapy alone or plus BAT. Patients with a history of CAD, prior myocardial infarction or coronary artery bypass graft were assigned to the CAD group with all others assigned to the no-CAD group. Of 71 BAT treated patients, 52 had CAD and 19 had no CAD. In the control group, 49 of 69 patients had CAD and 20 had no CAD. The system- or procedure-related major adverse neurological or cardiovascular event rate was 3.8% in the CAD group vs. 0% in the no-CAD group (p = 1.0). In the whole cohort, NYHA Class, Minnesota Living with Heart Failure score, 6-minute hall walk distance and NTproBNP were improved in BAT treated patients compared with controls. Statistical analyses revealed no interaction between the presence of CAD and effect of BAT (all p > 0.05). CONCLUSION: No major differences were found in BAT efficacy or safety between patients with and without CAD, indicating that BAT improves exercise capacity, quality of life and NTproBNP in patients with ischemic and non-ischemic cardiomyopathy. CLINICALTRIALS. GOV IDENTIFIER: NCT01471860 and NCT01720160.

Delayed Time to Peak Velocity Is Useful for Detecting Severe Aortic Stenosis.

BACKGROUND: Time to peak velocity (TPV) is an echocardiographic variable that can be easily measured and reflects a late peaking murmur, a classic physical finding suggesting severe aortic stenosis (AS). The aim of this study was to investigate the usefulness of TPV to evaluate AS severity. METHODS AND RESULTS: This study included 700 AS patients, whose aortic valve area (AVA) was <1.5 cm2, and 200 control patients. The TPV was defined as the time from aortic valve opening to when the flow velocity across the aortic valve reaches its peak. AS severity was classified as follows: High gradient severe AS, mean pressure gradient ≥40 mm Hg and AVA index (AVAI) <0.6 cm2/m2; Low gradient severe AS, mean pressure gradient <40 mm Hg, AVAI <0.6 cm2/m2, and dimensionless index <0.25; moderate AS, mean pressure gradient <40 mm Hg, AVAI ≥0.6 cm2/m2. The area under the receiver operating characteristic curve of TPV to predict high gradient severe AS was 0.94 (95% CI: 0.92-0.97, P<0.001). TPV was significantly delayed in low gradient severe AS compared with moderate AS both in patients with preserved (102±13 ms versus 83±13 ms, P<0.001) and with reduced ejection fraction (110±18 ms versus 88±13 ms, P<0.001). Delayed TPV was associated with increased all-cause mortality or need for aortic valve replacement after adjustment for confounders (hazard ratio for first quartile, reference is fourth quartile: 7.31, 95% CI 4.26-12.53, P<0.001). CONCLUSIONS: TPV is useful to evaluate AS severity and predict poor prognosis of AS patients.

Presence and Implication of Temporal Nonuniformity of Early Diastolic Left Ventricular Wall Expansion in Patients With Heart Failure.

BACKGROUND: Early-diastolic left ventricular (LV) longitudinal expansion is delayed with diastolic dysfunction. We hypothesized that, in patients with heart failure (HF), regardless of LV ejection fraction (EF), there is diastolic temporal nonuniformity with a delay of longitudinal relative to circumferential expansion. METHODS AND RESULTS: Echocardiography was performed in 143 HF patients-50 with preserved EF (HFpEF) and 93 with reduced EF (HFrEF)-as well as 31 normal control subjects. The delay of early-diastolic mitral annular velocity from the mitral Doppler E (TE-e') was measured as a parameter of the longitudinal expansion delay. The delay of the longitudinal early-diastolic global strain rate (SRE) relative to circumferential SRE (DelayC-L) was calculated as a parameter of temporal nonuniformity. Intra-LV pressure difference (IVPD) was estimated with the use of color M-mode Doppler data as a parameter of LV diastolic suction. Although normal control subjects had symmetric LV expansion in early diastole, TE-e' and DelayC-L were significantly prolonged in HF regardless of EF (P < .01 vs control for all). Multivariate analysis revealed that DelayC-L was the independent determinant of IVPD among the parameters of LV geometry and contraction (ß = -0.21; P < .05). CONCLUSION: An abnormal temporal nonuniformity of early-diastolic expansion is present in HF regardless of EF, which was associated with reduced LV suction.

C-Type Natriuretic Peptide Improves Left Ventricular Functional Performance at Rest and Restores Normal Exercise Responses after Heart Failure.

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. C-type natriuretic peptide (CNP) is elevated in HF; however, its functional effects are unclear. We tested the hypotheses that CNP with vasodilating, natriuretic, and positive inotropic and lusitropic actions may prevent this abnormal exercise response after HF. We determined the effects of CNP (2 µg/kg plus 0.4 µg/kg per minute, i.v., 20 minutes) on plasma levels of cGMP before and after HF and assessed LV dynamics during exercise in 10 chronically instrumented dogs with pacing-induced HF. Compared with the levels before HF, CNP infusion caused significantly greater increases in cGMP levels after HF. After HF, at rest, CNP administration significantly reduced LV end-systolic pressure (PES), arterial elastance (EA), and end-diastolic pressure. The peak mitral flow (dV/dtmax) was also increased owing to decreased minimum LVP (LVPmin) and the time constant of LV relaxation (τ) (P < 0.05). In addition, LV contractility (EES) was increased. The LV-arterial coupling (EES/EA) was improved. The beneficial effects persisted during exercise. Compared with exercise in HF preparation, treatment with CNP caused significantly less important increases in PES but significantly decreased τ (34.2 vs. 42.6 ms) and minimum left ventricular pressure with further augmented dV/dtmax Both EES, EES/EA (0.87 vs. 0.32) were increased. LV mechanical efficiency improved from 0.38 to 0.57 (P < 0.05). After HF, exogenous CNP produces arterial vasodilatation and augments LV contraction, relaxation, diastolic filling, and LV arterial coupling, thus improving LV performance at rest and restoring normal exercise responses after HF.

Surgical Experience and Long-term Results of Baroreflex Activation Therapy for Heart Failure With Reduced Ejection Fraction.

The purpose of this publication is to describe the intraoperative experience along with long-term safety and efficacy of the second-generation baroreflex activation therapy (BAT) system in patients with heart failure (HF) and reduced ejection fraction HF (HFrEF). In a randomized trial of New York Heart Association Class III HFrEF, 140 patients were assigned 1:1 to receive BAT plus medical therapy or medical therapy alone. Procedural information along with safety and efficacy data were collected and analyzed over 12 months. Within the cohort of 71 patients randomized to BAT, implant procedure time decreased with experience, from 106 ± 37 minutes on the first case to 83 ± 32 minutes on the third case. The rate of freedom from system- and procedure-related complications was 86% through 12 months, with the percentage of days alive without a complication related to system, procedure, or underlying cardiovascular condition identical to the control group. The complications that did occur were generally mild and short-lived. Overall, 12 months therapeutic benefit from BAT was consistent with previously reported efficacy through 6 months: there was a significant and sustained beneficial treatment effect on New York Heart Association functional Class, quality of life, 6-minute hall walk distance, plasma N-terminal pro-brain natriuretic peptide, and systolic blood pressure. This was true for the full trial cohort and a predefined subset not receiving cardiac resynchronization therapy. There is a rapid learning curve for the specialized procedures entailed in a BAT system implant. BAT system implantation is safe with the therapeutic benefits of BAT in patients with HFrEF being substantial and maintained for at least 1 year.

Role of Diastolic Function in Preserved Exercise Capacity in Patients with Reduced Ejection Fractions.

BACKGROUND: Some patients with markedly reduced ejection fractions (EFs) (<35%) have preserved exercise performance greater than predicted for age and gender. Because diastolic function may be a determinant of exercise performance, this study was conducted to test the hypothesis that patients with preserved exercise tolerance despite EFs < 35% may have relatively normal diastolic function. METHODS: Sixty-five subjects with EFs < 35% who underwent exercise Doppler echocardiography and had no inducible ischemia were retrospectively examined. Forty-five subjects with normal EFs (>60%) and preserved exercise capacity were analyzed as a control group. RESULTS: Sixteen of 65 patients with EFs < 35% had greater than predicted normal exercise capacity for their age and gender, and the remaining 49 patients had reduced exercise capacity. Patients with reduced EFs and preserved exercise capacity had E/e' ratios (mean, 10 ± 4) similar to those of control subjects (mean, 10 ± 3) and lower than those with reduced exercise tolerance (mean, 16 ± 8) (P < .01). In addition, they had better diastolic filling patterns and smaller left atrial sizes than patients with EFs < 35% and reduced exercise capacity. Multivariate logistic regression analyses indicated that E/e' ratio was an independent predictor of preserved exercise capacity in patients with reduced EFs. CONCLUSIONS: Relatively intact diastolic function contributes to preserved exercise capacity in patients with reduced EFs (<35%).

Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac resynchronization therapy.

AIMS: Increased sympathetic and decreased parasympathetic activity contribute to heart failure (HF) symptoms and disease progression. Carotid baroreceptor stimulation (baroreflex activation therapy, BAT) results in centrally mediated reduction of sympathetic and increase in parasympathetic activity. Because patients treated with cardiac resynchronization therapy (CRT) may have less sympathetic/parasympathetic imbalance, we hypothesized that there would be differences in the response to BAT in patients with CRT vs. those without CRT. METHODS AND RESULTS: New York Heart Association (NYHA) Class III patients with an ejection fraction (EF) ≤35% were randomized (1 : 1) to ongoing guideline-directed medical and device therapy (GDMT, control) or ongoing GDMT plus BAT. Safety endpoint was system-/procedure-related major adverse neurological and cardiovascular events (MANCE). Efficacy endpoints were Minnesota Living with Heart Failure Quality of Life (QoL), 6-min hall walk distance (6MHWD), N-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and HF hospitalization rate. In this sample, 146 patients were randomized (70 control; 76 BAT) and were 140 activated (45 with CRT and 95 without CRT). MANCE-free rate at 6 months was 100% in CRT and 96% in no-CRT group. At 6 months, in the no-CRT group, QoL score, 6MHWD, LVEF, NT-proBNP and HF hospitalizations were significantly improved in BAT patients compared with controls. Changes in efficacy endpoints in the CRT group favoured BAT; however, the improvements were less than in the no-CRT group and were not statistically different from control. CONCLUSIONS: BAT is safe and significantly improved QoL, exercise capacity, NTpro-BNP, EF, and rate of HF hospitalizations in GDMT-treated NYHA Class III HF patients. These effects were most pronounced in patients not treated with CRT.

Baroreflex Activation Therapy for the Treatment of Heart Failure With a Reduced Ejection Fraction.

OBJECTIVES: The objective of this clinical trial was to assess the safety and efficacy of carotid BAT in advanced HF. BACKGROUND: Increased sympathetic and decreased parasympathetic activity contribute to heart failure (HF) symptoms and disease progression. Baroreflex activation therapy (BAT) results in centrally mediated reduction of sympathetic outflow and increased parasympathetic activity. METHODS: Patients with New York Heart Association (NYHA) functional class III HF and ejection fractions ≤35% on chronic stable guideline-directed medical therapy (GDMT) were enrolled at 45 centers in the United States, Canada, and Europe. They were randomly assigned to receive ongoing GDMT alone (control group) or ongoing GDMT plus BAT (treatment group) for 6 months. The primary safety end point was system- and procedure-related major adverse neurological and cardiovascular events. The primary efficacy end points were changes in NYHA functional class, quality-of-life score, and 6-minute hall walk distance. RESULTS: One hundred forty-six patients were randomized, 70 to control and 76 to treatment. The major adverse neurological and cardiovascular event-free rate was 97.2% (lower 95% confidence bound 91.4%). Patients assigned to BAT, compared with control group patients, experienced improvements in the distance walked in 6 min (59.6 ± 14 m vs. 1.5 ± 13.2 m; p = 0.004), quality-of-life score (-17.4 ± 2.8 points vs. 2.1 ± 3.1 points; p < 0.001), and NYHA functional class ranking (p = 0.002 for change in distribution). BAT significantly reduced N-terminal pro-brain natriuretic peptide (p = 0.02) and was associated with a trend toward fewer days hospitalized for HF (p = 0.08). CONCLUSIONS: BAT is safe and improves functional status, quality of life, exercise capacity, N-terminal pro-brain natriuretic peptide, and possibly the burden of heart failure hospitalizations in patients with GDMT-treated NYHA functional class III HF. (Barostim Neo System in the Treatment of Heart Failure; NCT01471860; Barostim HOPE4HF [Hope for Heart Failure] Study; NCT01720160).

Mechanism of decreased sensitivity of dobutamine associated left ventricular wall motion analyses for appreciating inducible ischemia in older adults.

BACKGROUND: Dobutamine associated left ventricular (LV) wall motion analyses exhibit reduced sensitivity for detecting inducible ischemia in individuals with increased LV wall thickness. This study was performed to better understand the mechanism of this reduced sensitivity in the elderly who often manifest increased LV wall thickness and risk factors for coronary artery disease. METHODS: During dobutamine cardiovascular magnetic resonance (DCMR) stress testing, we assessed rate pressure product (RPP), aortic pulse wave velocity (PWV), LV myocardial oxygen demand (pressure volume area, PVA, mass, volumes, concentricity, and the presence of wall motion abnormalities (WMA) and first pass gadolinium enhanced perfusion defects (PDs) indicative of ischemia in 278 consecutively recruited individuals aged 69 ± 8 years with pre-existing or known risk factors for coronary artery disease. Each variable was assessed independently by personnel blinded to participant identifiers and analyses of other DCMR or hemodynamic variables. RESULTS: Participants were 80% white, 90% hypertensive, 43% diabetic and 55% men. With dobutamine, 60% of the participants who exhibited PDs had no inducible WMA. Among these participants, myocardial oxygen demand was lower than that observed in those who had both wall motion and perfusion abnormalities suggestive of ischemia (p = 0.03). Relative to those with PDs and inducible WMAs, myocardial oxygen demand remained different in these individuals with PDs without an inducible WMA after accounting for LV afterload and contractility (p = 0.02 and 0.03 respectively), but not after accounting for either LV stress related end diastolic volume index (LV preload) or resting concentricity (p = 0.31-0.71). CONCLUSIONS: During dobutamine stress testing, elderly patients experience increased LV concentricity and declines in LV preload and myocardial oxygen demand, all of which are associated with an absence of inducible LV WMAs indicative of myocardial ischemia. These findings provide insight as to why dobutamine associated wall motion analyses exhibit reduced sensitivity for identifying inducible ischemia in elderly. TRIAL REGISTRATION: This study was registered with Clinicaltrials.gov (NCT00542503).

Altered spatial distribution of the diastolic left ventricular pressure difference in heart failure.

BACKGROUND: The left ventricle fills in early diastole because of a progressive intraventricular pressure difference (IVPD) that extends from the left atrium to the left ventricular (LV). The aim of this study was to test the hypothesis that in patients with symptomatic heart failure (HF) regardless of LV ejection fraction (EF), an increase in left atrial (LA) pressure maintains early diastolic filling because of a preserved IVPD from the left atrium to the mid left ventricle, while the IVPD from the mid left ventricle to the apex is diminished because of reduced LV suction. METHODS: One hundred fifty-one patients with HF (50 with HF with preserved EF [HFpEF; EF ≥ 50%] and 101 with HF with reduced EF [HFrEF; EF < 50%]) and 28 normal controls were prospectively enrolled. The IVPDs from the left atrium to the LV apex (total IVPD), the left atrium to the mid left ventricle (basilar IVPD), and the mid left ventricle to the apex (apical IVPD) were determined using color M-mode Doppler echocardiographic data to integrate the Euler equation. The propagation of early diastolic filling was also assessed by color M-mode Doppler. RESULTS: The mean LV EF was 0.63 ± 0.07 in patients with HFpEF, 0.32 ± 0.09 in those with HFrEF, and 0.64 ± 0.06 in controls. Peak early diastolic transmitral flow velocities (E) were similar among the groups, and basilar IVPDs were maintained in the HFpEF and HFrEF groups (HFpEF, 1.59 ± 0.62 mm Hg; HFrEF, 1.49 ± 0.75 mm Hg; controls, 1.80 ± 0.61 mm Hg; P = NS, analysis of variance). However, apical IVPDs were decreased in both HF groups (HFpEF, 1.18 ± 0.56 mm Hg [P < .01 vs controls]; HFrEF, 0.87 ± 0.48 mm Hg [P < .01 vs controls]; controls, 1.65 ± 0.62 mm Hg), resulting in decreased total IVPDs in patients with HF (HFpEF, 2.55 ± 0.80 mm Hg [P < .01 vs controls]; HFrEF, 2.16 ± 0.80 mm Hg [P < .01 vs controls]; controls, 3.17 ± 0.91 mm Hg). E/e' ratios were increased in patients with HF, consistent with elevated LA pressure. In patients with HF, E was correlated with basilar IVPD but not with apical IVPD, whereas propagation of the filling was correlated with the apical IVPD but not with the basilar IVPD. CONCLUSIONS: In patients with HFpEF and those with HFrEF, apical IVPDs were reduced while basilar IVPDs were maintained by elevated LA pressure, resulting in preserved E.

Vortex formation time is not an index of ventricular function.

The diastolic intraventricular ring vortex formation and pinch-off process may provide clinically useful insights into diastolic function in health and disease. The vortex ring formation time (FT) concept, based on hydrodynamic experiments dealing with unconfined (large tank) flow, has attracted considerable attention and popularity. Dynamic conditions evolving within the very confined space of a filling, expansible ventricular chamber with relaxing and rebounding, and viscoelastic muscular boundaries diverge from unconfined (large tank) flow and encompass rebounding walls' suction and myocardial relaxation. Indeed, clinical/physiological findings seeking validation in vivo failed to support the notion that FT is an index of normal/abnormal diastolic ventricular function. Therefore, FT as originally proposed cannot and should not be utilized as such an index. Evidently, physiologically accurate models accounting for coupled hydrodynamic and (patho)physiological myocardial wall interactions with the intraventricular flow are still needed to enhance our understanding and yield diastolic function indices useful and reliable in the clinical setting.

Calculating intraventricular pressure difference using a multi-beat spatiotemporal reconstruction of color m-mode echocardiography.

This work aims to provide a methodology to improve the analysis of color-M-Mode (CMM) echocardiograms, as used to assess cardiac function. Specifically, we presented a methodology for the combined analysis of multiple heartbeat cycles and improve the accuracy of intraventricular pressure difference (IVPD) calculation. CMM sweep speed and heartbeat variations impact the accuracy of IVPD calculation. Proper orthogonal decomposition (POD) is used to decompose and reconstruct a representative CMM scan from multiple heartbeats, with reduced noise and improved resolution. For three demonstration subjects, at least 9 beats were recorded at sweep speeds of 25, 50, 75, 100, and 150 mm/s. For all subjects, the beats from the 25 mm/s group resulted in low IVPD (median values: 1.93, 1.94 and 3.15 mmHg) compared to the 150 mm/s group (median values: 3.67, 3.98 and 5.18 mmHg). Reconstructed heartbeats for these subjects returned IVPD of 4.74, 3.23, and 5.14 mmHg. These results demonstrate the strong dependence of IVPD on the temporal resolution and that the proposed reconstruction method can return more accurate IVPDs for low resolution CMMs. This new method was applied to 5 clinical cohorts (3 normals, 1 restrictive, and 1 hypertrophied) and returned increased median IVPD from 2.93-4.41 mmHg for Normal 1, 2.14-3.30 mmHg for Normal 2, 1.84-3.64 mmHg for Normal 3, 2.28-3.00 mmHg for restrictive and 1.56-1.69 mmHg for hypertrophied. Our results show that beat-to-beat variations and temporal resolution affect the IVPD. Our new method rectifies low resolutions and beat-to-beat variability of the CMM data and allows for more accurate IVPD measurement independent of scanner acquisition settings and beat variations.

Delay of left ventricular longitudinal expansion with diastolic dysfunction: impact on load dependence of e' and longitudinal strain rate.

The effect of diastolic dysfunction (DD) on the timing of left ventricular (LV) diastolic longitudinal and circumferential expansion and their load dependence is not known. This study evaluated the timing of the peak early diastolic LV inflow velocity (E), mitral annular velocity (e'), and longitudinal and circumferential global strain rates (SRE) in 161 patients in sinus rhythm. The intraventricular pressure difference (IVPD) from the left atrium to the LV apex was obtained using color M-mode Doppler data to integrate the Euler equation. The diastolic function was graded according to the guidelines. In normals (N = 57), E, e', longitudinal SRE, and circumferential SRE occurred nearly simultaneously during the IVPD. With DD (N = 104), e' and longitudinal SRE were delayed occurring after the IVPD (e': 18 ± 23 msec, longitudinal SRE: 13 ± 21 msec from the IVPD), whereas circumferential SRE (-8 ± 28 msec) and E (-2 ± 13 msec) were not delayed. The normal dependence of e' and longitudinal SRE on IVPD was reduced in DD; while the relation of circumferential SRE and E to IVPD were unchanged in DD. Thus, normally, the LV expands symmetrically during early diastole and both longitudinal and circumferential expansions are related to the IVPD. With DD, early diastolic longitudinal LV expansion is delayed, occurring after the IVPD and LV filling, resulting in their relative independence from the IVPD. In contrast, with DD, circumferential SRE and mitral inflow are not delayed and their normal relation to the IVPD is unchanged.

Randomized, double-blind, placebo-controlled study of sitaxsentan to improve impaired exercise tolerance in patients with heart failure and a preserved ejection fraction.

OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety of the selective endothelin type A (ETA) receptor antagonist sitaxsentan in patients who have heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Fifty percent of heart failure (HF) patients have a preserved ejection fraction. No treatment has been shown to improve their clinical outcomes. Previous studies have suggested that ETA receptor antagonists might improve diastolic function and exercise tolerance in some forms of HF. METHODS: In all, 192 HFpEF patients (EF ≥50%) were randomly assigned 2:1 to sitaxsentan 100 mg/day (n = 128) versus placebo (n = 64) for 24 weeks. The primary endpoint was change in treadmill exercise time after 24 weeks of treatment. Secondary objectives included changes in left ventricular mass, transmitral inflow velocity to early diastolic mitral annulus velocity ratio, and Minnesota Living With Heart Failure questionnaire, and New York Heart Association functional class. Subjects were age 65 ± 11 years, 63% female, 29% non-Caucasian, and in functional class II (56.5%) or III (43.5%). RESULTS: Subjects treated with sitaxsentan had an increase in median treadmill time (90 s) compared with placebo-treated subjects (37 s, p = 0.0302). There was no significant treatment differences in transmitral inflow velocity to early diastolic mitral annulus velocity ratio, left ventricular mass, Minnesota Living With Heart Failure questionnaire, New York Heart Association functional class, deaths, or HF hospital stay. The incidence of adverse events was similar for sitaxsentan and placebo. CONCLUSIONS: In HFpEF patients, treatment with a selective ETA receptor antagonist increased exercise tolerance but did not improve any of the secondary endpoints such as left ventricular mass or diastolic function. Further studies will be necessary to determine whether ETA receptor antagonists may be useful in the treatment of HFpEF. (A Study of the Effectiveness of Sitaxsentan Sodium in Patients With Diastolic Heart Failure; NCT00303498).

ß3-Adrenergic receptor antagonist improves exercise performance in pacing-induced heart failure.

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. We have previously shown that in HF at rest stimulation of ß3-adrenergic receptors by endogenous catecholamine depresses LV contraction and relaxation. ß3-Adrenergic receptors are activated at higher concentrations of catecholamine. Thus exercise may cause increased stimulation of cardiac ß3-adrenergic receptors and contribute to this abnormal response. We assessed the effect of L-748,337 (50 µg/kg iv), a selective ß3-adrenergic receptor antagonist (ß3-ANT), on LV dynamics during exercise in 12 chronically instrumented dogs with pacing-induced HF. Compared with HF at rest, exercise increased LV end-systolic pressure (PES), minimum LV pressure (LVPmin), and the time constant of LV relaxation (τ) with an upward shift of early diastolic portion of LV pressure-volume loop. LV contractility decreased and arterial elastance (EA) increased. LV arterial coupling (EES/EA) (0.40 vs. 0.51) was impaired. Compared with exercise in HF preparation, exercise after ß3-ANT caused similar increases in heart rate and PES but significantly decreased τ (34.9 vs. 38.3 ms) and LVPmin with a downward shift of the early diastolic portion of LV pressure-volume loop and further augmented dV/dtmax. Both EES and EES/EA (0.68 vs. 0.40) were increased. LV mechanical efficiency improved from 0.39 to 0.53. In conclusion, after HF, ß3-ANT improves LV diastolic filling; increases LV contractility, LV arterial coupling, and mechanical efficiency; and improves exercise performance.

Heart failure: what does ejection fraction have to do with it?

Heart failure (HF) occurs across the entire range of left ventricular (LV) ejection fractions (EF), not just reduced EF. Nearly half or more patients presenting with HF have a preserved EF>0.50 (HFpEF). Diastolic dysfunction is apparent in all patients with HF, regardless of EF. A preserved EF indicates that the end-diastolic volume is appropriate for the stroke volume, and a reduced EF indicates that the end-diastolic volume is enlarged relative to stroke volume (i.e. the LV is dilated). Most therapies proven to be effective in HF with a reduced EF (ACE-inhibitors, angiotensin receptor blockers, beta-blockers, and cardiac resynchronization) reverse LV dilation. These therapies have not been proven to be effective in HFpEF. Increasing c-GMP may be a treatment target in HFpEF, and potential ways of increasing c-GMP are being studied. Finally, comorbidities are important in HFpEF and are additional targets for therapy.