Growth factors and interleukin-6 across the lung circulation in pulmonary hypertension.

The aim of our study was to assess the levels of growth factors and interleukin (IL)-6 across the pulmonary circulation in patients with pulmonary arterial hypertension (PAH) and correlate them with clinical and haemodynamic data and outcome. Simultaneous arterial and pulmonary arterial blood samples in patients with PAH (n = 44) and controls (n = 20) were obtained during right heart catheterisation. Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF)-BB, transforming growth factor (TGF)-beta1 and IL-6 were measured using ELISA. Arterial median (interquartile range) values for VEGF, PDGF-BB, TGF-beta1 and IL-6 were significantly higher in patients (377 (218-588) versus 9.0 pg.mL(-1); 1,955 (1,371-2,519) versus 306 (131-502) pg.mL(-1); 26.42 (11.3-41.1) versus 7.0 (1.8-18.4) ng.mL(-1); and 3.98 (0.7-8.1) versus 0.7 pg.mL(-1), respectively; p<0.001 for all variables). There was a consistent step-up of VEGF, PDGF-BB and TGF-beta1 across the lungs in PAH patients (p<0.001, p = 0.002 and p<0.001, respectively), whereas in controls, arterial and pulmonary arterial serum levels of IL-6 and growth factors were similar (statistically nonsignificant). In multivariate analysis, increased IL-6 levels predicted mortality (hazard ratio 1.08 (95% confidence interval 1.02-1.15); p = 0.012). Our findings indicate increased release and/or decreased clearance of growth factors at the lung vascular level, which may contribute to vascular remodelling in PAH.

Pathological sympathoexcitation: how is it achieved?

AIM: Congestive heart failure (CHF) and obstructive sleep apnoea syndrome (OSAS) are both associated with an intense sympathoexcitation, including an increased muscle sympathetic nerve activity (MSNA). We have studied the firing characteristics of single vasoconstrictor fibres to the muscle vascular bed in CHF and OSAS patients, at rest and during transient sympathoexcitatory stimuli, to elucidate the mechanisms by which vasoconstrictor output is augmented in these conditions. RESULTS: The main alternatives for augmenting sympathetic output are an increased firing frequency of individual nerve fibres and an increased recruitment of nerve fibres. Starting with the frequency alternative, the inherent bursting character of MSNA provides two possibilities to increase the firing of individual fibres: (1) by increasing the proportion of neural bursts in which the fibre is active (increased firing probability) and (2) by increasing the number of spikes a fibre generates per burst (increased multiple within-burst firing). At rest and in cardiac sinus rhythm, an increased firing probability is seen in both CHF and OSAS patients, whereas increased multiple within-burst firing is found in OSAS but not in CHF. In response to transient sympathoexcitatory stimuli (such as pre-mature heart beats), both patient groups show marked shifts towards multiple within-burst firing. Thus, both mechanisms for augmenting discharge frequency are operating in these two pathological conditions, but the firing characteristics at rest differ significantly. During recording sessions in sympathoexcited patients, we have encountered vasoconstrictor fibres that are active almost exclusively during periods of transient sympathoexcitation, while being virtually silent at rest. This suggests that recruitment of previously inactive vasoconstrictor fibres, the second main alternative for increasing vasoconstrictor output, contributes to transient sympathoexcitatory responses in these patients. Although it seems reasonable to assume that recruitment may also contribute to the resting level of MSNA in CHF and OSAS, this issue is difficult to resolve in microneurographic studies. CONCLUSION: In conclusion, pathological sympathoexcitation appears to depend on both recruitment and increased firing frequency. A shift towards multiple within-burst firing, at rest or in response to transient stimuli, may constitute a risk factor per se as it entails neural volleys with high instantaneous firing frequencies and consequently higher release of neurotransmitters.

Skeletal muscle characteristics, muscle strength and thigh muscle area in patients before and after cardiac transplantation.

BACKGROUND: Patients with chronic heart failure demonstrate several skeletal muscle abnormalities. The underlying mechanisms are unclear. After cardiac transplantation, cardiac function is restored, but exercise capacity is still impaired. AIM: To evaluate the influence of cardiac transplantation on skeletal muscle fibre composition, fibre area and capillarization as well as muscle enzymes, lactate, thigh muscle area and strength. METHODS: Ten patients were longitudinally investigated before, 1-3 and 6-9 months after transplantation. Ten healthy individuals served as controls. A biopsy from the lateral vastus muscle was obtained and the thigh muscle area was measured with computed tomography. Muscle strength in the knee extensors and exercise capacity were also evaluated. RESULTS: Muscle lactate was elevated in patients vs. controls (3.6+/-3.0 vs. 1.5+/-0.7 mmol/kg wet wt., P=0.037), and decreased to normal (1.4+/-0.3 mmol/kg wet wt., P=0.038) after transplantation. Citrate synthase activity was decreased in patients (5.6+/-1.5 micromol/g wet wt./min) vs. controls (8.1+/-1.6 micromol/g wet wt./min, P=0.0018), and did not change post transplantation. Patients had decreased number of capillaries in contact with each fibre vs. controls (2.6+/-0.5 vs. 3.5+/-1.0, P=0.039) which persisted post transplantation. Exercise capacity increased after transplantation (74+/-22 vs. 118+/-26 W, P=0.0002), whereas muscle strength did not improve significantly. CONCLUSION: The persisting intrinsic abnormalities in skeletal muscle after cardiac transplantation may contribute to the impaired exercise capacity observed in cardiac transplant recipients.

Sympathetic neural burst amplitude distribution: A more specific indicator of sympathoexcitation in human heart failure.

BACKGROUND: Human muscle sympathetic nerve activity (MSNA) is usually measured as the number of pulse-synchronous bursts in multiunit mean voltage recordings. We recently suggested burst amplitude distribution as a more sensitive indicator of altered MSNA in congestive heart failure (CHF). Here, we test whether this distribution can discriminate between different conditions with increased MSNA burst frequency and whether it reflects single vasoconstrictor fiber firing intensity. METHODS AND RESULTS: We analyzed resting multiunit MSNA in 36 CHF patients (24 with mild to moderate CHF, 12 with severe CHF investigated before and after heart transplantation), 14 patients with pituitary deficiency, 25 matched healthy control subjects, and an additional 56 healthy men with a wider age range (21 to 71 years). Pituitary deficiency was associated with increased MSNA burst frequency (60 versus 37 bursts/min in control subjects), equivalent to that in mild to moderate CHF (61 bursts/min). However, burst amplitude distribution in hypopituitary patients (median burst amplitude, 37%) did not deviate from matched control subjects (36%), whereas amplitudes increased with disease severity in CHF (43% in mild to moderate, 52% in severe) and normalized after transplantation (36%). In the larger healthy group, MSNA burst frequency increased with age, and burst amplitude distribution remained unaffected. In 8 CHF patients, single-unit firing frequency showed a close positive relationship to multiunit burst amplitude distribution (r=0.82, P:<0.01) but none to burst frequency (r=0.39, P:=0.3). CONCLUSIONS: Muscle vasoconstrictor fiber activity is better reflected by multiunit MSNA burst amplitude distribution than by burst frequency, at least in CHF. This distribution can discriminate between conditions with increased burst frequency.

Differentiated response of the sympathetic nervous system to angiotensin-converting enzyme inhibition in hypertension.

Hypertension with renal artery stenosis is associated with both an activated renin-angiotensin system and elevated sympathetic activity. Therefore, in this condition it may be favorable to use a therapeutic modality that does not reflexly increase heart rate, renin secretion, and sympathetic nervous activity. The purpose of the present study was to assess overall, renal, and muscle sympathetic activity after short-term administration of an angiotensin-converting enzyme inhibitor (enalaprilat) and a nonspecific vasodilator (dihydralazine) to hypertensive patients with renal artery stenosis. Forty-eight patients undergoing a clinical investigation for renovascular hypertension were included in the study. An isotope dilution technique for assessing norepinephrine spillover was used to estimate overall and bilateral renal sympathetic nerve activity. In 11 patients simultaneous intraneural recordings of efferent muscle sympathetic nerve activity were performed. Thirty minutes after dihydralazine administration, mean arterial pressure fell by 15%, whereas plasma angiotensin II, muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover increased (P<0.05 for all). In contrast, after enalaprilat administration a fall in arterial pressure similar to that for dihydralazine was followed by decreased angiotensin II levels and unchanged muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover, whereas renal norepinephrine spillover increased by 44% (P<0.05). Acute blood pressure reduction by an angiotensin-converting enzyme inhibitor provokes a differentiated sympathetic response in patients with hypertension and renal artery stenosis, inasmuch that overall and muscle sympathetic reflex activation are blunted, whereas the reflex renal sympathetic response to blood pressure reduction is preserved.

Firing properties of single muscle vasoconstrictor neurons in the sympathoexcitation associated with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) in humans is associated with a marked sympathoexcitation, including an augmented muscle sympathetic nerve activity (MSNA) in intraneural multiunit recordings. In the present study, single-unit recording was used to evaluate whether the firing properties of individual muscle vasoconstrictor neurons can reveal underlying mechanisms for this increase in MSNA. METHODS AND RESULTS: Eight patients with CHF (NYHA class II to IV; left ventricular ejection fraction, 29+/-5%, mean+/-SEM) were studied. In standard multiunit recordings, MSNA burst incidence (bursts/100 heartbeats) ranged from 65% to 100% (88+/-5%). Using selective tungsten microelectrodes, we made recordings from 16 single muscle vasoconstrictor axons. Mean unit firing probability (ie, the percentage of cardiac intervals in which a single axon fired) was 54.5+/-5.2% (range, 21 to 89%), and mean firing frequency was 0.98+/-0.22 Hz (0.14 to 3.86 Hz), both of which were higher than seen previously in healthy subjects (P<0.001). Although single neurons occasionally generated multiple spikes per sympathetic burst, such multiple firing was rare and was not different from that seen in healthy subjects. CONCLUSIONS: An increased firing frequency of individual vasoconstrictor neurons is one mechanism for the increased number of multiunit MSNA bursts at rest in CHF. The neurons discharge in more diastoles than in healthy subjects (ie, firing probability is increased), but the likelihood of discharging >1 impulse per sympathetic burst is not increased. Despite the intense multiunit activity at rest, the firing characteristics of individual vasoconstrictor axons indicate a remaining capacity for transient increases of MSNA in CHF.

Increased sympathetic nerve activity in renovascular hypertension.

BACKGROUND: Increased sympathetic nerve activity may contribute to the progression of renovascular hypertension. Because previous results have been inconclusive, we investigated whether renovascular hypertensives show increased total and regional sympathetic nerve activity. METHODS AND RESULTS: Sixty-five patients underwent renal angiography and measurements of plasma renin activity and angiotensin II in conjunction with estimation of sympathetic nerve activity by means of radiotracer dilution and intraneural recordings of muscle sympathetic nerve activity (MSNA). Age-matched healthy subjects (n=15) were examined for comparison. Total body norepinephrine (NE) spillover, an index of overall sympathetic nerve activity, was increased by 100% and MSNA by 60% in the hypertensive patients compared with healthy subjects (P<0.01 for both). A subgroup of 24 patients with well-defined renovascular hypertension (cured or improved hypertension after renal angioplasty) showed similar increases in total body NE spillover compared with the group at large. Patients with arterial plasma renin activity and angiotensin II levels above median had higher values for total body NE spillover than patients below median (P<0.01). CONCLUSIONS: This study unequivocally demonstrates elevated sympathetic nerve activity in patients with renovascular hypertension. The adrenergic overactivity may contribute to the blood pressure elevation and perhaps also to the high cardiovascular mortality in renovascular hypertension.

Potential risk of beta-blockade withdrawal in congestive heart failure due to abrupt autonomic changes.

Beta-Blockers reduce mortality in patients with congestive heart failure and a proposed mechanism has been changes of autonomic tone. Heart rate variability is a non-invasive tool to estimate cardiac autonomic tone. The aim was to study changes of heart rate variability in patients with congestive heart failure on placebo, on the beta1-selective antagonist metoprolol or 24 h after metoprolol withdrawal. Forty-five patients with congestive heart failure were studied with Holter recordings. Heart rate variability measurements were performed before, after 6-12 months of treatment with 150 mg metoprolol/placebo, or 24 h after discontinued metoprolol. After treatment, patients on beta-blockade had a significantly longer mean RR interval and changes of heart rate variability, suggesting elevated vagal tone. Patients monitored in the rebound phase of beta-blocker withdrawal had a significant vagal reduction to the level of the placebo group. There was also a nonsignificant trend towards increased sympathetic tone (LF/HF over 24 h), compared with the beta-blockade group. Heart rate variability indicates an elevated vagal tone during treatment with metoprolol but beta-blockade withdrawal shifts the autonomic balance towards lower vagal and higher sympathetic tone within 24 h. These results could imply a potential risk when abruptly discontinuing beta-blockade medication in these patients.

Increased cardiovascular mortality in hypertensive patients with renal artery stenosis. Relation to sympathetic activation, renal function and treatment regimens.

BACKGROUND: Previous studies in hypertensive patients with renovascular disease have shown both elevated sympathetic nerve activity and increased cardiovascular mortality. OBJECTIVE: The aim of the present study was to assess long-term survival in hypertensive patients with renal artery stenosis in relation to sympathetic activation, renal function and treatment regimens. SUBJECTS AND METHODS: A total of 169 consecutive patients aged 54 +/- 1 years with hypertension underwent a clinical investigation for renovascular hypertension including renal angiography and measurement of bilateral renal renin secretion. In 107 of these patients, arterial plasma concentrations of noradrenaline were measured. The mean follow-up time was 7.1 +/- 0.3 years and survival data were available in all patients up to May 1997. For comparison, healthy age-matched normotensive controls were examined. RESULTS: Arterial noradrenaline concentrations were threefold elevated in hypertensive patients with renal artery stenosis compared to healthy controls (P < 0.01). During the follow-up time, 44 patients died. Cardiovascular mortality accounted for 75% of all deaths. The risk ratio for overall mortality in hypertensive patients with renal artery stenosis compared to the normal population of Sweden, matched for age, was 3.3 (2.4-4.4), whereas the risk ratio for cardiovascular mortality was 5.7 (3.9-8.0). The arterial plasma concentration of noradrenaline was 3.11 +/- 0.30 pmol/ml in patients who died compared to 3.84 +/- 0.26 pmol/ml in survivors. Reduced renal function and age were independent predictors of death. Survival did not differ between patients undergoing intervention with either renal angioplasty or surgical reconstruction for renal artery stenosis and patients not undergoing intervention. CONCLUSIONS: Although sympathetic nerve activity is elevated in hypertensive patients with renal artery stenosis, our results do not suggest that this adrenergic over-activity is directly linked to the observed high cardiovascular mortality. Mortality in hypertensive patients with renovascular disease remains high whether an interventional treatment is performed or not, possibly due to the concomitant coronary disease.

Different relationships of spillover to release of norepinephrine in human heart, kidneys, and forearm.

Spillover of norepinephrine (NE) into plasma is used frequently as an index of NE release and therefore of sympathetic nerve activity. An important limitation of NE spillover is that it reflects not only release but also uptake processes that intervene before the transmitter reaches the circulation. To overcome this limitation, we developed a method for estimating NE release based on measurements of the specific activities of [3H]NE in plasma and interstitial fluid during intravenous infusion of [3H]NE. We applied this method to examine relationships among NE release, tissue uptake, and spillover in the human heart, kidneys, and forearm. The sum of uptake and spillover of released NE provided an estimate of NE release into the interstitial fluid. In the kidneys, NE release averaged three times NE spillover, in skeletal muscle, 12 times NE spillover, and in the heart, >20 times NE spillover. Thus NE release greatly and variably exceeds NE spillover from these organs, so that assessing regional sympathetic function requires an understanding of the relationship of NE spillover to NE release.

Relative burst amplitude in human muscle sympathetic nerve activity: a sensitive indicator of altered sympathetic traffic.

Microneurographically recorded sympathetic outflow to the human muscle vascular bed is traditionally quantified by identifying pulse-synchronous bursts of impulses in a mean voltage neurogram and expressing them in terms of bursts per minute (burst frequency) or bursts per 100 heart beats (burst incidence). As both these measures show large inter-individual differences in resting healthy subjects, a problem arises when comparing sympathetic traffic in cross-sectional studies, making moderate differences in muscle sympathetic nerve activity (MSA) between groups difficult to identify. Absolute measures of the strength of the sympathetic discharges (burst amplitude or area) can also be evaluated. However, as they critically depend on the proximity of the microelectrode to the recorded fibres, such measures cannot be used for interindividual comparisons. The aim of the present study was to evaluate the use of relative burst amplitude spectra for quantification of MSA, describing the proportion of small vs large bursts in a neurogram. We recorded MSA in 18 patients with mild to moderate congestive heart failure (CHF) (New York Heart Association functional classes I-IIIA) and 18 matched healthy controls. Sympathetic activity was expressed as burst frequency, burst incidence and burst amplitude spectra. When comparing the traditional burst counts between the groups (presented as the median and 25th-75th percentiles) there was a tendency towards higher MSA in CHF patients, but the difference was not significant (42 (34-52) vs 53 (41-63) bursts/min, 62 (51-78) vs 69 (52-84) bursts/100 heart beats, both ns). Relative burst amplitude spectra, on the other hand, were clearly shifted to the right in the CHF group compared to the control group (median burst amplitudes 42 (34-45) vs 30 (28-35), P = 0.0002). Relative burst amplitude spectra thus appear to provide a more sensitive indicator of altered MSA than traditional burst counts. The right-ward shift of these spectra may suggest that sympatho-excitation occurs early in the development of CHF.

Determinants of cardiac tyrosine hydroxylase activity during exercise-induced sympathetic activation in humans.

This study assessed whether the mechanisms regulating cardiac norepinephrine (NE) synthesis with changes in NE release are influenced by functions of sympathetic nerves affecting transmitter turnover independently of transmitter release. Differences in arterial and coronary venous plasma concentrations of NE and its metabolites and of dihydroxyphenylalanine (DOPA), the immediate product of tyrosine hydroxylase (TH), were examined before and during cycling exercise. Relative increases during exercise in cardiac tyrosine hydroxylation (as reflected by the %increase in cardiac DOPA spillover) matched closely corresponding increases in NE turnover, but were much lower than increases in NE release. The much larger relative increases in release than turnover of NE were largely attributable to the extensive contribution to transmitter turnover from intraneuronal metabolism of NE leaking from storage vesicles. This contribution remains unchanged during sympathetic activation so that the relative increase in NE turnover is much smaller than that in exocytotic release of NE. To replenish the NE lost from stores during sympathetic activation, TH activity need increase only in proportion to the smaller increase in turnover rather than the larger relative increase in release. The ability to "gear down" increases in tyrosine hydroxylation relative to increases in NE release provides sympathetic nerves the capacity for a more extended range of sustainable release rates than otherwise possible.

Cardiorenal epinephrine kinetics: evidence for neuronal release in the human heart.

There are experimental data suggesting that epinephrine (Epi) may act as a cotransmitter in sympathetic nerves, stimulating presynaptic beta 2-receptors and enhancing norepinephrine (NE) release. To examine neuronal Epi release, patients with congestive heart failure and hypertension and healthy subjects were examined with the isotope-dilution method. At baseline, small cardiac and renal Epi spillovers were found in patients. During intense supine exercise, cardiac NE and Epi spillovers increased concomitantly with similar magnitude, whereas no renal Epi spillover could be detected. Blockade of neuronal uptake 1 caused a consistent decrease in both cardiac and renal fractional extractions of NE and Epi. The present study demonstrates baseline cardiorenal Epi release in patients with congestive heart failure and renal Epi release in hypertensive patients. Furthermore, Epi is removed by neuronal uptake in both the heart and kidney, and cardiac Epi spillover increases during exercise. This study, in contrast to other results, provides evidence for cardiac neuronal Epi release.

Intracoronary blockade of angiotensin-converting enzyme in humans: interaction with cardiac sympathetic neurotransmission?

The present study was designed to identify an interaction between the renin-angiotensin system and noradrenergic transmission in the human heart. It is still under debate whether angiotensin II facilitates noradrenaline release in the heart. Clinical studies of congestive heart failure, involving systemic angiotensin-converting enzyme (ACE) inhibitor administration, have indicated anti-adrenergic effects, without giving a clear mechanistic picture. The influence on cardiac sympathetic transmission by local intracardiac administration of an ACE inhibitor has not been determined. Seven angina patients with normal left ventricular function, who underwent control coronary angiography after successful percutaneous transluminal coronary angioplasty were studied. Baseline measurements of haemodynamics and total and cardiac noradrenaline spillover were followed by handgrip exercise in the absence and presence of intracoronary enalaprilat infusion (0.05 mg min-1, 1 mL min-1). Baseline total body and cardiac noradrenaline spillover remained unchanged following intracoronary enalaprilat infusion, being 3745 +/- 349 and 3896 +/- 257 pmol min-1, and 148 +/- 56 and 149 +/- 55 pmol min-1, before and after drug administration, respectively. Mean arterial pressure, peripheral plasma renin activity and angiotensin II levels were also unaffected by enalaprilat infusion. During handgrip exercise procedures, both total body and cardiac noradrenaline spillover increased substantially, showing no reduction in the presence of intracardiac enalaprilat. Direct administration of the ACE inhibitor enalaprilat to the human heart failed to attenuate cardiac sympathetic drive during baseline conditions or following cardiac adrenergic activation by handgrip exercise. Thus, in the non-failing heart, without chronic adrenergic activation, no angiotensin II-facilitated effect on cardiac noradrenaline spillover could be detected.

Rapid fall in sympathetic nerve hyperactivity in patients with heart failure after cardiac transplantation.

BACKGROUND: Severe heart failure is associated with an intense sympathetic nerve hyperactivity. After cardiac transplantation, neurochemical studies have indicated a normalization of sympathetic outflow. Intraneural recordings have, however, yielded varying results; both a normalization and a remaining hyperactivity have been obtained in cardiac transplant recipients, the latter being attributed to cyclosporine treatment. METHODS AND RESULTS: To circumvent the methodologic variation associated with different patient groups in cross-sectional studies, a longitudinal study design was employed in this study. Intraneural recordings of muscle sympathetic nerve activity in 21 heart failure patients were performed before, and repeatedly during the first year after, heart transplantation. Before surgery, muscle sympathetic nerve activity was augmented in all patients (78 +/- 4 bursts/min, 90 +/- 2 bursts/100 heartbeats). Both muscle sympathetic nerve activity burst frequency (burst/minute) and burst incidence (bursts/100 heartbeats) decreased rapidly following surgery. One month after surgery, burst frequency was reduced by 35% (51 +/- 5 bursts/min P < .05), whereas burst incidence decreased by 32% (61 +/- 5 bursts/100 heartbeats, P < .05). This decrease remained unchanged up to 1 year after surgery. The fall in posttransplant muscle sympathetic nerve activity was similar in transplant recipients who developed hypertension during the course of the study (n = 12) and those who remained normotensive (n = 9). CONCLUSIONS: The sympathoexcitation recorded in patients with heart failure was rapidly and substantially reduced after cardiac transplantation despite cyclosporine treatment, most likely reflecting improved central and peripheral hemodynamics.

Attenuated cardiac sympathetic responsiveness during dynamic exercise in patients with heart failure.

BACKGROUND: Cardiac norepinephrine (NE) spillover is increased in patients with chronic heart failure. This elevation is partly due to augmented NE release but also to reduced capacity for cardiac NE removal processes. In patients with mild to moderate heart failure, it is not known whether the described alteration in cardiac sympathetic function also affects cardiac NE spillover during intense sympathetic activation and whether other organs respond in proportion to the heart. METHODS AND RESULTS: Twenty-two patients with heart failure and 15 age-matched healthy subjects were studied. Whole-body and regional (NE) spillovers from the heart and kidneys were assessed at baseline and during supine cycling exercise (10 minutes) with the use of steady-state infusions of tritiated NE (isotope dilution). Cardiac performance was evaluated by means of catheterization of the right side of the heart. Cardiac NE spillover was higher (P < .05) at baseline in the patient group than in healthy subjects, whereas renal and whole-body NE spillovers were similar between the study groups. During exercise, cardiac NE spillover increased 13-fold (P < .05) in healthy subjects but only 5-fold (P < .05) in the cardiac failure group, the latter reaching a lower peak value (P < .05). In contrast, there was no difference between the study groups in either renal or whole-body NE spillover responsiveness to exercise. CONCLUSIONS: Patients with mild to moderate heart failure demonstrated a selective attenuation of cardiac sympathetic responsiveness during dynamic exercise. This attenuation may convey reduced inotropic and chronotropic support to the failing heart.