Fig. 20.1
Interaction of the sympathetic nervous system, kidney and activation of the renin-angiotensin-aldosterone pathway
In heart failure, sympathetic stimulation leads to activation of the renin-angiotensin-aldosterone system with increased sodium re-absorption from the distal and proximal tubules within the nephrons. Renin release and resultant angiotensin II generation results in activation of the sodium/hydrogen exchange transporters and sodium bicarbonate co-transporters, leading to re-absorption of sodium in the proximal tubules [17]. Water re-absorption is further increased through vasoconstriction of the efferent renal arteriole, increasing the hydrostatic gradient across the renal tubules [18]. Aldosterone acts on the distal tubule and collecting duct, activating the sodium-potassium pumps and further increasing sodium retention within the body’s circulation. This leads to an increase in circulating volume, with water re-absorbed with the sodium and potentially resulting in pulmonary and peripheral oedema.
Separately, sympathetic signalling to the heart itself is increased [19]. Release of norepinephrine from the right stellate ganglion results in an increased heart rate through actions on the sinus and atrioventricular nodes [12]. Increased sympathetic stimulation of the heart increases oxygen consumption by the myocardium and increases propensity to arrhythmia. The sympathetic nervous system also alters the chemoreceptor sensitivity to carbon dioxide, leading to an increased perception of shortness of breath and sleep disturbances such as periodic breathing. The increased sympathetic tone results in peripheral vasoconstriction, with a resultant increase in afterload which, over time, results in further myocardial impairment.
It is therefore not surprising that the level of sympathetic over-activity is predictive of adverse prognosis in heart failure. Plasma norepinephrine, the principal neurotransmitter in the sympathetic nervous system, was first shown to predict outcome in 1984 [20]. High renal norepinephrine levels measured invasively were later shown to be predictive of adverse outcome in a population of chronic heart failure patients followed for 6 years with a combined endpoint of all-cause mortality and heart transplantation [21]. Norepinephrine can be measured either globally (plasma norepinephrine) or regionally e.g. renal norepinephrine spillover, via invasive catheterisation. Renal norepinephrine in this study was independently predictive of outcome when entered into a model with total body norepinephrine spillover, glomerular filtration rate and ejection fraction. Patients with high sympathetic over-activity are also more symptomatic with a poorer functional capacity [22, 23] and an increased predisposition to arrhythmia [24]. Non invasive markers of high sympathetic tone, including heart rate variability [25, 26] have also been shown to predict adverse outcome in heart failure.
Tablets that target the sympathetic nervous system and the renin-angiotensin-aldosterone system have a strong prognostic benefit in systolic heart failure. There is less evidence for benefit in patients with heart failure and preserved ejection fraction, although trial data which included patients with mildly impaired systolic function did show some prognostic benefit.
Pharmacological Trials in Systolic Heart Failure
Inhibitors of the Renin-Angiotensin-Aldosterone Pathway
Inhibitors of the angiotensin converting enzyme (ACE) reduce the production of angiotensin II and aldosterone levels with a corresponding increase in renin. In systolic heart failure, treatment with ACE inhibitors leads to an improvement in levels of circulating plasma norepinephrine [27] thought to occur as a result of improved haemodynamics and the reduced angiotensin II leading to decreased stimulation of the sympathetic nervous system. Reduction in angiotensin II, a potent vasoconstrictor, causes improvement in the afterload through relaxation of the peripheral vascular system and reduction in venous dilatation decreases pulmonary congestion and the preload. Prognostic benefit of ACE inhibitors in systolic heart failure was shown in the SOLVD [28] and CONSENSUS [29] trials.
Aldosterone antagonists such as spironolactone reduce production of aldosterone, reducing retention of water and sodium. This was shown to have a prognostic benefit in systolic heart failure in the RALES trial, with a 30 % reduction in death compared to the placebo group and a 35 % decrease in hospitalization following commencement of spironolactone [30].
Direct renin inhibitors such as aliskiren have also been shown to reduce B-type natriuetic peptide in patients with chronic heart failure [31], although in a large double blinded randomised controlled trial, addition of aliskiren to standard therapy in a cohort of 1,639 patients with a recent heart failure hospitalisation did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge [32].
Beta blockers were initially thought to be harmful in systolic heart failure as administration to patients who were acutely fluid overloaded often caused haemodynamic decompensation. However in chronic systolic heart failure, beta blockers decrease total sympathetic activity, leading to improvement in symptoms and reduction in mortality. The β1 receptors on the myocardium are down-regulated in heart failure as a result of the excess sympathetic tone with loss of the force-frequency relationship and these changes are reversed by beta blocker therapy [33]. Cardiac Insufficiency Bisoprolol Study (CIBIS) was the first trial to demonstrate a prognostic benefit of beta blockage in chronic systolic heart failure [34]. This was confirmed in the CIBIS-II which demonstrated a significant reduction in all cause and sudden death in patients treated with bisoprolol compared with placebo [35]. Beta blockers have also been shown to reduce plasma renin activity in heart failure [36].
Centrally Acting Inhibitors of the Sympathetic Nervous System
Interest in global sympathetic activation led to the investigation of centrally acting inhibitors of the sympathetic nervous system. Small studies in the late 1990s in systolic heart failure demonstrated that administration of clonidine, a centrally acting agent causing a decrease in global sympathetic tone, led to a decrease in cardiac and global norepinephrine spillover [37]. This promising finding led to the multicentre randomised double blinded Moxonidine in Congestive Heart Failure (MOXCON) trial, which randomised patients with NYHA class II–IV heart failure and reduced ejection fraction to a sustained release preparation of monoxidine or placebo. Measurement of plasma norepinephrine demonstrated a significant decrease in total sympathetic nervous activity, with a 19 % decrease in the monoxidine group compared to a small increase (7 %) in the placebo group.
However, the trial was terminated prematurely due to an excess of deaths in the monoxidine group after 1,934 patients were entered. As well as an excess in all cause mortality, there were increased rates of hospitalisation for heart failure and acute myocardial infarction in the monoxidine group [38]. Questions were raised regarding the up-titration regimen of the trial and whether the doses used were too high, however in view of the excess of mortality in the trial, no further investigation of centrally acting sympathetic antagonists are currently planned.
Pharmacological Trials in Heart Failure with Preserved Ejection Fraction
The evidence base for pharmacological treatment in patients with heart failure and preserved ejection fraction is much smaller. Trials in HF-PEF are challenging as accurate identification of patients is less clear-cut than for systolic heart failure, due to clustering of disease processes leading to shortness of breath [39]. Most trials included patients with mild systolic left ventricular impairment (EF of 45 % or greater) on the basis that diastolic impairment is likely to be accompanied by systolic heart failure.
The PEP-CHF trial [40] enrolled patients aged 70 or greater with a clinical diagnosis of heart failure due to LV diastolic dysfunction, based on signs and symptoms of heart failure, left atrial enlargement, left ventricular hypertrophy and echocardiographic markers of impaired LV filling based on E/A ratio and isovolaemic relaxation time. Patients with atrial fibrillation were considered to have LV impaired filling. This trial showed a significant reduction in hospitalization for heart failure at 1 year with improvement in functional class and 6-min walk distance, although the trial was hampered by a high number of patients withdrawing from the trial to take open-label ACE-inhibitors, reducing its power.
I-PRESERVE [41] studied a population of 4,128 patients with a diagnosis of HF-PEF, defined as an ejection fraction of 45 % or greater with a hospitalisation in the previous 6 months and NYHA class II-IV. Patients had a mean blood pressure of 137 ± 15/79 ± 9. Patients were randomised to 300 mg irbesartan or placebo. During a mean follow-up of 50 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group with no difference in outcome between the two groups.
The CHARM-Preserved trial [42] randomised 3,023 patients with LVEF greater than 40 % and New York Heart Association functional class II-IV to candesartan (titrated up to a target of 32 mg) or placebo. There was no difference in rates of cardiovascular between the groups but fewer patients assigned to candesartan had heart failure admissions compared to the placebo group (230 vs 279, p = 0.017).
The SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure) trial [43], assessed the effect of nebivolol in a cohort of 2,111 patients aged 70 and above. The study cohort was examined to assess cohorts of impaired ejection fraction (<35 %) and “preserved ejection fraction” with an EF of 35 % or above. The primary endpoint of all-cause mortality and cardiovascular hospitalization was reached in a similar proportion of patients in both groups. Both groups showed similar benefit from nebivolol treatment.
The DIG-PEF trial enrolled 988 patients with symptomatic heart failure with an ejection fraction greater than 45 %. Digoxin had no effect on all cause or cause specific mortality or all-cause or cardiovascular hospitalisation [44]. By contrast, in the reduced ejection fraction cohort of the same trial, while digoxin had no effect on mortality, it did lead to a significant decrease in rates of hospitalisation [45].
Pharmacological treatment of heart failure is challenging in both systolic heart failure and HF-PEF. In systolic heart failure, few patients attain maximal doses of beta blockers, ACE inhibitors or aldosterone antagonists with up-titration often limited by renal impairment, symptomatic hypotension and other side effects. In HF-PEF, the evidence base for treatment is much smaller and may therapies have not been shown to improve survival.
There is therefore an unmet need in both pathologies for novel treatments. Therapy that is able to target the maladaptive signal processes at an early stage, reducing chronic sympathetic stimulation would theoretically be of benefit.
The Role of the Kidney in Pathogenesis of Heart Failure
The kidney plays a key role in heart failure pathophysiology, both responding to increased sympathetic tone, via the efferent signalling pathways and also in stimulation of increased sympathetic tone, via the afferent signalling pathways. The reduced cardiac output of heart failure increases both renal efferent and afferent nerve discharge. The renal sympathetic supply innervates the renal arteries and veins, the juxtaglomerular apparatus and the renal tubules.
Discharge of norepinephrine from the renal efferent nerves activates the renin-angiotensin system, reducing renal blood flow and leading to increased sodium reabsorption from the proximal tubules and water retention. There is an increase in renal vascular resistance resulting from the relatively greater constriction of the afferent compared to the efferent renal arterioles to the glomeruli, resulting in a decreased glomerular filtration rate.
Meanwhile, increased afferent nerve discharge enhances central sympathetic drive increasing heart rate, arterial tone, and myocardial oxygen consumption. These afferent fibres transmit sensory information from the kidney to the central nervous system [46, 47], largely the brain stem and hypothalamus. The afferent renal sensory nerves are stimulated by hypoxia, renal ischaemia and oxidative stress. Increased afferent sympathetic signalling is likely to lead to a reflex increase in renal sympathetic tone, known as the reno-renal reflex [15].
Cardio-Renal Syndrome
Most patients hospitalised for acute decompensated heart failure have renal impairment [48]. Cardiorenal syndrome describes the complex interaction of the heart and the kidney (Fig. 20.2). The failing heart can cause a previously normally functioning kidney to behave as though it were intrinsically diseased and vice versa. For the failing heart, renal impairment and dysfunction may occur as a result of decreased renal perfusion, but there are a number of neurohormonal, immune and cytokine mediated mechanisms that link the two organs. Treatment of the underlying heart failure in the presence of significant renal impairment is further complicated by the adverse effect of ACE inhibitors on renal function, in particular requiring caution to avoid hyperkalaemia. While sympathetic activity has a deleterious effect on both organs, this is only a small part of the interaction [49].
Fig. 20.2
Complex interaction of the heart and the kidney. The interplay between the two describes the cardiorenal syndrome (Adapted from Ronco et al. [49])
Chemoreceptors: A Further Source of Increased Sympathetic Tone
Sympathetic over-activity in heart failure is also mediated by the baro- and chemo-receptors. The arterial baroreceptor reflexes, which inhibit the sympathetic nervous system, are suppressed, whereas the chemoreceptor reflexes, which increase sympathetic activity, are augmented [12, 50]. As well as modulating overall sympathetic activity, the chemoreceptors are likely to also impact on patient perception of symptoms. Increased chemoreceptor sensitivity to carbon dioxide leads to an increased perception of shortness of breath and sleep disturbances such as periodic breathing [51, 52]. Enhanced chemosensitivity to hypercapnia is an adverse prognostic marker in chronic systolic heart failure and is known to be associated with greater neurohormonal activation [53]. There is therefore a potential role for renal denervation not only in modulation of sympathetic tone but also in resultant reduction in chemoreceptor sensitivity, leading to improvement in shortness of breath.
Evidence for Renal Denervation as a Potential Treatment for Heart Failure
Animal Models
Small animal models of denervation use surgical ligation of the renal nerves rather than radiofrequency energy. Selective division of the dorsal spinal nerve roots prevented hypertension in a rat model of renal failure, demonstrating that afferent nerve fibres were implicated in development of hypertension in chronic renal failure [54]. Conversely, direct renal injury using phenol resulted in an acute increase in renal sympathetic efferent and afferent nerve discharge and an increase in norepinephrine secretion, resulting in hypertension [55] and demonstrating the effect of renal efferent signalling in global increase in sympathetic tone with a corresponding increase in blood pressure.
Rats with heart failure produced by ligation of the left anterior descending artery showed a reduction in sodium retention following surgical renal denervation [56]. Rabbits with pacing-induced heart failure have also allowed assessment of the effects of renal denervation. Those with surgical renal denervation prior to pacing did not exhibit changes in renal vascular resistance or expression of angiotensin II receptors compared to the non-denervated population [57].
Data from the Hypertension Trials of Renal Denervation
Radiofrequency ablation of the renal sympathetic nerves has been shown to lead to a decrease in both renal efferent and afferent outflow in hypertensive patients [46]. If the same holds true in heart failure, reduction in efferent outflow will lead to activation of the renin-angiotensin-aldosterone system, while decrease in the afferent signalling will decrease further positive feedback via the hypothalamus, leading to a decrease in total sympathetic activity. Data from the hypertensive population demonstrated a marked decrease in renal norepinephrine spillover following bilateral percutaneous denervation (47 % reduction at 1 month) and a corresponding 50 % decrease in plasma renin. These results suggest a successful reduction in both renal efferent and afferent activity post denervation [47].
Pilot Data in Chronic Heart Failure
REACH–pilot was an open label study which explored the safety of renal denervation in chronic systolic heart failure [58]. Seven patients in NYHA class III or IV on maximal tolerated medical therapy, including a beta-blocker, ACE inhibitor or angiotensin receptor blocker, and spironolactone underwent bilateral renal denervation. Patients were admitted for 5 days for inpatient monitoring to assess for any change in haemodynamics following the procedure.
All seven patients successfully completed the procedure and all felt symptomatically improved. There was a small but significant increase in the 6 min walk distance (by 27 ± 10 m, Fig. 20.3). No patients had symptomatic hypotension as a result of the procedure and blood pressure remained stable over the 6 month follow up with only a small trend to blood pressure reduction (−7/−0.6 mmHg) immediately post procedure (Fig. 20.4) and a similar, non significant, decrease in heart rate (ΔHR −4 ± 4.6 beats per minute). No patients were re-admitted for heart failure symptoms or complications as a result of the procedure. Renal function remained stable over the 6 month period following the procedure.
Fig. 20.3
Six minute walk distance increased over the 6 months following renal denervation in the REACH pilot study (Reprinted from Davies et al. [58] with permission from Elsevier)
Fig. 20.4
Blood pressure over 6 month follow up following renal denervation in chronic heart failure in the REACH-pilot study (Reprinted from Davies et al. [58] with permission from Elsevier)
Four patients had their loop diuretic stopped following renal denervation due to a reduction in peripheral odema. There was a need to decrease prognostically important heart failure medications (ACE inhibitors and beta blockers) in four (57 %) of the patients, although two other patients had their beta blocker and ACE inhibitor up-titrated over the 6 months following renal denervation.
The OLOMOUC study, presented at the European Society of Cardiology in 2012, compared patients with advanced heart failure (NYHA class III–IV) assigned to either renal denervation or standard medical therapy [59]. The primary endpoint was rehospitalisation at 12 months and change in left ventricular end diastolic dimensions. Of the 26 patients assigned to renal denervation, there was one complication, an arterio-venous fistula in the renal artery, requiring surgical revision. At 12 months, patients assigned to renal denervation showed significant improvement in their ejection fraction (25 ± 12 % rising to 31 ± 14 %, p < 0.001) and improvements in the end diastolic dimensions (LVEDD 68 ± 5 mm increased to 60 ± 7 mm, p < 0.001). There was no evidence of remodelling in the group undergoing standard therapy. The full data are awaiting publication.
The overriding conclusions coming from REACH-pilot and OLOMOUC trials was that renal denervation could be performed safely in patients with systolic heart failure and that theoretical concerns regarding hypotension post procedure were not borne out in practice. Renal function also remained stable in both populations, despite renal impairment at baseline.
While no trials of renal denervation recruiting exclusively heart failure with preserved ejection fraction have yet reported, Brand et al. studied patients with hypertension and left ventricular hypertrophy, demonstrating regression of LVH at 6 months following the procedure [60]. Enrolled patients were hypertensive with an office blood pressure of ≥160 mmHg (≥150 mmHg for type 2 diabetics) or more, despite treatment with at least three antihypertensive drugs including a diuretic. There was a significant reduction in left ventricular mass from 53.9 ± 15.6 g/m2 at baseline to 44.7 ± 14.9 g/m2 at 6 months (p < 0.001). There was also an improvement in diastolic function with reduction in the mitral E wave deceleration time and improvement in the isovolaemic relaxation time. Tissue Doppler imaging parameters also improved, with a statistically significant reduction in lateral E/E′ seen at 1 month and with further improvement at 6 months.
In this study, the percentage of patients with normal LV filling pressures, (an E/E′ ratio ≤8) increased from 39 % at baseline to 68 % at 6 months post renal denervation and the percentage of patients with an E/E′ ratio ≥12, indicating elevated filling pressures, declined from 29 % at baseline to 4 % after 6 months. The left atrial size also significantly reduced in the renal denervation group compared to an increase in the control group.
Ongoing Trials of Renal Denervation in Heart Failure
Further trials are in progress. The Symplicity-HF trial will recruit 40 patients with NYHA class II to III systolic heart failure with an ejection fraction less than 40 %, a glomerular filtration rate of 30–75 ml/min/1.73 m2 and on optimal stable medical therapy [61]. The study is an open label Phase 4 clinical trial of the Symplicity catheter, due to report on the primary endpoint in 2017. The primary end point is safety data as measured by adverse events at 6 month follow up. Secondary measures of change in ventricular function and renal function at 6 months will also be assessed.
The Renal Artery Denervation in Chronic Heart Failure Study (REACH) trial, a double blinded prospective trial of renal denervation (RDN) in chronic systolic heart failure with a sham arm (3:2, treatment : sham), will assess the effect of RDN on symptomatology and exercise capacity [62] in a population of 100 patients with symptomatic systolic heart failure, NYHA class II or higher, with an ejection fraction less than 40 % and on maximal medical therapy. Denervation will also be performed using the Symplicity catheter. The primary endpoint is change in symptomatology at 6 months as assessed using the Kansas City Questionnaire. Secondary endpoints will be change in peak VO2 on cardiopulmonary exercise testing, improvement in 6 min walk test, change in chemoreflex sensitivity and change in NYHA functional classification at 12 months. The trial will report in early 2015.
Trials are also underway in diastolic heart failure. The Denervation of the renal sympathetic nerveS in hearT Failure With nOrmalLv Ejection Fraction (DIASTOLE) underway in Utrechtis will recruit patients with heart failure and preserved ejection fraction and co-existent hypertension into an open label single group assignment safety and efficacy study. Study patients will have signs or symptoms of heart failure with normal or mildly abnormal systolic function, defined as an ejection fraction of 50 % or greater and evidence of left ventricular diastolic dysfunction, hypertension (defined as BP of 140/90 or greater and treated with two or more antihypertensive agents and be clinically stable prior to recruitment. The primary outcome measure is change in E/E′ at 12 months with a secondary safety outcome. The trial will report in December 2014.
The Renal Denervation in Heart Failure With Preserved Ejection Fraction (RDT-PEF) is a randomised open label trial comparing renal denervation to medical therapy in heart failure with preserved ejection fraction. The primary endpoint is a composite of symptoms, change in exercise capacity measured by cardiopulmonary exercise testing, change in B-type natriuretic peptide and measures of left ventricular remodelling, with change in left ventricular mass index and left atrial volume measured by cardiovascular magnetic resonance and diastolic function by echocardiography [63].
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