Current treatment strategies ignore plasma neurohumoral levels, despite their status as independent markers of function and prognosis in cardiac disease, including heart failure, and their utility in guiding therapy. Many large trials have shown that angiotensin-converting enzyme (ACE) inhibitors, P-blockers, and spironolactone all decrease mortality. Further promising treatments are now on the horizon: endothelin antagonists, neutral endopeptidase inhibitors, and cytokine blockers.
One problem is that each of these new treatments further reduces the already low blood pressure in heart failure, to the extent that hypotension may become a limiting factor in treatment. This has led to the concept of individualizing therapy, instead of simply adding each new treatment to the regimen once its efficacy is proven. Thus, instead of giving ACE inhibitors, the cornerstone therapy of heart failure, to every patient, renin levels can be used to select the most likely responders.
Data from the Cooperative North Scandinavian ENalapril SUrvival Study (CONSENSUS)-I and Vasodilator-Heart Failure Trial (V-HeFT)-II suggest that ACE inhibitors only improve mortality in patients with neurohumoral activation. Thus, ACE inhibitors should probably only be given to those with renin-angiotensin-aldosterone system activation, especially following diuretic treatment. Patients without activation may have nothing to gain from ACE inhibition and even much to lose in terms of side effects, while the drugs themselves still cost money. Lim et al found low renin status with a nonactivated renin-angiotensin-aldosterone system despite diuretic treatment in one third of their population of 38 patients in stable heart failure. ACE inhibition did not alter natriuresis in this subgroup. In those with high renin levels following chronic diuretic treatment, on the other hand, ACE inhibition significantly enhanced natriuresis. This study takes us a step closer to the concept of renin profiling in selecting patients for ACE inhibition in chronic heart failure.
Richards et al showed that elevated pretreatment cardiac peptide levels predict benefit from P-blockers, in contrast to elevated plasma norepinephrine. Lower norepinephrine levels may in fact have simply indicated less advanced (or better compensated) heart failure likely to respond to many possible additional treatments. The mechanism underlying the prediction of 13-blocker benefit by raised levels of atrial and brain-type natriuretic peptide (ANP/BNP) is unknown. p-Block-ers elevate plasma ANP levels. This may reflect drug-induced downregulation of natriuretic peptide clearance receptors. It is possible that P-blockers achieve some of their benefit by elevating plasma ANP or BNP levels, thereby causing natriuresis, vasodilatation, and relative suppression of the sympathetic and renin-angiotensin-aldosterone systems.
BNP, in particular its aminoterminal portion (N-BNP), appears the most potent neurohumoral predictor of left ventricular function and prognosis. BNP and N-BNP are secreted mainly in response to left ventricular wall stretch. Their levels reflect left ventricular filling pressures and wall stress. BNP levels fall after treatment with loop diuretics and ACE inhibitors, reflecting lower left ventricular filling pressures. Pilot data have shown that vasodilator therapy can be titrated to lower BNP levels into the normal range. This led Troughton et al to hypothesize that plasma N-BNP-guided drug therapy would outperform empirical trial-based therapy dictated by clinical acumen. Accordingly, they randomized 69 patients with impaired systolic function and symptomatic heart failure to treatment guided by N-BNP levels vs by standardized clinical assessment. Their results showed that circulating N-BNP levels could be lowered by intensified heart failure therapy. Mean plasma N-BNP levels in the N-BNP group declined to well within the target range while remaining stable and above the target range in the clinical group. N-BNP-guided treatment lowered the total number of cardiovascular events vs clinically guided treatment using the same range of therapies. Cardiovascular deaths, admissions, and new episodes of decompensated heart failure were all lower in the N-BNP group, thanks to higher doses of ACE inhibitors, loop diuretics, and spironolactone. These results set the scene for large studies of neurohumoral-guided management incorporating more recent therapies and possibly other agents.
Lim PO, MocFodyen RJ, Struthers AD. Is there a role for renin profiling in selecting chronic heart failure patients for ACE inhibitor treatment? Heart. 2000;83:257-261.
Richards AM, Doughty R, Nkhoils MG, et al. Neurohumoral prediction of benefit from carvedilol in ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group. Circulation. 1999;99:786-792.
Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nkhoils MG, Richards AM. Treatment of heart failure guided by plasma aminoter-minal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000;355:1126-1130.
biochemistry; neurohumoral activation; biological marker; renin; natriuretic peptide; management; ACE-inhibition; fi-blockade