Transplanted and Supported Hearts Keep a Hormonal Memory of Heart Failure, Study Finds

When a failing heart is replaced through transplantation, or its workload is offloaded by a mechanical pump, physicians expect the body’s stress chemistry to calm down. The rationale seems straightforward: heart failure is driven in large part by a runaway neurohormonal response, and if the hemodynamic catastrophe is corrected, that response should switch off. A new prospective study from the Medical University of Vienna, published in Clinical Research in Cardiology, challenges that expectation in a striking way. Even after the circulation has been restored by a donor heart or a left ventricular assist device, the renin-angiotensin system, one of the most powerful hormonal engines of cardiac damage, remains stubbornly active in the large majority of patients, a phenomenon the researchers describe as a hormonal memory of heart failure.

The renin-angiotensin-aldosterone system, or RAAS, is a peptidergic cascade with angiotensin II as its key effector. In healthy physiology it regulates blood pressure and fluid balance. In heart failure, reduced cardiac output, arterial underfilling and direct renal sympathetic stimulation push the system into overdrive, and the consequences are destructive: vasoconstriction, oxidative stress, inflammation, fibrosis of the heart and vasculature, and amplification of sympathetic nervous activity. Blocking this cascade with ACE inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors and mineralocorticoid receptor antagonists is a cornerstone of modern heart failure therapy. Yet guidelines do not routinely recommend these drugs after heart transplantation, and the question of whether the hormonal storm actually resolves once hemodynamics are corrected has remained largely unanswered.

To find out, the Vienna team enrolled patients with end-stage heart failure who were undergoing either heart transplantation or implantation of a left ventricular assist device, or LVAD, into a prospective registry. In total, 49 transplant recipients and 12 LVAD recipients were followed, with blood sampling shortly before and approximately six months after the intervention. The investigators measured NT-proBNP, the widely used marker of cardiac stress, plasma active renin concentration, aldosterone, and crucially the complete profile of circulating angiotensin peptides. Blood was drawn into tubes containing an inhibitor cocktail that instantly freezes angiotensin metabolism, allowing the researchers to capture a faithful snapshot, or fingerprint, of the circulating RAS at the moment of sampling.

The fingerprinting technique itself is a technical tour de force. Plasma samples were spiked with stable isotope-labeled internal standards for ten different angiotensin metabolites, then analyzed by liquid chromatography tandem mass spectrometry after solid-phase extraction. Because renin-dependent generation of angiotensin I is the rate-limiting step of the cascade, and ACE converts angiotensin I into angiotensin II, the relative abundance of downstream peptides such as angiotensin 1-7, angiotensin 1-5, angiotensin III and angiotensin IV reveals both the magnitude of systemic RAS activation and the mode of any pharmacological blockade. The sum of angiotensin I and angiotensin II served as a measure of the angiotensin burden carried by the classical RAS axis.

The results were unambiguous. After heart transplantation, the use of RAS inhibitors dropped significantly, as beta-blocker use fell from 63 to 2 percent and mineralocorticoid antagonist use collapsed from 55 to 8 percent, reflecting the standard de-escalation of heart failure drugs after transplant. In LVAD patients, by contrast, neurohormonal therapy remained broadly comparable before and after implantation, consistent with the strategy of continuing medication to promote reverse remodeling and myocardial recovery. Both interventions produced marked improvements in the visible signs of neurohumoral dysregulation. NT-proBNP fell from a median of 3015 to 1140 pg/mL after transplantation and from 8980 to 1836 pg/mL after LVAD implantation, while active renin concentration declined from 278 to 87 µIU/mL and from 847 to 131 µIU/mL respectively.

But the improvement stopped well short of normal. Not a single patient achieved normal NT-proBNP values after either intervention, and only 24 percent of transplant recipients and 33 percent of LVAD recipients reached normal renin levels. Plasma renin remained elevated in 76 percent of heart transplant patients and 67 percent of LVAD recipients, and in those patients clearly measurable angiotensin II persisted in the circulation. The angiotensin burden of the classical axis fell substantially after transplantation, from a median of 159 to 47 ng/L, and dropped numerically in the LVAD group from 214 to 42 ng/L, but it did not vanish. Aldosterone concentrations, notably, showed no significant change after either procedure. A tight correlation between renin and the combined angiotensin I plus angiotensin II levels, with a Spearman coefficient of 0.87, confirmed that renin remains the rate-limiting driver of the circulating cascade even after hemodynamic rescue.

Why does the hormonal system refuse to reset? The authors suggest a combination of mechanisms. In transplant recipients, persistent natriuretic peptide elevation has been attributed to cardiac denervation, immunosuppressive therapy, ventriculo-vascular uncoupling, endothelial dysfunction and subclinical allograft rejection. Prior studies have shown that natriuretic peptide levels peak within months of transplantation and decline gradually, but rarely normalize even years later; importantly, a late rise in NT-proBNP correlates strongly with allograft rejection, making these biomarkers clinically meaningful rather than mere curiosities. In LVAD patients, the picture is complicated by the devices themselves. Continuous-flow pumps may fail to stimulate arterial baroreceptors the way pulsatile flow does, potentially desensitizing receptors and raising intrinsic sympathetic tone, which in turn drives RAAS activation. Non-pulsatile kidney perfusion may independently activate the system, and preclinical work has linked continuous flow to impaired endothelial function, renal cortical artery hypertrophy and inflammatory infiltration.

The clinical implications are considerable. Ongoing angiotensin II spill-over is not a benign biochemical footnote: the peptide promotes the very processes, remodeling, fibrosis, inflammation and vascular dysfunction, that produce complications such as right ventricular failure in LVAD patients and possibly graft injury in transplant recipients. The study’s findings support a rationale for cardioprotective treatment, particularly with RAS inhibitors, in most patients after both transplantation and LVAD implantation, even though current transplant guidelines do not routinely recommend these agents. The Vienna group cautions, however, that this remains a hypothesis in this population. The impact of RAS inhibition specifically after transplantation and mechanical support should be tested in dedicated studies, and the long-term consequences of such a strategy, including interactions with immunosuppression and renal function, need careful evaluation.

Beyond its immediate therapeutic message, the study offers a conceptual shift. It reframes advanced heart failure not simply as a pumping problem that surgery can fix, but as a systemic neurohormonal disease whose imprint survives the replacement of the organ that caused it. The angiotensin fingerprints captured by mass spectrometry provide a new window into individual RAS regulation, showing exactly how pharmacological blockade reshapes the peptide landscape and where activation persists. For the growing population of patients living with transplanted hearts or mechanical circulatory support, the message is that the endocrine apparatus retains a memory of the failure it once served, and that memory may be a modifiable target for improving long-term outcomes.

Subject of Research: Persistent renin-angiotensin system activation and neurohormonal memory after heart transplantation or LVAD implantation in end-stage heart failure patients

Article Title: Memory of the renin-angiotensin system following heart transplantation or implantation of a left ventricular assist device

Article References: Memory of the renin-angiotensin system following heart transplantation or implantation of a left ventricular assist device. (n.d.). https://doi.org/10.1007/s00392-026-03018-x

Image Credits: AI Generated

DOI: 10.1007/s00392-026-03018-x

Keywords: heart failure, heart transplantation, LVAD, renin-angiotensin system, angiotensin II, NT-proBNP, neurohormonal activation, mass spectrometry, cardiac remodeling, RAS inhibitors, aldosterone, plasma renin