Phenotyping the Heart Failure Syndrome: Towards Individualized Patient Care

Abstract

Despite major advances over the last five decades in the treatment of chronic heart failure with reduced ejection fraction, important challenges still lay ahead. The steadily increasing prevalence of heart failure and the improved survival of patients suffering from it have caused a dramatic rise in hospital admissions, mostly for signs and symptoms of congestion. Novel pharmacological therapies, innovative devices and new treatment strategies are underway and tested in diverse clinical studies, which will undoubtedly provide clinicians with more tools to tackle this problem. However, also with currently available therapeutic options, one can make a difference through better targeting of the right therapy for the right patient. Yet, such individualized care requires a better phenotyping of the heart failure syndrome. In this Ph.D. thesis, the first chapter reinforced uptitration of neurohumoral blockers as an easy, cheap and effective strategy to improve clinical outcome in heart failure patients with reduced ejection fraction after a hospital admission. Moreover, our data suggest that while guideline recommended target doses continue to apply for renin-angiotensin system antagonists, uptitration of beta-blocking agents might be guided better by the resting heart rate response. The second chapter focused on response to CRT, which is certainly the most important advancement in heart failure device therapy. It was demonstrated that patients at advanced age and with multiple comorbid conditions continue to benefit from this life-saving treatment. However, age and comorbidities clearly impact on survival and may influence the decision whether to add a defibrillator function to CRT. Increasing use of CRT and other cardiac devices also provides an opportunity for better cardiac rhythm monitoring. Device-registered episodes of atrial tachyarrhythmia are detected in as much as one third of CRT patients, but our data show that a conservative approach is often warranted provided that the biventricular pacing percentage remains acceptably high. In addition, an intriguing retrospective analysis in this Ph.D. thesis suggests that CRT implantation more early after the diagnosis of heart failure could lead to better clinical outcomes. These results should be replicated in a randomized study design. Finally, DFTC was proposed as an easy measurement of diastolic dyssynchrony with high reproducibility in clinical practice. Short DFTC might help to identify patients without class I CRT indication that are still likely to respond well. Renal dysfunction is frequent in heart failure and associated with worse outcomes. In the third chapter of this Ph.D. thesis, it was demonstrated that kidney dysfunction in decompensated heart failure is often functional, i.e., without major structural damage to the renal tubules. Traditionally, renal function in the context of heart failure is monitored by measurements of serum creatinine that are used to estimate GFR. However, as extracellular volume homeostasis is largely governed by sodium handling in the renal tubules, other biomarkers, which better represent tubular function may be warranted. The urinary electrolyte composition could provide useful information regarding volume status to guide decongestive treatment. Moreover, it was demonstrated that natriuresis corrected for diuretic dose (i.e., diuretic efficacy) is a powerful predictor of clinical outcome in patients hospitalised with decompensated heart failure, even after correction for GFR. Indeed, poor diuretic efficacy is associated with inadequate decongestion and more pronounced neurohumoral activation. The pathophysiology of systemic congestion and its impact on different organ systems is complex and remains insufficiently understood. In this Ph.D. thesis, we developed a rat model to study the effects of abdominal congestion on the kidneys and abdominal organs. In a separate clinical study, invasive hemodynamics at rest and exercise were assessed in patients with decompensated heart failure and pulmonary hypertension, immediately after decongestive therapy. It was shown that exercise hemodynamics allowed better characterization of a patient phenotype responding well to pure afterload-reducing therapy with hydralazine. In contrast, another group of patients needed additional support of nitric oxide donor medication to maintain low PVR and adequate right ventricular function. Finally, it was demonstrated using CMR imaging that episodes of decompensated heart failure are associated with the presence of myocardial oedema. This phenomenon was reversible with effective decongestive treatment and not observed in peripheral muscle. Relief of myocardial oedema demonstrated an excellent correlation with ventricular unloading (i.e., change in pulmonary arterial wedge pressure), but not with changes in body weight or net fluid balance. This highlights the disconnect between volume and pressure in the vascular compartment, although both are often used interchangeable when defining congestion. Finally, to implement the findings from this Ph.D. thesis into clinical practice, efficient care management strategies are needed. The final study of this Ph.D. thesis therefore explored the concept of a modern heart failure clinic in which patients are not bounded by the borders of a ward, but instead transmural disease management is brought towards the patient. Very promising, such an approach was able to bring down heart failure readmissions significantly in patients with advanced heart failure suffering from repeated hospitalisations.