Using multi-parametric imaging and multi-nuclear cardiac magnetic resonance to investigate novel treatment strategies for heart failure

Heart failure (HF) remains the leading cause for hospitalisation in patients over the age of 65 years in industrialised nations. Furthermore, prognosis of HF remains poor and lags behind the improvements observed for similar chronic conditions like cancer, despite efforts for new therapies. However, these therapies are mostly available for patients with HF and a reduced ejection fraction (HFrEF), whereas prognostically relevant therapies for patients with HF and a preserved ejection fraction (HFpEF) have been absent for more than 20 years and this only changed very recently with the results of the EMPEROR-preserved trial investigating treatment with empagliflozin (10 mg once daily) in patients with HFpEF. Equally, a significant improvement of quality of life and physical limitations has been shown for patients with HFpEF following treatment with dapagliflozin in PRESERVED-HF.
An increasing amount of evidence describes more subtypes of the complex and rather arbitrarily classified syndrome of HF and thus, there is a growing need for comprehensive, non-invasive imaging techniques to identify and individually phenotype patients affected. Furthermore, the same approach could be used to assess novel treatments as well as identify treatment responders, further tailoring individual patient management and aid efforts to improving prognosis. Additionally, use of a model imaging technique may lower the exponential costs of drug development by reducing the numbers of subjects needing to be enrolled and increasing reproducibility of findings.
Cardiovascular magnetic resonance (CMR) fulfils many of the demands for a model imaging technique in the context of HF-phenotyping and -drug development. Firstly, CMR is the gold standard method to assess cardiac structure and function. More importantly, it allows examination of imaging and metabolic parameters alike and, with novel techniques like dynamic nuclear polarisation (i.e. hyperpolarized MR spectroscopy), even direct assessments of molecular cellular pathways. Thirdly, HF is a syndrome affecting multiple organ systems and thus, has complex and incompletely understood links in need of exploration. MR offers the possibility of multi-organ assessment in the same session and therefore, is perfectly placed to gather information on the biological interplay in HF.
The underlying mechanism for the observed benefits of sodium glucose like transporter 2 inhibitors (SGLT2i) like empagliflozin in HFrEF are not yet understood. One of the leading hypotheses brought forward was that SGLT2i may induce changes in myocardial substrate selection via increased availability of ketone bodies which may serve as an additional energy source for the failing heart. Thus, I sought to investigate whether empagliflozin treatment (10mg per day) would enhance myocardial energetics in patients with HFrEF (phosphocreatine to adenosine triphosphate ratio, PCr/ATP). In this randomised controlled trial (RCT), patients did not improve measures of resting or dobutamine stress myocardial energetics (Chapter 3) and empagliflozin treatment neither altered a panel of 19 serum metabolites assessed by targeted metabolomic analysis. However, there were interesting changes to the amount of triglycerides stored in the heart, myocardial cell volume and hypertrophy as well as markers of fibrosis and quality of life (QoL). This exemplifies the usefulness of CMR in the interrogation of novel treatments and likewise emphasises that the broad range of indications for SGLT2i (diabetes, chronic kidney disease, heart failure) is possibly mirrored by a multi-organ rather than a single cardio-specific effect in patients with HFrEF.
As it was unclear until very recently if patients with HFpEF would equally benefit from treatment with SGLT2i, I further integrated a HFpEF cohort into the RCT and investigated the identical variety of parameters as for the HFrEF patients (Chapter 4). Similarly to the findings in the HFrEF cohort (Chapter 3), I could not observe any changes to myocardial energetics (resting PCr/ATP as primary endpoint) or whole-body substrate usage (targeted metabolomics). Interestingly, I detected certain similarities nevertheless as myocardial triglycerides reduced in the treatment arm but not in the placebo group. Furthermore, systolic function (peak circumferential and radial strain) and measures of pulmonary function improved. This was also paralleled by a numerically improved walking distance in the six-minute walk test (6MWT) and increased QoL (assessed by the Kansas City Cardiomyopathy Questionnaire; KCCQ). The present results reinforce the need for mechanistic experiments in human subjects in-vivo, as they highlight the disparity of results from animal models that previously showed a metabolic effect following treatment with SGLT2i. Furthermore, more research is needed into effects of drugs in different HFpEF subtypes (e.g. diabetic, obese) to improve risk stratification and adequate treatment.
To explore novel, non-pharmacological treatments targeting unique subgroups under the ‘HFpEF-umbrella’, I aimed to explore whether a lifestyle intervention of weight loss is an effective treatment for patients with obesity and HFpEF (Chapter 5). Accordingly, I enrolled patients with a clinical diagnosis of HFpEF and observed cardio-metabolic effects following 10 weeks of a very low energy diet (VLED). Assessments included exercise CMR and dobutamine stress phosphorus magnetic resonance spectroscopy (31P-MRS). While cardiac energetics at rest or during dobutamine stress did not change, prognostic serum markers (n-terminal pro-BNP; NT-proBNP) and symptom burden (New York Heart Association; NYHA) improved significantly and cardiac structure (LV-mass) as well as function (diastolic function on echo and RV function at rest and during exercise) ameliorated. The results emphasise that lifestyle treatments in select patient groups are underutilised yet cost-efficient, safe and successful. Furthermore, the obesity paradox (describing the observation that mild obesity appears to be protective in HF) may not equally apply to the group of severely obese HFpEF patients (BMI>30 kg/m2) and thus, this should be investigated in larger trials.
Finally, I was interested to examine the feasibility of CMR in the context of early (phase IIa) cardio-metabolic drug development. In Chapter 6, I enrolled 22 patients with type 2 diabetes (T2D) but no underlying HF and investigated the effects of ninerafaxstat, a novel drug intended to enhance myocardial substrate metabolism via restoring metabolic flexibility in the heart. Here I show that the drug’s proposed mechanism of action can indeed be successfully investigated by using [1-13C]pyruvate hyperpolarized MRS. The pyruvate dehydrogenase (PDH) flux was improved in the majority of subjects (7/9). Furthermore, this resulted in significantly improved PCr/ATP and reduced myocardial steatosis. Diastolic function and early LV-filling also improved following drug treatment for 4 or 8 weeks. Based on these results, hyperpolarized MRS is a suitable tool to investigate the mechanism of action in early drug development in humans with reduced sample sizes. The broader implication is certainly that, similar to treatments for immune modulation (e.g. canakimumab), patient selection is key for metabolic assessments in clinical trials.
To summarise, this Thesis examines cardio-metabolic effects of different pharmacological and lifestyle treatments in distinct populations and further demonstrates the suitability of CMR as an investigational tool for drug development. While the results underpin the importance of substrate selection and implications on cardiac structure and function, improved patient selection is key for demonstrating these effects with statistical significance. Furthermore, refuting the ‘fuel hypothesis’ theory as the main contributor to SGLT2i’s mode of action, I provide evidence for multi-organ effects of SGLT2i being likely responsible for the benefits observed in HF. Secondly, I add to the existing evidence that intentional weight loss is a safe and effective treatment in obese HFpEF patients.

Keywords: SGLT2i
heart failure
randomised controlled trial
ketones
cardiac energy metabolism
CMR
Advisor: Neubauer, S
Mahmod, M
Valkovic, L