Quantification of pH in the human myocardium by 7T 31P MRS

Disorders of the cardiovascular system are the most frequent cause of morbidity and mortality in the European population. Diseases are accompanied by alterations in myocardial energy metabolism and changes to the myocardial acid-base equilibrium, expressed by the pH value. This is a very sensitive marker of tissue health and disease progression, to date, no reliable method for its detection in the heart exists. pH can be derived from 31P magnetic resonance spectra (MRS), acquired using specially equipped magnetic resonance imaging (MRI) scanners. In particular, the resonance frequency of inorganic phosphate (Pi) is pH-dependent in a predictable way. This is a standard procedure in tissues like skeletal muscle or the brain. In the heart, the relevant signal from Pi is obscured by diphospho-glycerate (DPG) found in blood. The spatial and spectral resolutions of in vivo MRS is not good enough to unambiguously distinguish DPG and Pi signals. In this project, methods to suppress the DPG signal are investigated. The goal is to develop a reliable method for pH detection in the myocardium in patients and healthy subjects. The primary approach is to use the fact that a large fraction of the blood pool in ventricles is ejected every cardiac cycle. It is possible to tag spins and wait with the detection for one or two cardiac cycles. Only spins that are still in the volume of interest contribute to the signal, which thus is very sensitive to motion. Techniques based on this principle are used routinely in perfusion MRI, angiography or dark blood MRI. In this project, several of these techniques will be investigated to suppress DPG while retaining the signal of cardiac Pi. An additional challenge is the low concentration of Pi and therefore its weak signal. The last reported only partially successful attempts to measure Pi date back at least two decades. Fortunately, recent developments in magnet technology allowed for stronger fields (7 T), which are available at the Oxford and Vienna MR centres, and better probes (arrays of antennae). In combination, an increase in signal to noise ratio by approximately a factor 10 compared to systems used in earlier reports can be expected. The combined expertise of the applicant and the hosting institution are essential and well suited to the success of this endeavour. The combination of improved hardware and new measurement approaches will result in a measurement protocol that can reliably be used to quantify myocardial pH non- invasively in healthy and diseased humans. The settings at both the Oxford and Vienna MR centres allow for rapid translation of the basic technical developments to clinical applications. In the long run, the techniques developed within this project will result in significant improvements to cardiovascular research and the European population and healthcare systems.

Disorders of the cardiovascular system are the most frequent cause of morbidity and mortality in the European population. Diseases are accompanied by alterations in myocardial energy metabolism and changes to the myocardial acid-base equilibrium, expressed by the pH value. In this project we developed techniques to obtain myocardial pH and new markers of cardiac energy metabolism by means of phosphorus magnetic resonance spectroscopy (31P RMS). The pH value can be derived from inorganic phosphate (Pi) 31P MRS signal, acquired using specially equipped magnetic resonance imaging (MRI) scanners. This is a standard procedure in tissues like skeletal muscle or the brain. In the heart, the relevant signal from Pi is obscured by diphosphoglycerate (DPG) found in blood. The spatial and spectral resolutions of in vivo MRS is not good enough to unambiguously distinguish DPG and Pi signals using traditional acquisition techniques. In this project, methods to suppress the DPG signal were developed. A reliable method for Pi detection and pH quantification in the myocardium was found using the stimulated echo acquisition method (STEAM) which is known to generate dark blood contrast in magnetic resonance imaging. We were able to quantify Pi and pH both in healthy subjects and patients. An additional challenge is the low concentration of Pi and therefore its weak signal. The last reported only partially successful attempts to measure Pi in the human myocardium date back at least two decades. Fortunately, recent developments in magnet technology allowed for stronger fields (7 T), which are available at the Oxford and Vienna MR centres, and better probes (arrays of antennae). In combination, signal-to-noise ratio has increased considerably over the last twenty years. The combined expertise of the applicant and hosts were essential for the development of new acquisition techniques which resulted in a measurement protocol that has been used to reliably quantify myocardial Pi and pH non-invasively in both healthy volunteers and patients with diabetes mellitus or dilated cardiomyopathy. Our measurements were not only performed at rest but also during dobutamine infusion. This is an otherwise routinely performed cardiac stress test which we report for the first time being used within a 7 T scanner. The data obtained so far shows that the Pi and pH values add new sensitive markers of the pathophysiology in cardiovascular diseases. The settings at both the Oxford and Vienna MR centres allow for rapid translation of the developed procedures and findings to clinical research applications. The knowledge gained within this project will result in significant improvements to cardiovascular research and, in the long run, the European population and healthcare systems.