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Prof. Danilo Neglia
In a Congress dedicated to Heart Failure, it was very appropriate to draw the attention of participants to heart metabolism. Until very recently, this was a somewhat neglected issue by clinical cardiologists - firstly because it is difficult to assess in man and secondly, because specific and effective treatment strategies targeted to modulating heart metabolism are not yet clinically established. However, as the participation in this symposium indeed demonstrated, the evolution of clinical imaging techniques able to reliably assess myocardial metabolic pathways and the increasing knowledge of new potential treatment targets has renewed clinicians’ interest.
As basic scientists have known for many years, heart metabolism is the key to understanding the mechanisms that lead to the development of heart failure. However, they could surely not predict that one day, tools able to quantitatively measure heart metabolism in man would be available. Surely this was the case of Prof. George Radda when 30 years ago he published his first paper on “Phosphorus NMR studies on perfused heart” demonstrating that high energy phosphate compounds in the beating heart could be quantified by MR spectroscopy. The path from the perfused mouse heart to the investigation of the human heart has been completed in these 30 years. But investigating animal models is still essential to understand the role of myocardial metabolism. George Radda underlined the relevance of experimental studies in insuline resistance (IR) models. IR is a key factor able to alter myocardial metabolism and to render the myocardium more vulnerable to ischemia. This is a concept of great clinical relevance if one considers the high prevalence of diabetes and IR in HF patients. Prof. Radda showed data demonstrating that in insulin resistance states, the increased concentration of circulating FFA drives myocardial changes consisting in downregulation of GLUT4 receptors and upregulation of fatty acid oxidation (FAO) enzymatic chain through PPAR-alfa stimulation. These modifications ultimately lead to decreased glucose and increased FFA utilization by the myocardium. Such a metabolic condition is unfavourable, since FFA is a less efficient substrate than glucose to be utilized and this causes a higher susceptibility of the myocardium to the ischemic insult.
It must be remarked that even if IR and heart failure are often associated, myocardial metabolic changes in dysfunctioning myocardium are not superimposable with those described in IR states. Prof. Lionel Opie from Cape Town (South Africa), a recognized “father” of studies in heart metabolism, pointed out that IR may cause LV dysfunction but may also be the result of HF in a sort of “vicious circle”. In particular, activation of the sympathethic system increases lipolysis and circulating FFA concentrations and these will drive at the myocardial level FAO pathways over glucose utilization pathways. According to this paradigm, one would expect to find increased FFA uptake and utilization in patients with HF associated with reduced myocardial efficiency. Moreover, according to the “glucose is better than FFA” paradigm, acutely decreasing circulating FFA availability should decrease lipid metabolism, increase myocardial glucose metabolism, function and efficiency. These hypotheses were tested in very recent and elegant clinical studies performed by Dr. Tuunanen and Prof. Knuuti in Turku (Finland) using Positron Emission Tomography (PET). They evaluated patients with idiopathic dilated cardiomyopathy (IDCM) and control subjects by a complex PET protocol which allowed measurement of myocardial oxidative metabolism by 11C-acetate, myocardial FFA uptake and betaoxidation rate by [18F]FTHA or [11C]palmitate. IDCM patients actually demonstrated reduced FFA uptake, which was associated with reduced FFA oxidation rate if IR was present. This observation is not in agreement with experimental data previously reported in IR states, but is in line with multiple clinical and large animal experimental studies showing increased myocardial glucose metabolism in IDCM. Accordingly, something other than circulating FFA availability modifies heart metabolism in these patients. This view is reinforced by the unexpected finding that acute reduction of circulating FFA by acipimox administration, caused in IDCM patients a decrease in FFA uptake but an increase in FFA oxidation rate and further deterioration of myocardial efficiency. These observations led the researchers and Prof. Opie to the conclusion that the failing heart is dependent on every substrate available since it exhausted metabolic reserve. This is a very relevant concept that recently came out and has potential implications for evolution of metabolic treatment. Clearly more studies are needed to understand which metabolic modulation will have a clinical impact in patients with HF.
For sure, the availability of PET is a very important tool for the evaluation of heart metabolism in the clinical setting and for monitoring the effects of metabolic treatment. Prof. Henrich Schelbert from UCLA, Los Angeles, has pioneered the use of PET in cardiology and presented the most recent data on the use of this tool to understand the relationships between myocardial perfusion and function. As far as myocardial metabolic changes are concerned, dysfunctioning myocardium in ischemic patients shows a very consistent pattern at PET examination characterized by increased or preserved uptake of glucose in the presence of reduced resting flow and reduced flow reserve (“mismatch pattern”). The unique capability of PET to quantitatively and non-invasively assess myocardial blood flow and metabolism also makes it possible to explore very early stages of heart disease. A striking finding reported by Prof. Schelbert was that flow-metabolic mismatch is not a “black or white” phenomenon occurring in advanced coronary disease when a subocclusive coronary stenosis reduces flow and this causes an increase in glucose utilization. On the contrary, there exists a continuous spectrum of flow-metabolism-function interactions. As flow and flow reserve are progressively impaired, a parallel progressive shift of myocardial metabolism towards more glucose utilization is observed. Whether this is due to chronic reduction of myocardial blood flow (hibernation) or repetitive episodes of myocardial ischemia (repetitive stunning) is an open question. In any case, this observation underlines the strict relationship that exists between abnormal myocardial perfusion and myocardial metabolism, with oxygen availability being one of the major determinants of myocardial substrate utilization. Since myocardial blood flow can be impaired also in the absence of obstructive coronary stenosis (in another symposium Prof. Schelbert reported evidence of reduction of coronary flow reserve due to endothelial dysfunction) perfusion-metabolism mismatch can be an early mechanism in heart disease.
The most surprising and newest tool for the clinical study of heart metabolism was presented by Dr. Juerg Schwitter from Zurich, Switzerland. It consists in the utilization of hyperpolarized C11 compounds as metabolic tracers in conjunction with MRI imaging. This is potentially the most innovative evolution of in vivo MR spectroscopy. This application is based on the fact that hyperpolarized molecules are able to produce images with a very high signal to noise ratio in an incredibly short time. Dr. Schwitter very efficaciously explained that to obtain an image similar to that obtained by use of hyperpolarized compounds would need an acquisition lasting for more than 3000 years with conventional MRI. The scale of this improvement sounds really incredible. At present, preliminary experience is being accumulated by the use of hyperpolarized C11-pyruvate. This approach could allow a comprehensive evaluation of organ perfusion and metabolism. As far as myocardial metabolism is concerned, the most relevant possibility is to obtain, in the first 2 minutes after tracer injection, different heart images corresponding to different spectral windows that follow incorporation of C11 in different metabolites. So you would obtain the original “pyruvate” image, the “lactate” image, the “alanine” image and the “bicarbonate” image related to tissue pH, and all this in real time. One could easily imagine which research or clinical application could possibly be developed in this direction. Of course, many technical problems must still be solved but the enthusiastic presentation of Dr. Schwitter promises very interesting developments.
In conclusion it is my impression that, according to the title, this symposium really demonstrated how the assessment of heart metabolism is a key to understanding heart disease. The availability of very advanced imaging tools to study cardiac metabolism in men will surely promote further research in this field and will help to identify innovative treatments in heart failure specifically targeted to modulation of myocardial metabolism.
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