Giovanni Davogustto

Remodeling of Glucose Metabolism Precedes Pressure Overload -Induced Left Ventricular Hypertrophy: Review of a Hypothesis

When subjected to pressure overload, the ventricular myocardium shifts from fatty acids to glucose as its main source for energy provision and frequently increases its mass. Here, we review the evidence in support of the concept that metabolic remodeling, measured as an increased myocardial glucose uptake using dynamic positron emission tomography (PET) with the glucose analogue 2-deoxy-2-[18F]fluoro-D-glucose (FDG), precedes the onset of left ventricular hypertrophy (LVH) and heart failure. Consistent with this, early intervention with propranolol, which attenuates glucose uptake, prevents the maladaptive metabolic response and preserves cardiac function in vivo. We also review ex vivo studies suggesting a link between dysregulated myocardial glucose metabolism, intracellular accumulation of glucose 6-phosphate (G6P) and contractile dysfunction of the heart. G6P levels correlate with activation of mTOR (mechanistic target of rapamycin) and endoplasmic reticulum stress. This sequence of events could be prevented by pretreatment with rapamycin (mTOR inhibition) or metformin (enzyme 5′-AMP-activated protein kinase activation). In conclusion, we propose that metabolic imaging with FDG PET may provide a novel approach to guide the treatment of patients with hypertension-induced LVH.

Acute disseminated encephalomyelitis following seasonal influenza vaccination in an elderly patient

ABSTRACT Although such occurrences are rare, it should be recognized that certain vaccines might trigger serious neurological immune phenomena such as Guillain-Barre syndrome, seizures, cranial neuropathy, and acute disseminated encephalomyelitis (ADEM). Here we report on an elderly woman with ADEM following seasonal influenza vaccination who recovered after plasma exchange.

Noninvasive Detection of Early Metabolic Left Ventricular Remodeling in Systemic Hypertension

Objectives: Hypertension (HTN) is a common cause of left ventricular hypertrophy (LVH). Sustained pressure overload induces a permanent myocardial switch from fatty-acid to glucose metabolism. In this study, we tested the hypothesis that metabolic remodeling, characterized by increased myocardial glucose uptake, precedes structural and functional remodeling in HTN-induced LVH. Methods: We recruited 31 patients: 11 with HTN only, 9 with HTN and LVH and 11 normotensive controls without LVH. Transthoracic echocardiography was performed to assess the function, mass, wall thickness and diastolic function of the left ventricle. Positron emission tomography imaging was performed, and the rate of myocardial 2-deoxy-2-[18F]fluoro-D-glucose uptake, Ki, was determined using a 3-compartment kinetic model. Results: The mean Ki values were significantly higher in HTN patients than in those with HTN and LVH (p < 0.001) and in controls (p = 0.003). The unexpected decrease in Ki with LVH may be secondary to a decreased Ki with diastolic dysfunction (DD), 0.039 ± 0.032 versus 0.072 ± 0.013 (p = 0.004). There was also a significant stepwise decrease in Ki with increasing DD grade (p = 0.04). Conclusion: Glucose metabolic remodeling is detectable in hypertensive patients before the development of LVH. Furthermore, lower glucose uptake rates are observed in patients with DD. The mechanism for this last finding requires further investigation.

Cardiac metabolism in perspective

The heart is a biological pump that converts chemical to mechanical energy. This process of energy conversion is highly regulated to the extent that energy substrate metabolism matches energy use for contraction on a beat-to-beat basis. The biochemistry of cardiac metabolism includes the biochemistry of energy transfer, metabolic regulation, and transcriptional, translational as well as posttranslational control of enzymatic activities. Pathways of energy substrate metabolism in the heart are complex and dynamic, but all of them conform to the First Law of Thermodynamics. The perspectives expand on the overall idea that cardiac metabolism is inextricably linked to both physiology and molecular biology of the heart. The article ends with an outlook on emerging concepts of cardiac metabolism based on new molecular models and new analytical tools.

Methicillin-Resistant Staphylococcus aureus Prostatic Abscess in a Liver Transplant Recipient

Prostatic abscesses are usually related to gram-negative bacilli. However, methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a substantial cause of prostatic abscesses in recent years. Herein, we report the case of a 31-year-old man with a history of orthotopic liver transplantation 10 years ago who presented with acute onset dysuria and abdominal pain and was diagnosed with a MRSA prostatic abscess. To our knowledge, this is the first case describing a prostatic abscess in a liver transplant recipient and the first reporting MRSA as the causative organism of a prostatic abscess in a solid organ transplant recipient.

Oncometabolic Tracks in the Heart

The term cancer and the heart is readily associated with the cardiotoxicity of antineoplastic agents, such as anthracyclines or receptor tyrosine kinase inhibitors. This Viewpoint offers a different perspective, drawing attention to the consequences of metabolic dysregulation in cancers for energy substrate metabolism and contractile function of the heart and to common cellular strategies present in cancers and in the failing heart. On the basis of his observations in proliferating ascites tumor cells, Otto Warburg1 proposed that cancer cells derive their energy from the glycolytic breakdown of glucose even in oxygen-rich conditions. Warburg postulated that this metabolic shift, or oncometabolism, arose from dysfunctional mitochondria, and the inability of cancer cells to carry out oxidative phosphorylation. The term oncometabolism refers to an ensemble of metabolic rearrangements that accompany oncogenesis and tumor progression. Recent advances in cancer cell metabolism research have amended Warburg’s seminal findings by showing, for example, that mitochondrial metabolism in cancer cells is not defective. Today’s system-oriented view is that the metabolism of cancer cells is reprogrammed to optimize the flux of glucose and amino acids into biosynthetic pathways supporting proliferation and cell division.2,3 In the context of cancer, metabolic rearrangements are required to enable tumor growth. Similar to cancer cells, cardiac metabolism is remodeled in response to stress, which allows fluxes of intermediary substrates to meet the challenges of energy demand and macromolecule synthesis. There are several lines of evidence for this hypothesis. First, the failing human heart reverts to the metabolic gene program of the fetal heart,4 which causes a shift from predominately utilization of fatty acids to glucose. Second, when stressed by pressure overload, the heart responds with an increase in glucose metabolism, as shown both ex vivo and in vivo.5 In other words, the metabolic remodeling …

Sudden cardiac death in the soccer field: a retrospective study in young soccer players from 2000 to 2013.

Abstract Soccer is the most popular sport in the world, with over 200 million active players. Sudden cardiac death (SCD) represents the most striking as well as the most common cause of death in the soccer field. Underlying cardiovascular pathologies predispose to life threatening ventricular arrhythmias and SCD in soccer players. Up to thousands to hundred thousands players might have an underlying condition that predisposes them for SCD. After several media striking SCD events in soccer players the Fédération Internationale de Football Association (FIFA) has made screening recommendations that are more thorough than the ones recommended for the American Heart Association and the European Society of Cardiology. We present a retrospective search through Internet databases that resulted in 54 soccer players with SCD events from 2000 until 2013. In this article, we will describe and discuss the conditions of those cases of SCD in order to provide more knowledge of the factors that may precipitate SCD in young soccer players.

Gastrointestinal Stromal Tumor Arising From a Gastric Duplication Cyst.

Gastric duplication cysts (GDC) are rarely diagnosed in adults, but previous cases have been associated with malignancy. We present a case of gastrointestinal stromal tumor (GIST) arising from a GDC in a 71-year-old woman who presented with 3 years of early satiety, anorexia, abdominal distention, and weight loss. Abdominal CT showed a 9.3 x 5.2 x 9.5-cm well-circumscribed cystic mass arising 3 cm above the gastroduodenal junction. The cyst was resected, and histopathology was consistent with GDC. Future studies are needed to clarify the malignant potential of GDC and the molecular pathways for its development.

Sca-1+ cardiac fibroblasts promote development of heart failure

The causative effect of GM‐CSF produced by cardiac fibroblasts to development of heart failure has not been shown. We identified the pathological GM‐CSF‐producing cardiac fibroblast subset and the specific deletion of IL‐17A signaling to these cells attenuated cardiac inflammation and heart failure. We describe here the CD45−CD31−CD29+mEF‐SK4+PDGFRα+Sca‐1+periostin+ (Sca‐1+) cardiac fibroblast subset as the main GM‐CSF producer in both experimental autoimmune myocarditis and myocardial infarction mouse models. Specific ablation of IL‐17A signaling to Sca‐1+periostin+ cardiac fibroblasts (PostnCreIl17rafl/fl) protected mice from post‐infarct heart failure and death. Moreover, PostnCreIl17rafl/fl mice had significantly fewer GM‐CSF‐producing Sca‐1+ cardiac fibroblasts and inflammatory Ly6Chi monocytes in the heart. Sca‐1+ cardiac fibroblasts were not only potent GM‐CSF producers, but also exhibited plasticity and switched their cytokine production profiles depending on local microenvironments. Moreover, we also found GM‐CSF‐positive cardiac fibroblasts in cardiac biopsy samples from heart failure patients of myocarditis or ischemic origin. Thus, this is the first identification of a pathological GM‐CSF‐producing cardiac fibroblast subset in human and mice hearts with myocarditis and ischemic cardiomyopathy. Sca‐1+ cardiac fibroblasts direct the type of immune cells infiltrating the heart during cardiac inflammation and drive the development of heart failure.

Response to: Regarding sudden cardiac death in soccer players

To the Editor, We would like to thank Dr Green and Dr Kim for their kind interest in our article [1], ‘Sudden cardiac death in the soccer field: a retrospective study in young soccer players from 2000 to 2013’ and to bring forth an important issue, such as the use of true denominators in the evaluation of SCD events, that we were able to document after a search of online databases. We would like to respond to their following comments: They mention that the lack of a total denominator prevented us from calculating ‘a true incidence of SCD in this population’. However, the goal of our article was not to assess the incidence of SCD but rather to evaluate the surrounding or associated factors leading to SCD events as a hypothesis-generating approach to understand what triggers SCD at a specific time in athletes who, in most cases, have had an underlying congenital condition throughout their whole life and career [2]. After completing our data gathering, we were able to document less events compared with previous reports [3] published by members of the Fe de ration Internationale de Football Association Medical Assessment and Research Centre (F-MARC), by sending questionnaires to every Fe de ration Internationale de Football Association member association. Therefore, we did not attempt to calculate the incidence knowing that our database has fewer events that those reported by F-MARC, and would result in an underestimation of the problem. Drs Green and Kim make a good point with their observation that the difference in events observed by each player position might be due to the relative percentage of players at each specific position, and we appreciate the time taken to conduct their search. In our discussion, this possibility could have been included as we did while discussing the observed distribution of events according to the athlete’s continent of origin. However, we realized that with their argument, they assume that every player of the squad is at the same risk at all times. This would be true if soccer was a game where all the members of the squad exercise a similar amount of time to the same level, as happens during training sessions. Vigorous physical activity can increase the risk of SCD in susceptible individuals [4] and during matches, only 10 field players – and possibly 3 substitutions – of the whole squad can participate; with this, they would be at greater risk compared with their non-participating teammates. Keeping this in mind, and that in our group almost 2/3 events occurred in players in matches rather than training, we decided to test their hypothesis even further. If the SCD frequency per position is a mere consequence of players distribution, we should not observe a difference of SCD events frequencies per position during matches, a setting in which measurements of covered distance and high-intensity running (we referred to in our article) were assessed [5-7]. To this end, we decided to study the characteristics of those who collapsed during a match setting in the group we previously reported. We included those patients who collapsed during a match for whom their position was available (numerator). Events that occurred during training or more than 1 hour after physical activity were excluded. Goalkeepers were excluded from computation as no events were observed in this position