In the below I will be referencing and discussing quotes from the paper “Fatty acid metabolism in pulmonary arterial hypertension: role in right ventricular dysfunction and hypertrophy” by M. Talati. Basically, I’m distilling the key points that I’ve learned, summarizing them, and including any thoughts I may have.

Overall it appears that the running thread through this paper is the following: Can metabolic syndrome or insulin resistance in PH cause RV dysfunction? Or is the dysfunction a result of PH? In sum, there is a dysregulation in fatty acid oxidation and glucose oxidation, with increased intracellular lipid accumulation, and an overall switch to glycolysis in the heart. Although teasing out whether or not this is a cause or consequence is still not apparent from the article. Most of the evidence in the article comes from animal models, with only a few human RV’s were analyzed, and these were post-mortem.

Some terms:

RV = Right Ventricle, LV = Left Ventricle
FAO = Fatty Acid Oxidation
GO = Glucose Oxidation
PH = Pulmonary Hypertension, PAH = Pulmonary Arterial Hypertension
PVR = Pulmonary Vascular Resistance

  • For context, in PAH, the RV hypertrophies in response to an increase in afterload due to elevated pulmonary vascular resistance and pressure. This is the initial response of the RV to increased afterload. It includes an elevation of protein synthesis and cardiomyocyte size due to an increase in the amount of sarcomeres, to compensate for increased pressure. With chronic sustained afterload, however, the RV transitions from hypertrophy to thinning and dilation, and eventually dysfunction.
  • This “pathological RV remodeling in PAH can be reversed with lung transplantation or with pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension (CTEPH).” If this is the case, then this gives weight to evidence to the hypothesis by NF Voelkel that the sick lung circulation in Pulmonary Hypertension affects the RV: once the “sick” lung is replaced, then there is no longer pathological signaling to the heart, which is the next organ immediately after the lungs. Just for reference, the “sick lung circulation” hypothesis is a hypothesis that implies that the circulation from the lung, including all of the metabolites and signaling molecules from the lung vasculature, arriving at the heart (specifically the microcirculation of the heart, or the coronary vessels) affects the heart. Of course, however, this RV reverse remodeling mentioned above could also be due to decreased pulmonary artery pressures since the lung has been replaced and thus there is no longer any increased pulmonary vascular resistance.  
  • “In PAH, RV ejection fraction (RVEF) is a better predictor of the long-term outcome of a disease than PVR.” This makes sense since heart failure is the major cause of mortality in PAH, and one sign of heart failure is a reduction in the functional ability of the heart, of which RVEF is one determining factor of this.
  • “RV dysfunction can progress in PAH patients despite a decrease in PVR.” This adds weight to sick lung circulation hypothesis, as well as to the previous bullet of RVEF being a better predictor of long-term outcome in PAH compared to PVR.
  • The heart is versatile in its ability to derive energy from various sources. Since it has to continuously operate, this makes sense; it needs to operate no matter what substrates are present. Typically the human heart has a metabolic pattern similar to oxidative slow twitch muscle fibers, which includes a primary reliance on utilization of fatty acid oxidation and glucose oxidation: “The adult healthy heart is an organ with very high energy utilization rates, which is derived from various oxidizable energy sources like fatty acids, glucose, lactate, ketones, and amino acids. The normal heart adapts to changes in the environment and subsequent nutrient delivery by switching from one substrate to another. In its basal metabolic state, free fatty acid is the predominant source of energy production (60%– 90%), and carbohydrates (e.g., glucose) are secondary sources. Mitochondrial metabolism can use either carbohydrates (after glycolysis) or fatty acids to generate adenosine triphosphate (ATP).”
  • Metabolic syndrome, which “is a cluster of metabolic risk factors defined by dyslipidemia, systemic hypertension, elevated fasting glucose level, and central obesity”, is implicated in PH. To my knowledge though, PH patients have dyslipidemia and and hyperglycemia but not systemic hypertension, and there are PH patients that are both obese and not obese. However, another feature of metabolic syndrome is insulin resistance, and insulin resistance, as well as “hyperglycemia, and dyslipidemia have been reported in human PAH and appear to portend a worse prognosis.”
  • “Metabolic syndrome may affect RV compensatory capacity or may even underlie RV failure in PAH. There is a large amount of evidence demonstrating the impact that metabolic syndrome has on the structure and function of the LV. All of the metabolic syndrome criteria significantly affect LV dysfunction. LV diameters proportionally increase with increasing severity of metabolic syndrome. LV hypertrophy increases progressively as the number of metabolic syndrome risk factors increases. Systolic and diastolic blood pressure and waist circumference are associated with LV hypertrophy.” Even though the LV and RV are different functionally and morphologically, they are still part of one organ, the heart. Thus, she is suggesting that factors (metabolic syndrome in this case) that affect the LV may also affect the RV. And from this quote further along in the paper, it appears that she may be correcting in inferring this: “Among metabolic syndrome criteria, systolic blood pressure, waist circumference, hyperlipidemia, and glucose level are also shown to be independently associated with RV structure and function. Specific to the RV, there may be impaired RV function in metabolic syndrome patients with preserved LV ejection fraction. We have recently presented data from the MESA-RV cohort showing that in otherwise healthy humans insulin resistance may affect RV structure and function as measured by cardiac magnetic resonance. Specifically, insulin resistance was associated with reduced RV mass and ejection fraction.” She also has evidence of this from animal model experiments: “Recent work by our group and others in both animal models of PAH and human disease suggested that in PAH insulin resistance (1) can be measured systemically, (2) worsens pulmonary vascular disease in animal models, and (3) may affect RV function.”
  • “Direct measurement of RV glucose uptake has also been implemented in PAH. In idiopathic PAH patients, myocardial glucose uptake is increased and correlates with mean pulmonary arterial pressure, presumably indicating the presence of RV functional impairment with a shift from fatty acid utilization to myocardial glucose utilization.” While it is true that not all patients probably have insulin resistance, my question here is that, for the ones that do have insulin resistance, doesn’t insulin resistance result in a decrease in the ability of cells to import glucose (through downregulation of glucose transporters)? If this is the case, then why would there be an increase in glucose uptake? It is known that the glucose uptake is preferentially shunted to the glycolysis pathway, as opposed to glucose oxidation: “Recently, Lundgrin et al. suggested that PAH hearts have a pathological glycolytic metabolism as indirectly measured by increased 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake in the RV that quantitatively relates to cardiac dysfunction over time; furthermore, FDG uptake in the RV also correlates with circulating CD34+ CD133+ cells.”
  • There are conflicting results regarding cardiomyocyte metabolism in animal models of RV hypertrophy: “Using pulmonary arterial banding (PAB), a model of compensatory RV hypertrophy, Takayama et al. have shown in Wistar rats that chronic pulmonary arterial constriction causes an increase in RV myocardial glucose uptake but not in fatty acid uptake, whereas acute pulmonary arterial constriction causes an increase in fatty acid uptake in free walls of the RV. In contrast, in Sprague-Dawley rats, another model of chronic PAB induced RV hypertrophy, Fang et al. demonstrated that an increase in FAO is associated with reductions in cardiac output and exercise tolerance.” Perhaps this is because Fatty Acid Oxidation (FAO) and Glucose Oxidation are slower processes than glycolysis? But is this an accurate comparison? 
  • “In a recent study in rats with RV dysfunction, modeled by the administration of the vascular endothelial growth factor inhibitor Sugen with hypoxia, a gene expression profile showed impairment of fatty acid metabolism and mitochondrial dysfunction, which was partially independent of chronic pressure overload. Similarly, we have shown by gene expression analysis of human RVs that there is at least a twofold differential regulation of metabolic pathway genes in heritable PAH compared with controls. Our data suggest suppression of the tricarboxylic acid (TCA) cycle, an increase in glycolysis, and a decrease in derivation of energy from lipid oxidation.” My emphasis (in bold) was added. The reason being that if RV mitochondrial dysfunction is independent of chronic pressure overload, then this also gives weight to the “sick lung circulation” hypothesis. For reference, the Sugen hypoxia model is the administration of a VEGF inhibitor + hypoxia in an animal. How this creates PH: when there is an insult to an endothelial cell in the lung by hypoxia/low oxygen conditions, and VEGF, a natural growth factor in the bloodstream, is inhibited in the lung, what occurs is apoptosis of the affected cell, and a corresponding growth of new endothelial cells in the lung with a new phenotype of “excessive and dysregulated growth”.
  • “Recently, we have shown that in heritable PAH impaired RV hypertrophy is associated with RV lipotoxicity, as demonstrated by increased lipid deposition in RV cardiomyocytes.” It is important to note here that these cardiomyocytes were not taken from living humans, but from autopsied patients.
  • “In uncomplicated type 2 diabetes mellitus, high myocardial triglyceride content strongly correlates with RV systolic and diastolic dysfunction. In hearts from fatty Zucker rats, triglyceride droplets are clearly visible close to mitochondria within myocardial cells. In light of reduced mitochondrial use of lipids with at least normal cellular fatty acid uptake, one might hypothesize that lipid intermediaries would be increased in the cytoplasm and lead to a ‘lipotoxic cardiomyopathy’.”
  • “In a mouse model universally expressing a mutant form of bone morphogenic protein receptor type 2 (BMPR2), which underlies most forms of human heritable PAH, we have shown increased lipid content, especially triglycerides and ceramides, in RV tissue compared with control littermates. However, no study has quantified levels of lipid intermediates in the living human RV.” My emphasis added. This is probably the most important quote of the whole paper, given the massive discrepancies between animal and human PH forms. We really need to be able to quantify lipid intermediates in human RV’s.
  • “Our recent findings in our mutant BMPR2 mouse model of PAH demonstrate an increase in the expression of CD36 protein in the mouse RV, which may lead to increased uptake of fatty acids. Similarly, in a model of LV failure, RV hypertrophy is associated with an increase in CD36 gene expression.” Given that LV failure is more frequent than RV failure, and that LV failure can induce RV hypertrophy due to increased afterload, why haven’t we studied the RV’s in LV heart failure patients to get a better idea of the PH remodeled RV?
  • “A permanent relocation of CD36 to the sarcolemma can increase cardiac fatty acid uptake and induce cardiac hypertrophy and contractile dysfunction. However, it is important to remember that the reduced RV function is associated with an increase in the expression of several genes that regulate fatty acid metabolism, especially those regulating fatty acid uptake and intracellular transport. These include CD36, peroxisome proliferator–activated receptor (PPAR) α, and PPARγ coactivator 1α. However, not all increases in CD36 expression are pathological; for example, exercise-induced cardiac hypertrophy does not lead to cardiac failure.” My emphasis added.
  • “The energetics of myocardium is affected by the myocardial substrate provided. In cardiomyocytes, FAO is the major source of ATP production and oxygen consumption (60%–90%), whereas glucose metabolism (glycolysis and GO) is considered a secondary source (10%–40%) of energy production. That said, it is known that the external power of the LV is higher for a given myocardial oxygen consumption when the myocardium has a low rate of fatty acid β-oxidation relative to glucose and lactate oxidation.”
  • “Increasing GO and inhibiting FAO may be beneficial because FAO uses 12% more oxygen than GO to generate a given amount of ATP; this may be at least in part due to capillary rarefaction in RV failure with resultant ischemia.” Perhaps though it may not be such a good idea, especially if the heart is glycolytic for a reason: for example, if it is switching to glycolysis to compensate for the higher pulmonary pressures, because glycolysis provides a faster means of energy albeit not as much as FAO or GO. Also, the last part of that sentence, after the semicolon, I don’t quite understand. Any thoughts anyone may have, feel free to leave in the comments!
  • PPAR alpha upregulates import of free form fatty acids into cardiomyocytes, and upregulates formation of lipid droplets, triacylglycerol, and ceramides in cardiomyocyte. PPAR delta upregulates mitochondrial beta-oxidation and decreases cellular lipid droplets, triacylglycerol, and ceramides. This perhaps suggests that targeting increased PPARdelta and decreased PPARalpha may be beneficial for myocardium in PH.
  • “In PAH, increased delivery of fatty acids could affect FAO rates and thus alter compensatory RV hypertrophy and/or promote RV dysfunction.” This is technically correct, but it only implies an increase in the rate of FAO, because utilization is typically proportional to delivery, according to this quote by Keith Frayn in Metabolic Regulation: “The overall rate of utilization of non-esterified fatty acids from the plasma depends almost entirely on their plasma concentration: the higher the concentration of non-esterified fatty acids, the higher their rate of utilization.”
  • Gene expression analysis of PAH patient and control RV from autopsied subjects showed that there was suppression of TCA cycle and fatty acid oxidation and increased glycolysis. This same metabolic signature was also noticed via metabolomic analysis of pulmonary artery endothelial cells in the lung microvasculature. She also mentioned later in the article that via metabolomic analysis, an increase in medium and long chain acyl carnitines were observed in the peripheral blood of PAH patients. Acyl carnitines are the form of fatty acid needed to be transported into the mitochondria. This suggests that there is an overload in their production compared to utilization. Perhaps there is something wrong with the transport mechanism to bring these into the mitochondria? Or perhaps because the fatty acid oxidation pathway is down-regulated, they are not being utilized? If the fatty acid oxidation pathway was downregulated, however, one might suspect that the mechanism of transport into the cell in the first place would be downregulated.
  • “Another important molecule in the mitochondrial metabolism of cardiomyocytes is PPARδ. PPARδ is the predominant subtype in the heart, where it plays an important role in cardiac metabolism by regulating the expression of genes involved in fatty acid and glucose utilization. In mice, cardiomyocyte-restricted deletion of the PPARδ gene results in decreased myocardial FAO, increased myocardial lipid accumulation, and dilated cardiomyopathy. In neonatal cardiomyocytes, phenylephrine-induced hypertrophy is accompanied by a reduction in the expression of the genes for M-CPT1 and PDK4 (involved in fatty acid metabolism and activation of nuclear factor κB), which can be abolished by activators of PPARδ, but it is not studied specifically in RV.”
  • “In PAH, aerobic glycolysis, or a shift from GO to glycolysis in the presence of adequate oxygen, is known to occur in pulmonary vascular cells and hypertrophied RV myocytes. Aerobic glycolysis is also known as the Warburg effect and induces glutaminolysis.”
  • “The increased sarcolemmal CD36 abundance, together with an increased plasma fatty acid concentration, demonstrates an increased rate of fatty acid uptake. Without a concomitant substantial increase in the mitochondrial FAO rate, this can lead to excess production of long-chain acyl-CoA in the cytoplasm, which can be converted into a number of complex intracellular lipid intermediates (like esterification into triacylglycerols [TAG]), and to increased concentrations of fatty acid metabolites, such as diacylglycerols (DAG) and ceramides. The conversion of fatty acids into complex lipids such as TAG, DAG, and ceramides has recently received considerable interest, as the accumulation of these potentially harmful intermediates have been implicated in the development of insulin resistance, cardiac dysfunction, and right heart failure.”
  • There is evidence for lipid accumulation resulting in cardiomyopathy, independent of elevated glucose or lipid dysregulation (albeit this is from transgenic mice): “Lipids that accumulate in the form of triglycerides are synthesized by the enzyme diacylglycerol acyl transferase (DGAT), the final enzyme in the synthesis of triglycerides. Cardiomyocyte-specific DGAT1-overexpressing transgenic mice demonstrate an increase in LV lipid accumulation and a reduction in mitochondrial biogenesis, with the development of significant cardiomyopathy and systolic dysfunction over time. This occurs in the absence of hyperglycemia or plasma dyslipidemia, suggesting that triglyceride accumulation results in cardiac dysfunction.”
  • Overexpression of PPARα in mouse hearts increases lipid accumulation and cardiac dysfunction. She also mentioned that it isn’t PPARα alone, but the upregulation of both PPARα and CD36 that induces lipotoxicity: “In a genetic mouse model of cardiac lipotoxicity overexpressing PPARα but deficient in CD36 (Myh-Ppara/Cd36 −/− ), myocyte triacylglyceride accumulation and cardiac dysfunction is prevented and glucose uptake and oxidation is increased, although fatty acid utilization remains unchanged; this suggests that CD36 is required for the development of lipotoxic cardiomyopathy, and novel therapeutic strategies aimed at reducing CD36-mediated fatty acid uptake may prevent or treat cardiac dysfunction.” My emphasis added.
  • Intracellular ceramides can induce apoptosis in cultured cardiomyocytes.
  • One interesting thing mentioned was the following, but I’m not quite sure what to make of it: “Palmitate-treated cardiomyocytes show an increase in ceramides or triglycerides accompanied by a decrease in the rate of glycolysis and insulin resistance.” Shouldn’t these molecules have the opposite effect?
  • PPARδ agonists seem to be a potentially promising target to reduce cardiomyopathy. But this runs somewhat counter to her implication in the paper to suppress fatty acid oxidation to promote glucose oxidation. The reason is because PPARδ upregulates fatty acid beta-oxidation, and ligands for PPARδ are fatty acid molecules or molecules derived from fatty acids: “PPARβ/δ agonist GW0742 has been shown to reduce RV hypertrophy and systolic pressures in an animal model of hypoxia induced PAH. Another selective PPARδ agonist, GW610742X, has been shown to normalize cardiac substrate metabolism and reduce RV hypertrophy in an experimental model of congestive heart failure. These findings suggest that PPARδ has the potential to be a therapeutic target for the treatment of RV failure in PAH associated with reduced FAO and lipid accumulation, such as lipotoxic cardiomyopathy. Unfortunately, the track record of prior PPARδ agonists in heart failure is poor, dimming enthusiasm at least for the thiazoladinedione class of medications targeting this important molecule.”

A few other things I learned:

  • Magnetic resonance spectroscopy can reliably measure RV triglyceride content.
  • HbA1C can be used as a marker for prognosis of PH. It also implies a link between glucose utilization and RV function: “In PAH, RV failure is the strongest predictor of mortality—thus the finding that a measure of chronic hyperglycemia, hemoglobin A1C (HbA1C), can serve as an independent prognostic factor of long term PAH with a hazard ratio of 2.2 per unit increase in HbA1c, indirectly suggesting that there is an interaction between glucose homeostasis and RV function.”
  • “In the context of Warburg metabolism, glutamine serves as an alternate carbon source. Cells can oxidatively metabolize glutamine derived α-ketoglutarate (αKG) in the TCA cycle and generate pyruvate from malate by glutaminolysis. Alternatively, cells can reductively carboxylate αKG to generate citrate via an isocitrate dehydrogenase reaction, which is highly reversible. The monocrotaline mouse model of RV hypertrophy demonstrates an increase in glutaminolysis accompanied by an increase in the expression of glutamine transporters (solute carrier family [SLC] 1A5 and SLC7A5) and mitochondrial malic enzymes (Me1 and Me2), which convert malate to pyruvate, in the RV. Similarly, in PAH patients with RV hypertrophy there is a capillary rarefaction and upregulation of glutamine transporter, suggesting that cardiac glutaminolysis is associated with microvascular rarefaction/ischemia.”

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