Stem cells, mitochondria disfunction, right heart failure, and pulmonary hypertension. Leading physician shows the complexity of precise diagnosis. Precision medicine treatment of heart and lung disease patients today. Is there a clinical case you could discuss? Dr. Anton Titov, MD. Perhaps a situation that could illustrate pulmonary arterial hypertension and right-sided heart failure? Dr. Anton Titov, MD. There are many clinical cases. Here are the clinical situations that come to mind. Dr. Aaron Waxman, MD. We obviously have many patients who present with symptoms of pulmonary arterial hypertension and right-sided heart failure. Some patients presented with very advanced lung disease. We are using multi-modality treatments. These are patients who generally have idiopathic pulmonary arterial hypertension. Dr. Aaron Waxman, MD. Patients present in right-sided heart failure. We start patients on aggressive therapy with intravenous prostacyclins. We also use acombination therapy with endothelin antagonists and PDE5 inhibitors (sildenafil, tadalafil). But that is the limits of our ability to treat patients with pulmonary arterial hypertension and right ventricular heart failure. We have worked with companies to develop novel treatment approaches to pulmonary arterial hypertension and right-sided heart failure. That includes fully implantable medication delivery systems. Dr. Aaron Waxman, MD. We are waiting for FDA approval on one such implantable treatment system at this time. But we have been able to get rid of Hickman catheters. We put everything inside the body of a patient. We limit the infection risk and a complication risk with the medication delivery systems. We have also been able in those patients with pulmonary arterial hypertension to think outside the box. We use targeted therapy. Dr. Aaron Waxman, MD. We use anti-inflammatory immunosuppressive therapies in low doses. That might help reverse some of the abnormal pathway functions that are driving lung blood vessel remodeling. An example is using a medication like tacrolimus. It is normally used for transplantation and immunosuppression. In low doses we have evidence that tacrolimus may reverse some of the genetic abnormality that is acquired in pulmonary arterial hypertension lung disease. We work with collaborators at Stanford University. We have been treating some of our more advanced pulmonary arterial hypertension patients with tacrolimus. There is another targeted therapy that we use in these patients. It that targets mitochondrial function. Because we have learned in all of these patients that there is dysfunction of mitochondria. There is an inefficient approach to metabolism. Patients with right-sided heart failure tend to shift to glycolysis rather than oxidative phosphorylation. We use different medications that we know might do the reversal of that pathological process. Dr. Aaron Waxman, MD. We have started treating some of patients with pulmonary arterial hypertension. These patients have responded well to these treatments. It is very interesting! Because you showed that there is a mitochondrial dysfunction in many lung diseases. The mitochondria are energy-generating power stations of the cell. It could explain some of the shortness of breath that the patients with lung disease are experiencing. Yes, mitochondria. As an intensive critical care specialist, I see patients with severe lung disease and septic shock. Dr. Aaron Waxman, MD. Patients come to the intensive care unity with other types of shock you want to address. It is probably ultimately the mitochondria that are getting damaged or become dysfunctional or become hibernating. We should have targeted therapies that can get into the cell, get into that mitochondria and regenerate mitochondria. Then we will probably change how we treat patients with septic shock. One of the goals when we started our stem stem cell studies is this. When we see patients in heart failure, there is a clear shift in metabolism to glycolysis from oxidative phosphorylation in the myocardium. We thought that because of data from in vitro studies, stem cells and diseased cells can fuse and transfer mitochondria and restore normal bioenergetics. Dr. Aaron Waxman, MD. There are experiments when you take stem cells and you mix them with diseased cells. We thought, why can't we do that in the living heart? Dr. Anton Titov, MD. That is why we did our initial stem cell studies to infuse stem cells into the heart. We looking at mesenchymal stem cells infused directly into the right coronary artery in these models. We were able to see that these stem cells go into the heart. Stem cells proliferate. They were surviving much longer inside the heart than any other prior stem cell studies had shown. These are novel approaches that could change the way we treat lung disease and heart failure patients in the long run. Well, mitochondria are very interesting. Statins also work on the mitochondria. Dr. Aaron Waxman, MD. Yes, a number of medications work on mitochondria. That gets to the topic of medication repurposing. A lot of medications that we use for one treatment indication, we are learning that the same medication may be useful in other disease indications. This not only could save money but it could save time to getting medications approved for treating these lung diseases. Dr. Aaron Waxman, MD. We are open to any novel idea. Sometimes someone comes up with an idea and it makes physiologic, metabolic, biochemical sense. Then that idea is worth investigating!