Good morning. This week, we're going to talk about cardiomyopathies. So I am very anxious to kind of get through here and talk about the different types. So let's just start with, we've got three categories of cardiomyopathy. The first one is dilated, and there's really two types. You've got primary dilated and secondary dilated. The second one is hypertrophic. So that again, we've got thickening then of the heart muscle. And then the third one is restrictive. And again, restrictive would be more related to some sort of infiltrative disease where that myocardium is thickened or stiffened and fibrosed, and it just doesn't relax as well, and the myocardium loses its pliability. I would say of the three, by far, the most common is secondary dilated cardiomyopathies, and we're going to talk a little bit more. Okay, so as we're starting to delve into cardiomyopathies, I want to take a minute to go back to some really foundational physiologic terminology and what's happening, and again, not because you don't necessarily know this information, but if you do have a good deep understanding of it, it makes everything else just fall into place and make sense. So we're going to talk about systolic versus diastolic. So I'm going to start with thinking about that left ventricle, and there's a couple of key things here that it took me a while to really understand, and that is that the left ventricle is by far much larger than our right ventricle. Now, this is a little thick, but the muscle mass is significant more muscle on the left ventricle than what we have on the right, and so you end up with a much higher pressure system, which makes sense because we've got to contract and the blood has to empty out into the body, versus the right ventricle that's really only contracting into the lungs, and the lungs in a normal person are a pretty low pressure area. So we've got lots of muscle versus just a little bit of muscle. Now, when we get into the concept of systology or systole versus diastole and systolic dysfunction, again, not a new concept, I'm sure, but it is important to understand and remember that systole is really part of that contractility. So it's the normal contraction of the left ventricle and the ability of the left ventricle to empty its contents. Now, this is where the term ejection fraction comes in, and again, we've all heard ejection fraction a million and one times, but that ejection fraction is really about when the left ventricle contracts, how much of that contents does it empty from the end of diastole or the end of filling to its full contractility, and normal in a resting heart should be somewhere between 50% and 65%, so a half and two-thirds, which is another thing I want to make sure you have a good understanding of. Ejection fraction of 50% to 65% is normal. It's not half of normal. 100% is not normal in a resting heart. All right, so systole or systolic dysfunction is an issue with contractility, and the reason I think it's important to understand is because when we start talking about the different types of heart failure, you're going to hear half-ref or heart failure with reduced ejection fraction. That's heart failure due to systolic dysfunction versus half-pef, which is heart failure with preserved ejection fraction. Those patients have an issue with diastolic dysfunction, so when we think of diastole or what's happening with good diastolic function, it's the ability of that left ventricle to stretch, so if we take you back to basic physiology, we all learned about Starling's Law, and that's the concept. If you think about the heart as a balloon, it's got an elasticity to it, and it should be able to stretch, and the more pressure we put on those myocytes and those fibrils, as it's fuller, when it goes to contract, you're going to have much stronger contraction, and a good normal heart has an ability to be dynamic and an ability to stretch for good diastolic function. What happens when we start to get some dysfunction here is that left ventricle becomes less compliant, it becomes stiff, it doesn't stretch as easily, and in some cases, it really doesn't stretch at all, so we're not getting that good contractility. Now, the overall contraction, the ejection fraction may still be emptying a half to two-thirds of its content, but it's not filling in the way that it's supposed to, so your overall cardiac output will be down, and this really sets the patients up for that congestion and for those heart failure-type symptoms. So again, when we go back to the thinking about heart failure and cardiomyopathies, really having a good understanding of systolic function versus diastolic function is important because our therapies might look different, the way our patients present, although many times are similar, the pathophysiology behind it is different. So again, systolic dysfunction, which is issues with contractility, versus diastolic dysfunction, which is issues with relaxation. All right, right-sided versus left-sided failure. So again, referring back to the whiteboard talk, we did kind of describe that when that right ventricle is failing, what we're going to see is congestion back up into the body. So on physical exam, you'll see JVD, you'll see hepatomegaly, you'll see ascites, and of course, you'll see the peripheral edema. Now, one of the things that I want to really, again, comment on is the fact that that right ventricle is a very low-pressure ventricle. There's not a lot of pressure on the right side. Remember, it's kind of venous return that's coming back to fill, and it's contracting against pulmonary artery pressures that are around 35 millimeters of mercury. You compare that to the left side, or that left ventricle, you've got a much thicker myocardium, a much stronger level of contractility, simply because that left ventricle is really emptying into a much higher system, into the arterial beds. So again, the reason that's important is because when you get into comorbidities in patients with significant lung disease and pulmonary artery pressure, that right heart begins to fail. So we do oftentimes see right-sided failure in patients, again, with, you know, maybe severe sleep apnea that have some pulmonary hypertension, and patients with primary pulmonary hypertension that develop core pulmonality. So it's just, again, I think it's one of those concepts that if you can remember that, as you start to, again, look at treatments and look at signs and symptoms, it will begin to make sense. All right, so we're going to talk here about that dilated cardiomyopathy. And one of the things that I want to take, again, back to physiology is to understand the concept of cardiac remodeling. So what cardiac remodeling is, is a maladaptive response to contractile dysfunction. So that's that left ventricle or even right ventricle, its inability to contract in a normal fashion. In this case, we'll talk about the left ventricle, but the concept is the same. So when you start to, that ventricle starts to weaken, the volume and the pressure go up. And so what happens is the body says, I need to contract stronger or contract more powerfully. So what happens is first we end up with a complex process, initially causing hypertrophy of the myocytes. So at a cellular level, those cells become enlarged because they're trying to work harder. And the concept I use around that is when you think about weightlifting and you increase muscle mass. Now, again, myocardium is a different type of muscle, but the concept is the same. When that muscle has to work harder, a degree of hypertrophy occurs in order to maintain that workload. The problem is it's not sustainable. So then what happens is that ventricle will eventually dilate and begin to fail. And it kind of is a little bit of a cycle. Once that dilatation occurs, that chamber size, so that's the inside of the myocardium, increases, wall thickness decreases. So now we have a thinning of the myocardial wall and you get a progressive cardiomyocyte dysfunction. So we get the cells start to break down and now you lose even more contractility. At this point, we end up with this neurohormonal activation and it involves both the sympathetic and the renin-angiotensin-aldosterone system. This is important because when we think about pharmacologic therapy, this is what we're targeting. So when we move into this, now here's just kind of a picture of what that dilated cardiomyopathy looks like. We get a very thickened, I'm sorry, a thinned out myocardium that you'll see here on the right. And then you get a very enlarged chamber size. So you can really see the difference between the normal heart on the left and the dilated heart on the right. Now, we talked about the neurohormonal. There's two pieces of this. There's the sympathetic activation and then we're going to talk about the renin-angiotensin system in a minute. But what we end up with is the body senses through lack of perfusion to the kidneys and to other organs that it needs to increase contractility. So again, part of that maladaptive result is we get this autonomic nervous system. So in a normal resting state, the left ventricle functions under the parasympathetic tone. So it's kind of that fight, flight type concept versus rest. So we're kind of hanging out in that parasympathetic. So we're not really working that hard. But when we get left ventricular dysfunction, sympathetic activation occurs and actually becomes predominant. So I kind of describe it as we're flogging a very sick heart. We're pushing it and we're asking it to work harder, which in turn just increases the continued breakdown, the myocyte dysfunction, and then more dilatation. The heart is trying to compensate and sometimes we can get some improvement. But over time, that increase in sympathetic tone actually increases mortality. So there's a release of norepinephrine. It harms the myocardium by promoting apoptosis and promoted programmed cell death. So again, we're starting to really break that myocyte and that myocardium down even further. The second piece of this is the renin-angiotensin-aldosterone system. So what happens here is the angiotensin two levels are increased with LV dysfunction. How does that happen? Well, we get decreased perfusion pressure that then senses and is sensed by the juxtaglomerular cells that then go and secrete renin. This stimulates the production of angiotensin one and the conversion then to angiotensin two. Well, the reason that that's important is because that angiotensin two causes continued adverse remodeling. What we get here is we get peripheral vasoconstriction. So again, it's a maladaptive response. What's happening is because we don't have good perfusion, we've got the peripheral part of the body vasoconstricting down to try to preserve the cardiac output to go to the main organs. But what that also does, though, is it increases blood pressure. So because it increases that systemic vascular resistance and the heart has to work even harder. The other thing that happens is the stimulation of aldosterone production. So that increases sodium retention and therefore water retention. And we're actually increasing volume. We get an increased circulation of catecholamines, increased bradykinin degradation, which all worsen LV function and symptoms of heart failure. So in essence, what we've done between the sympathetic system and the renin, angiotensin, aldosterone system is we've increased contractility. We've asked that heart to work harder. We maybe have even increased heart rate. So if you look at a patient that's decompensated, oftentimes they're quite tachycardic. So the sympathetic nervous system and then the renin, angiotensin, aldosterone system, again, it's a maladaptive response. But what it's trying to do is increase volume with sodium retention because it thinks it's not got enough volume because it doesn't have good perfusion. And peripheral vasoconstriction occurs. So it's trying to increase blood pressure and then convert or have the blood flow go back to those main organs. So again, all in a process to try to compensate for that weakened heart muscle and that drop in ejection fraction. But what we're really doing is we're flogging a very sick heart and we're actually creating more workload through increased volume and increased blood pressure. So it's just not sustainable. So here's kind of that picture of the angiotensin too. And as you can see, there's a lot of effect from this. We've got things such as the cardiac and vascular hypertrophy. So we've got endothelial dysfunction. We've got vascular dysfunction. We talked about the systemic vasoconstriction. It actually increases thirst. So it makes people want to drink more. So when our patients that are decompensated are describing that they're thirsty all the time, there's a reason for that. It increases blood volume. It increases renal sodium and fluid retention. It affects the pituitary gland. And then again, we talked about how it increases aldosterone. So you can see several different mechanisms in which it causes the sodium and the fluid retention. So none of these things, when you think about it, are what we want to see in a patient with decompensated heart failure. So you can see how it just turns into a spiral. So the other one we wanted to cover was the aldosterone. So aldosterone levels are elevated due to the increased production by the adrenal glands. This is related to stimulation by the renin and dietary sodium restriction and decreased hepatic clearance resulting from the decreased hepatic flow. So again, a lot of mechanisms going on, but so much of it's related to that lack of good blood flow or perfusion. Aldosterone in turn causes sodium and water retention and a secretion of potassium, both which are bad for fluid balance. So again, as you think about those decompensated heart failure patients, this perfectly makes sense. We also see with this myocardial fibrosis. So we now start to take that very dilated cardiomyopathy. We have cell breakdown, and now we've got fibrosis, which actually then starts to stiffen even that very weakened heart muscle. We've got vascular fibrosis. We have baroreceptor dysfunction. Again, our baroreceptors is what helps us regulate our blood pressures, and we have prevention then of myocardial norepinephrine uptake. So a lot of things going on between the sympathetic system, the renin-angiotensin, and then the aldosterone piece. Here's kind of a picture related to another way of looking at it, but what we're doing is we're both increasing preload and we're increasing afterload. So again, when we think about that pressures that are coming in and the venous return is our preload, we've increased volume. So we're increasing volume coming through the heart on the right side, and then because of the vasoconstriction, we've now increased afterload. So we've got more volume coming in, and we've got harder to get the volume out because our systemic vascular resistance is elevated. So again, just take-home message here is if gone unchecked, these neurohormonal activation changes really can create quite a cycle that just worsens overall cardiac function. So I hope that makes sense. Now, a couple things as we think about that neurohormonal when we talk about the pharmacologic therapies, and these are the things that you're going to read about in your content this week. I really want you to pay close attention to the utilization of beta blockers. So again, it's the beta blockers that are affecting the sympathetic system. So we're trying to block that sympathetic activation down or minimize that, and then our use of ACE inhibitors. That's where we're really affecting that angiotensin II level or at least the receptor related to that activation and really blocking down that vasoconstriction, that sodium and water retention, and those other effects from that particular neurohormone. And that is why with the combination of our beta blocker and our ACE inhibitors or ARBs, we can really begin to see some improvement. You know, I've been in this business long enough that even before we were using beta blockers consistently, that we really said once the ejection fraction has dropped, there wasn't a lot in the early days that we could do to improve that. And with the introduction of utilization of the beta blockers and the ACEs in combination, we really can see ejection fractions begin to return, maybe not completely to normal, but certainly improve. And the key to that is catching that remodeling, that maladaptive process. So if you can get on top of that early, when the myocardium is still functional and provides some healing, oftentimes we can see an improvement of an ejection fraction now. So we're doing much better from a pathophysiologic standpoint than we did 15 to 20 years ago. So again, as you get through your reading, if you have any questions, please feel free to reach out and we'll be happy to either give you a reference and point you in the right direction or answer any questions you may have. Thank you.

dilated cardiomyopathy

systolic dysfunction

diastolic dysfunction

heart failure

pharmacologic therapy