0:00:07.069,0:00:10.279 The topic of our conference this afternoon 0:00:10.279,0:00:12.409 is is a very important one 0:00:12.409,0:00:13.789 namely, heart 0:00:13.789,0:00:15.959 failure 0:00:15.959,0:00:19.096 and its important, as you'll hear[br]from my colleagues, 0:00:19.096,0:00:24.082 for a number of reasons. The sheer[br]prevalence of heart failure in our population 0:00:24.082,0:00:25.009 says that 0:00:25.009,0:00:29.079 you're going to deal with a tremendous numbers of patients having 0:00:29.079,0:00:30.449 related problems. 0:00:30.449,0:00:31.769 The associated 0:00:31.769,0:00:36.056 morbidity and mortality is very significant and 0:00:36.056,0:00:40.095 heart failure, one way or another,[br]consumes a very, very significant 0:00:40.095,0:00:43.055 fraction of our health care resources. 0:00:43.055,0:00:46.057 So it's a problem that you're going to[br]be dealing with 0:00:46.057,0:00:48.092 a lot of the time. 0:00:48.092,0:00:51.068 I will spend my time 0:00:51.068,0:00:55.008 just introducing the[br]general concept which we've had a little 0:00:55.008,0:00:58.044 bit in lecture, but will try to embellish[br]that 0:00:58.044,0:01:02.007 and illustrate some of the[br]pathologic anatomy associated with heart 0:01:02.007,0:01:03.082 failure one way or another. 0:01:03.082,0:01:07.026 Then I'll pass the baton to Dr Matthews 0:01:07.026,0:01:11.095 who will make clinical reality out of[br]this 0:01:11.095,0:01:16.004 and translate all of this into signs and[br]symptom that the patients manifest 0:01:16.004,0:01:16.091 and 0:01:16.091,0:01:19.086 appropriate strategies 0:01:19.086,0:01:23.034 of medical therapy and then we[br]will conclude the afternoon with 0:01:23.034,0:01:25.033 Dr Jonathan Haft 0:01:25.033,0:01:28.077 and with the participation of a[br]patient of his 0:01:28.077,0:01:32.008 and discuss the treatment of[br]advanced heart failure 0:01:32.008,0:01:36.036 with mechanical support and[br]cardiac transplantation. 0:01:36.036,0:01:37.044 So that's 0:01:37.044,0:01:42.051 the agenda for this afternoon. 0:01:42.051,0:01:43.034 Now in its 0:01:43.034,0:01:47.098 very simple definition, and there are a[br]lot of ways to define it, the very simple 0:01:47.098,0:01:50.018 definition of heart failure 0:01:50.018,0:01:53.002 involves the inability of the heart 0:01:53.002,0:01:55.729 to meet 0:01:55.729,0:02:00.033 to really pump sufficient[br]blood to meet the metabolic needs of 0:02:00.033,0:02:02.012 the body. 0:02:02.012,0:02:06.056 Now this can happen in a in a variety of[br]ways. 0:02:06.056,0:02:10.589 It can come to pass, and this isn't as frequent, that the 0:02:10.589,0:02:14.579 heart is putting out a normal or even an excessive amount of blood. 0:02:14.579,0:02:16.659 It's really pumping it out there, but it's being 0:02:16.659,0:02:18.051 driven by 0:02:18.051,0:02:23.009 an increased demand in the peripheral[br]tissues that it just can't keep up with. 0:02:23.009,0:02:26.439 This sort of thing we see in thyrotoxicosis. 0:02:26.439,0:02:28.059 It used to be seen, 0:02:28.059,0:02:31.789 we don't see it much any more thankfully, in beriberi - vitamin deficiency 0:02:31.789,0:02:33.659 with vasodilatation 0:02:33.659,0:02:36.409 all over the place and[br]the heart just couldn't keep up with 0:02:36.409,0:02:37.042 that volume 0:02:37.042,0:02:38.139 of the 0:02:38.139,0:02:40.209 cardiovascular system. 0:02:40.209,0:02:45.839 It's seen occasionally with[br]arteriovenous fistulas 0:02:45.839,0:02:49.559 that dump a lot of blood[br]directly from arteries into the veins in the heart 0:02:49.559,0:02:52.709 The heart just can't keep up. Or severe anemia. 0:02:52.709,0:02:56.499 Those sorts of things will result in what we call a high output sort of failure, 0:02:56.499,0:02:57.489 but much more 0:02:57.489,0:02:59.119 often, we're dealing with 0:02:59.119,0:03:00.085 the problem of 0:03:00.085,0:03:03.799 not enough blood being ejected 0:03:03.799,0:03:06.269 for one reason or another 0:03:06.269,0:03:11.359 from the heart to support even normal[br]demands 0:03:11.359,0:03:15.039 and this is a combination really of 0:03:15.039,0:03:18.489 the loss of systolic umph, 0:03:18.489,0:03:22.069 in other words, the contracting[br]heart just can't get it out there 0:03:22.069,0:03:23.059 in the way it should and 0:03:23.059,0:03:27.052 often this can be accompanied by 0:03:27.052,0:03:29.069 diastolic, 0:03:29.069,0:03:34.279 i've listed it here as diastolic failure but[br]it's a difficulty in diastolic filling 0:03:34.279,0:03:38.419 which can impair the heart action. If[br]the heart muscle can't relax and is ineffective 0:03:38.419,0:03:39.004 it's stiff 0:03:39.004,0:03:40.459 it won't 0:03:40.459,0:03:41.809 accept 0:03:41.809,0:03:44.009 the right volume coming into it and[br]that's going to lead 0:03:44.009,0:03:46.989 also to failure. 0:03:46.989,0:03:52.229 One way or another, these factors can lead to a constellation 0:03:52.229,0:03:54.033 of signs and symptoms, 0:03:54.033,0:03:57.009 we'll get to that at the end. 0:03:57.009,0:04:00.689 It's really related on the one hand to[br]congestion of organs which you know all 0:04:00.689,0:04:02.439 about now after 0:04:02.439,0:04:02.095 your 0:04:02.095,0:04:08.034 lectures in pathology and[br]hypoprofusion of tissues which 0:04:08.034,0:04:10.099 we haven't emphasized as much, but it's a 0:04:10.099,0:04:13.068 very important point. 0:04:13.068,0:04:18.659 Now, when we look at the causes of heart failure[br]and there are many, many of them, far more 0:04:18.659,0:04:20.869 than we can talk about, 0:04:20.869,0:04:22.319 but 0:04:22.319,0:04:25.819 if we look at those[br]situations where there is 0:04:25.819,0:04:28.061 some unusual demand 0:04:28.061,0:04:31.041 on the heart, and the heart just can't meet it, they 0:04:31.041,0:04:33.229 fall into a number 0:04:33.229,0:04:35.319 of categories, and I will 0:04:35.319,0:04:37.919 illustrate each of these in a[br]moment, 0:04:37.919,0:04:41.028 but one very important[br]category is resistance 0:04:41.028,0:04:42.759 to flow, in other words, 0:04:42.759,0:04:46.769 if something is keeping the flow of blood from going so 0:04:46.769,0:04:50.879 the heart has to work harder to push it[br]past that resistance 0:04:50.879,0:04:55.629 it will come to the point where the[br]heart could no longer do it and it fails. 0:04:55.629,0:04:59.009 Another problem is what we call regurgitant[br]flow, I mean you like to think of the 0:04:59.009,0:05:03.979 blood flowing in one direction through[br]the cardiovascular system, but 0:05:03.979,0:05:05.769 sometimes it comes to pass where, at a point, 0:05:05.769,0:05:06.007 there's 0:05:06.007,0:05:09.089 regurgitation, instead of things pulsing forward, they slosh 0:05:09.089,0:05:11.569 backward, and that 0:05:11.569,0:05:16.439 imposes a strain on the heart[br]as you will see 0:05:16.439,0:05:21.037 and thirdly and very importantly there is[br]disease of various sorts, lots of sorts, 0:05:21.037,0:05:25.439 targeting the myocardium itself 0:05:25.439,0:05:29.015 so that there's no resistance to flow,[br]there's no regurgitant flow 0:05:29.015,0:05:29.999 perhaps, but the 0:05:29.999,0:05:32.559 heart muscle is sick. 0:05:32.559,0:05:34.019 And finally, we won't talk 0:05:34.019,0:05:38.079 at all about this, I won't, about conduction abnormalities 0:05:38.079,0:05:40.064 which can also lead to decompensation 0:05:40.064,0:05:42.018 of the heart. 0:05:42.018,0:05:43.369 Now, I'd like 0:05:43.369,0:05:46.619 to illustrate some of these[br]very quickly, don't get lost in the details, 0:05:46.619,0:05:47.069 just 0:05:47.069,0:05:51.047 let it flow over you, you're going[br]to get these details later on 0:05:51.047,0:05:52.097 in the year 0:05:52.097,0:05:57.509 later on in your careers, but just[br]for a little orientation, 0:05:57.509,0:06:03.011 I'll give you an example first of resistance to flow, 0:06:03.011,0:06:04.709 there is a good hallmark for 0:06:04.709,0:06:08.309 it, I can't show you[br]hypertension obviously 0:06:08.309,0:06:09.179 but think of 0:06:09.179,0:06:14.559 the situation when a patient[br]has established significant hypertension, 0:06:14.559,0:06:16.081 it means that 24/7 0:06:16.081,0:06:19.759 every minute, every beat of the[br]heart 0:06:19.759,0:06:24.219 that poor left ventricle is having to[br]force against an increased resistance to flow, 0:06:24.219,0:06:25.003 that's what hypertension 0:06:25.003,0:06:27.509 is all about. The result 0:06:27.509,0:06:28.008 0:06:28.008,0:06:32.028 one of the results you see here is[br]is this rather massive 0:06:32.028,0:06:34.048 myocardial hypertrophy which i'm sure[br]you all recognize, 0:06:34.048,0:06:35.969 so that's one 0:06:35.969,0:06:40.036 kind of resistance to flow. Here's another one, this takes a 0:06:40.036,0:06:44.919 little explaining, it's an unusual plane of section of the heart, 0:06:44.919,0:06:48.289 but what attracts your[br]attention right away is that the left ventricle 0:06:48.289,0:06:51.009 is immensely hypertrophied, very thick 0:06:51.009,0:06:52.819 and very heavy, and the reason 0:06:52.819,0:06:56.479 for it is not terribly[br]well shown here 0:06:56.479,0:07:00.849 but here is the aortic outflow, this is the aorta here, and this would be the aortic valve 0:07:00.849,0:07:03.005 which you can't get a good view[br]of, but 0:07:03.005,0:07:08.043 a common lesion is stenosis of the aortic valve, 0:07:08.043,0:07:13.024 and obviously, in that situation, it's very[br]analogous to hypertension, every time 0:07:13.024,0:07:16.159 the ventricle contracts, it's got to push that blood 0:07:16.159,0:07:18.449 through a stenotic valve 0:07:18.449,0:07:20.269 and it's a lot of work. 0:07:20.269,0:07:23.839 I'll show you one of these valves from[br]above, this is an interesting one, 0:07:23.839,0:07:27.849 this is a pretty typical example of[br]aortic stenosis, 0:07:27.849,0:07:31.004 you're standing in the ascending[br]aorta, looking back 0:07:31.004,0:07:33.859 towards the left ventricle, and 0:07:33.859,0:07:39.939 you're aware from your gross anatomy[br]that this should be a three cusp valve 0:07:39.939,0:07:42.033 and you're seeing a couple of things here, 0:07:42.033,0:07:45.129 first of all this is only two cusps 0:07:45.129,0:07:47.009 and that was a congenital problem 0:07:47.009,0:07:50.279 and it's a fairly frequent one[br]in our population, there are probably a 0:07:50.279,0:07:51.499 couple of so-called 0:07:51.499,0:07:53.699 bicuspid valves in this room 0:07:53.699,0:07:55.499 and 0:07:55.499,0:07:57.009 whatever the case 0:07:57.009,0:08:01.021 the aortic valve is very susceptible to calcification 0:08:01.021,0:08:04.119 and stiffening with age, and if you 0:08:04.119,0:08:07.969 plot it against the aging[br]population, we see an increasing 0:08:07.969,0:08:09.409 incidence of stenotic 0:08:09.409,0:08:11.319 aortic valves even if they're not 0:08:11.319,0:08:15.409 bicuspid, if they're congenitally bicuspid like this they get wrecked 0:08:15.409,0:08:16.689 very frequently 0:08:16.689,0:08:18.609 earlier on so that 0:08:18.609,0:08:21.959 instead of maybe in the[br]seventies or eighties, it might be in the 0:08:21.959,0:08:24.049 fifties and sixties that the patient[br]would suffer from such stenosis. 0:08:24.049,0:08:25.006 But you can see 0:08:25.006,0:08:26.919 that every time 0:08:26.919,0:08:30.004 the ventricle is trying to push[br]blood through that orifice, and it's really like brick 0:08:30.004,0:08:31.619 it doesn't move. 0:08:31.619,0:08:32.082 It's going to be a 0:08:32.082,0:08:37.024 tremendous load on[br]the left ventricle. 0:08:37.024,0:08:41.047 here's another valve stenosis for you,[br]we don't see this as much anymore, 0:08:41.047,0:08:45.093 it's a result usually of old rheumatic fever[br]in childhood, but the mitral valve 0:08:45.093,0:08:50.001 here is reduced to[br]a fish mouth, it's all puckered up 0:08:50.001,0:08:54.035 and scarred, and frequently calcified, 0:08:54.035,0:08:55.649 and the valve leaflets 0:08:55.649,0:08:57.026 can't move at all, 0:08:57.026,0:08:59.096 so that the blood coming out of the lungs into the 0:08:59.096,0:09:01.059 into the left atrium trying to get through 0:09:01.059,0:09:04.039 into the left ventricle, you're looking down towards the left ventricle, 0:09:04.039,0:09:08.072 it's got to pass by that stenotic slit. 0:09:08.072,0:09:10.009 The result is damming back, 0:09:10.009,0:09:15.043 very obviously you know about passive[br]congestion, you can see this immensely dilated 0:09:15.043,0:09:16.017 left atrium 0:09:16.017,0:09:17.003 and you can imagine 0:09:17.003,0:09:20.007 what was happening in the[br]lungs 0:09:20.007,0:09:21.669 behind that sort of obstruction. 0:09:21.669,0:09:22.082 Now as far as 0:09:22.082,0:09:25.094 regurgitant flow, hold on with me 0:09:25.094,0:09:30.035 and i'll try to explain[br]it, here is another mitral valve, we've chopped off the 0:09:30.035,0:09:32.004 the atrium and you're[br]looking right at the 0:09:32.004,0:09:34.088 mitral valve, and 0:09:34.088,0:09:38.023 think about what you saw in gross anatomy, the[br]mitral valve leaflets usually come together 0:09:38.023,0:09:41.003 like that and keep the blood, during systole, 0:09:41.003,0:09:45.023 keep the blood from[br]flowing back into the atrium so all the blood goes out 0:09:45.023,0:09:47.044 the aorta like it should. 0:09:47.044,0:09:49.071 Here, 0:09:49.071,0:09:54.084 and this happens for a variety of[br]reasons, but here this leaflet of the valve 0:09:54.084,0:09:57.043 is sort of pooched up and 0:09:57.043,0:10:02.071 and with every ventricular systole, blood is able to force its way back 0:10:02.071,0:10:04.048 into the atrium, which means 0:10:04.048,0:10:08.015 the poor old left ventricle is[br]pumping some of that blood more than once 0:10:08.015,0:10:11.063 in other words it's putting part of it out[br]the aorta, part of it back up the atrium, 0:10:11.063,0:10:12.044 and that comes 0:10:12.044,0:10:14.047 sloshing down for the next 0:10:14.047,0:10:16.028 beat of the heart 0:10:16.028,0:10:18.084 and it consists, 0:10:18.084,0:10:22.649 it induces a volume overload on the valve 0:10:22.649,0:10:24.075 and 0:10:24.075,0:10:26.059 on the ventricle 0:10:26.059,0:10:29.016 and it may fail. 0:10:29.016,0:10:33.026 Now when you get to the realm of myocardial[br]abnormality per se, in other words disease of the myocardium 0:10:33.026,0:10:34.098 0:10:34.098,0:10:36.022 there are lots 0:10:36.022,0:10:42.012 and lots of examples, and the most frequent one and most important one is myocardial ischemic disease 0:10:42.012,0:10:46.098 in other words, the result of coronary artery disease, atherosclerosis 0:10:46.098,0:10:50.062 and its complications, and what happens when the myocardium 0:10:50.062,0:10:52.001 becomes ischemic. 0:10:52.001,0:10:55.075 Clearly many patients who have a[br]myocardial infarct, an acute heart attack 0:10:55.075,0:10:56.095 will go into 0:10:56.095,0:11:01.012 acute failure if enough of[br]the myocardium is involved right then and there in the 0:11:01.012,0:11:04.023 emergency room. 0:11:04.023,0:11:06.097 But chronically it can become a big problem[br]even when the 0:11:06.097,0:11:11.057 situation heals. Here, for example, 0:11:11.057,0:11:15.045 a slice of a heart, this is left ventricle over here, 0:11:15.045,0:11:19.012 and this individual sustained a[br]myocardial infarct, I don't know how long ago, 0:11:19.012,0:11:20.089 it could be years ago, 0:11:20.089,0:11:25.014 months ago, and you see a lot of scar 0:11:25.014,0:11:28.022 throughout the ventricular wall, a little[br]bit back there, a little bit in the septum, 0:11:28.022,0:11:31.005 but a tremendous scar here 0:11:31.005,0:11:36.399 and when this involves enough of the[br]ventricular myocardium, it puts a strain 0:11:36.399,0:11:39.056 on what's left of viable myocardium, because this 0:11:39.056,0:11:43.000 obviously doesn't contract. 0:11:43.000,0:11:47.005 Patients can sustain a lot of myocardial infarcts, 0:11:47.005,0:11:52.025 here's serial sections of the same heart,[br]and you can see at least a couple of infarcts 0:11:52.025,0:11:52.809 that involve 0:11:52.809,0:11:54.015 a tremendous 0:11:54.015,0:11:55.072 fraction of the 0:11:55.072,0:11:56.024 left ventricle 0:11:56.024,0:11:57.093 and again when 0:11:57.093,0:11:59.639 that happens, the rest of 0:11:59.639,0:12:02.048 this can't keep up with it, and the left 0:12:02.048,0:12:04.083 ventricle fails. 0:12:04.083,0:12:06.059 Here is a heart that was 0:12:06.059,0:12:09.093 was removed from a patient[br]who was still alive 0:12:09.093,0:12:12.071 happy and well as far as i know 0:12:12.071,0:12:15.073 This is an explant to the heart, in[br]other words, taken out of the time of transplantation 0:12:15.073,0:12:16.889 and this was also 0:12:16.889,0:12:19.239 ischemic disease, and this 0:12:19.239,0:12:22.459 individual had scraped through 0:12:22.459,0:12:26.083 with this much of the heart converted into 0:12:26.083,0:12:29.085 what amounted to a fibrous sack, totally 0:12:29.085,0:12:32.021 non-contractile 0:12:32.021,0:12:36.006 and you can see there's even a clot in there because it wasn't moving 0:12:36.006,0:12:37.002 and that had 0:12:37.002,0:12:41.018 produced failure of the remaining myocardium. 0:12:41.018,0:12:42.093 So that's a 0:12:42.093,0:12:45.002 good sample of 0:12:45.002,0:12:46.012 ischemic 0:12:46.012,0:12:49.021 disease leading to chronic failure of the left ventricle. 0:12:49.021,0:12:49.679 0:12:49.679,0:12:51.084 Now, beyond 0:12:51.084,0:12:55.017 ischemic disease there are a whole lot of them,[br]don't worry about the details 0:12:55.017,0:12:58.092 I'll show you this as an example[br]of an inflammatory process targeted at 0:12:58.092,0:13:01.013 the myocardium. We see this 0:13:01.013,0:13:05.049 with certain viral infections, certain protozoan infections, 0:13:05.049,0:13:06.074 with bacterial 0:13:06.074,0:13:11.004 infections, but you can[br]get inflammation of the myocardium 0:13:11.004,0:13:13.076 and you can almost literally hear 0:13:13.076,0:13:16.018 these cells chewing at the myocytes 0:13:16.018,0:13:18.025 and obviously 0:13:18.025,0:13:22.059 obviously that can produce failure. 0:13:22.059,0:13:25.049 We see that not infrequently, 0:13:25.049,0:13:29.048 then the heart can be involved in a[br]variety of systemic diseases, in other words 0:13:29.048,0:13:32.097 you can have something[br]going on affecting many tissues in 0:13:32.097,0:13:36.041 the body, but that something may affect the heart and produce 0:13:36.041,0:13:37.669 failure. Here's an example 0:13:37.669,0:13:39.093 now I don't know 0:13:39.093,0:13:44.021 if I want to dart in the[br]auditorium completely to show you this 0:13:44.021,0:13:49.093 did you discuss hemochromatosis in genetics? Yes? Not a complete blank. 0:13:49.093,0:13:52.025 0:13:52.025,0:13:56.016 It's an ineffective storage[br]disease because the body absorbs too much iron 0:13:56.016,0:13:56.083 from the gut, 0:13:56.083,0:13:58.003 and the iron 0:13:58.003,0:14:01.087 gets stored in a variety of[br]issues and one of the tissues it gets stored in 0:14:01.087,0:14:03.066 is the heart, 0:14:03.066,0:14:07.024 and you recognize instantly that this is myocardium 0:14:07.024,0:14:11.021 and as you stare at it a little bit, you'll pick out some nice golden brown pigment 0:14:11.021,0:14:16.045 there and there and there, you see a little[br]more over there, and little bit down there and over there. 0:14:16.045,0:14:18.071 and one of the pigments 0:14:18.071,0:14:21.088 you'd think of in the heart, someone asked me a question about this last week, 0:14:21.088,0:14:25.052 it would be lipofuscin (wear and tear pigment) 0:14:25.052,0:14:30.066 but another pigment you got to think about is iron, and this is stored iron 0:14:30.066,0:14:31.989 in this myocardium. Here is 0:14:31.989,0:14:33.038 that blue 0:14:33.038,0:14:37.099 Prussian blue iron stain, tremendous iron 0:14:37.099,0:14:38.096 load, iron is bad for you 0:14:38.096,0:14:44.024 if it gets deposited in certain tissues. This can produce myocardial failure. 0:14:44.024,0:14:46.089 This was from a relatively young man who presented with 0:14:46.089,0:14:49.004 very advanced heart failure 0:14:49.004,0:14:51.013 because of his unrecognized 0:14:51.013,0:14:52.004 hemochromatosis. 0:14:52.004,0:14:54.056 0:14:54.056,0:14:55.009 One other that you will hear about 0:14:55.009,0:14:58.045 probably next year 0:14:58.045,0:15:01.026 is amyloidosis. Amyloid 0:15:01.026,0:15:02.109 0:15:02.109,0:15:06.058 is an abnormal protein that could[br]get deposited in a number of tissues 0:15:06.058,0:15:08.082 for a number of reasons, which I won't go into. 0:15:08.082,0:15:10.149 But all of this 0:15:10.149,0:15:15.002 sort of translucent, gray stuff surrounding the 0:15:15.002,0:15:19.066 myocytes, you're looking at a cross-sectional view of myocardium, 0:15:19.066,0:15:23.049 and you can see that each myocyte is enveloped in this 0:15:23.049,0:15:24.062 casing 0:15:24.062,0:15:26.035 of amyloid. 0:15:26.035,0:15:27.063 And this is 0:15:27.063,0:15:31.007 a marvelous example of[br]something that renders the heart rigid 0:15:31.007,0:15:31.093 and unable to 0:15:31.093,0:15:34.074 expand diastolically, and it can be 0:15:34.074,0:15:36.063 a cause of heart failure. 0:15:36.063,0:15:38.092 Finally, 0:15:38.092,0:15:41.061 this is not a complete list, I'm just showing 0:15:41.061,0:15:43.006 the examples, there are 0:15:43.006,0:15:47.082 a number of genetic diseases[br]of the heart muscle itself, where from 0:15:47.082,0:15:49.078 the get go, because of 0:15:49.078,0:15:51.087 abnormal genetic endowment 0:15:51.087,0:15:52.046 0:15:52.046,0:15:53.085 the heart is 0:15:53.085,0:15:56.003 made wrong. Here's an example 0:15:56.003,0:16:00.021 of something we call hypertrophic cardiomyopathy. 0:16:00.021,0:16:06.012 Cardiomyopathy means[br]heart muscle disease. 0:16:06.012,0:16:09.083 This particular heart was immensely[br]hypertrophic, you can see that left ventricle 0:16:09.083,0:16:11.086 it's really tremendous with no 0:16:11.086,0:16:14.009 valve disease, no hypertension to explain that, 0:16:14.009,0:16:17.001 but look at the 0:16:17.001,0:16:19.063 goofy muscle, you know 0:16:19.063,0:16:23.031 what myocardium is supposed to look like, and the histology people never show you 0:16:23.031,0:16:24.001 the kind of 0:16:24.001,0:16:27.055 disarray and criss-crossing of[br]fibers like that. 0:16:27.055,0:16:33.056 This is the result of the genetic[br]abnormality of this myocardium. 0:16:33.056,0:16:37.004 All right, these are just a few examples[br]of the things that can go wrong 0:16:37.004,0:16:40.013 0:16:40.013,0:16:41.093 and most frequently, 0:16:41.093,0:16:46.000 if I had to pick from this whole list, I'd say hypertension and 0:16:46.000,0:16:47.062 ischemic disease 0:16:47.062,0:16:52.062 are the big actors at least in our population. 0:16:52.062,0:16:55.052 Whatever the cause, as the heart is 0:16:55.052,0:16:56.086 overburdened, 0:16:56.086,0:17:00.005 there are certain compensatory[br]mechanisms that kick in 0:17:00.005,0:17:02.091 for a while, in other words, enable[br]the heart to keep up 0:17:02.091,0:17:05.042 with the abnormal strain, 0:17:05.042,0:17:08.077 and some of these you know about, you've[br]heard about I'm sure about the Frank Starling 0:17:08.077,0:17:10.179 mechanism, 0:17:10.179,0:17:11.000 0:17:11.000,0:17:11.066 0:17:11.066,0:17:17.005 where the myocyte is stretched by[br]increased filling pressure, it's stretched 0:17:17.005,0:17:19.002 and contracts then 0:17:19.002,0:17:20.094 with greater vigor, 0:17:20.094,0:17:23.429 in other words, it can put out more UMPH 0:17:23.429,0:17:27.069 if it starts from a slight stretch. The[br]trouble with that mechanism is that it fails. 0:17:27.069,0:17:28.209 In other words, for a while 0:17:28.209,0:17:31.085 it's adaptive, you get more and more UMPH for each 0:17:31.085,0:17:34.017 contraction and then it peters out 0:17:34.017,0:17:37.003 for a variety of reasons. 0:17:37.003,0:17:40.039 A second compensation is hypertrophy, 0:17:40.039,0:17:44.049 and you know about this, we talked about[br]it last summer I guess. 0:17:44.049,0:17:46.159 It's a situation where the same number 0:17:46.159,0:17:49.149 of muscle cells are there 0:17:49.149,0:17:51.071 but more sarcomeres are added 0:17:51.071,0:17:54.089 and the muscle cells enlarge the whole 0:17:54.089,0:17:56.074 tissue grossly 0:17:56.074,0:17:59.001 enlarges and there's more UMPH. 0:17:59.001,0:18:00.089 I mean it's very definitely 0:18:00.089,0:18:03.097 a compensatory mechanism. 0:18:03.097,0:18:05.001 A third compensation 0:18:05.001,0:18:08.023 mechanism I've listed 0:18:08.023,0:18:11.061 is activation of neuro-humoral systems and we're not going to go into that 0:18:11.061,0:18:13.649 in much detail, just enough detail 0:18:13.649,0:18:15.002 so you know that 0:18:15.002,0:18:17.006 they are there. 0:18:17.006,0:18:19.083 Now here's hypertrophy! 0:18:19.083,0:18:22.051 Normal size myocytes you see over here 0:18:22.051,0:18:25.092 and each one is on the average just a[br]little bit thicker 0:18:25.092,0:18:27.007 than the normal 0:18:27.007,0:18:28.038 0:18:28.038,0:18:32.051 That's because of addition of sarcomeres, not much change in the number of cells 0:18:32.051,0:18:36.005 and you can imagine these cells having[br]more UMPH like a weight lifter, 0:18:36.005,0:18:41.095 imagine that, like a weight lifters arm 0:18:41.095,0:18:44.389 This is maybe what we see 0:18:44.389,0:18:48.789 grossly, there's an increase in[br]the muscle, increase in the weight of the heart, 0:18:48.789,0:18:49.071 and sometimes 0:18:49.071,0:18:53.093 we see concentric hypertrophy, meaning 0:18:53.093,0:18:58.039 the chamber is not enlarged, it may even be a[br]little smaller, gross thickening of the walls 0:18:58.039,0:18:59.098 and its 0:18:59.098,0:19:00.077 concentric. 0:19:00.077,0:19:03.048 We see that usually with[br]pressure overload. 0:19:03.048,0:19:06.039 With a volume overload, we may see 0:19:06.039,0:19:07.052 what looks like no hypertrophy 0:19:07.052,0:19:10.058 at all except that's a lot more muscle 0:19:10.058,0:19:13.046 than there is normal, it's just that it's[br]dilated. 0:19:13.046,0:19:16.015 That also happens in very advanced[br]failure 0:19:16.015,0:19:19.005 from any cause, you see this sort of[br]eccentric picture. 0:19:19.005,0:19:20.038 0:19:20.038,0:19:24.009 When it comes to the neuro-humoral[br]mechanisms, I'm just going to race through these now, 0:19:24.009,0:19:25.053 there is 0:19:25.053,0:19:28.021 first of all 0:19:28.021,0:19:30.001 0:19:30.001,0:19:32.077 all of these things tend to be triggered[br]by pressure and 0:19:32.077,0:19:36.409 stretch receptors that are[br]scattered through the heart 0:19:36.409,0:19:38.789 the aorta, the carotids, 0:19:38.789,0:19:41.031 and the kidney even there is such sensing. 0:19:41.031,0:19:45.074 When the cardiac output[br]begins to drop, these receptors say UH OH 0:19:45.074,0:19:50.015 and they trigger a number of things, one of the things they trigger is 0:19:50.015,0:19:51.093 a central nervous system, 0:19:51.093,0:19:54.035 i'm sorry, the sympathetic nervous[br]system 0:19:54.035,0:19:57.559 with release of norepinephrine 0:19:57.559,0:19:59.005 and this can produce 0:19:59.005,0:20:02.056 a contractile boost for the heart 0:20:02.056,0:20:04.029 0:20:04.029,0:20:07.086 this can produce an increased heart[br]rate 0:20:07.086,0:20:11.094 these things will help meet[br]an abnormal load 0:20:11.094,0:20:16.005 and also this will produce vasoconstriction peripherally. 0:20:16.005,0:20:18.061 This is designed, 0:20:18.061,0:20:20.053 this evolved this way presumably to 0:20:20.053,0:20:26.006 to make sure that[br]blood gets shunted to essential organs 0:20:26.006,0:20:29.026 so there's peripheral[br]vasoconstriction 0:20:29.026,0:20:33.549 which increase, well we'll talk about[br]what the bad things it does. 0:20:33.549,0:20:35.219 Vasopressin is released 0:20:35.219,0:20:38.091 from the hypothalamus, that's also a vasoconstrictor, 0:20:38.091,0:20:41.017 and we talked in class previously about 0:20:41.017,0:20:44.092 the renin-angiotension-aldosterone system. 0:20:44.092,0:20:45.095 0:20:45.095,0:20:51.549 The kidney senses the decreased flow[br]that's coming to it, secretes renin which 0:20:51.549,0:20:56.005 acts on angiotensinogen which is[br]circulating protein 0:20:56.005,0:20:56.095 0:20:56.095,0:20:58.093 forms angiotensin I 0:20:58.093,0:21:02.004 and then there's angiotensin[br]converting enzyme which takes angiotensin II 0:21:02.004,0:21:03.038 that in turn 0:21:03.038,0:21:05.001 stimulates the production 0:21:05.001,0:21:10.018 in the adrenals of aldosterone. 0:21:10.018,0:21:11.005 0:21:11.005,0:21:14.859 The importance of all of this is first of all angiotensin II 0:21:14.859,0:21:18.064 is also a vasoconstrictor 0:21:18.064,0:21:20.047 and 0:21:20.047,0:21:24.083 between angiotensin II and aldosterone, there is 0:21:24.083,0:21:29.038 sodium retention, salt[br]retention, sodium retention and water retention 0:21:29.038,0:21:30.067 and that has 0:21:30.067,0:21:33.083 some important consequences. 0:21:33.083,0:21:38.061 I just listed, I don't have time to go into it, the natriuretic peptides 0:21:38.061,0:21:42.085 secreted by the heart which[br]tend to counteract the renin-angiotensin-aldosterone 0:21:42.085,0:21:45.087 system to some extent. 0:21:45.087,0:21:49.058 Unfortunately, all of these 0:21:49.058,0:21:52.036 mechanisms 0:21:52.036,0:21:56.000 are limited in how much help they can provide and there's a downside 0:21:56.000,0:21:57.033 to a lot of them. 0:21:57.033,0:21:58.069 Now 0:21:58.069,0:22:02.028 problems with hypertrophy, it just gets bigger and 0:22:02.028,0:22:04.004 bigger and bigger muscle, 0:22:04.004,0:22:08.051 it doesn't work out that way because[br]the capillary network in the muscle 0:22:08.051,0:22:11.269 does not increase in parallel and you 0:22:11.269,0:22:15.259 end up with perfusion problems[br]so there's a limit to how much hypertrophy 0:22:15.259,0:22:18.039 the tissue can stand. 0:22:18.039,0:22:21.064 Same is true for the ratio between mitochondria and 0:22:21.064,0:22:27.033 and contractile protein, so to speak,[br]the mitochondria-to-meat ratio 0:22:27.033,0:22:31.038 does not keep up to what it should be so[br]the energy is a problem. 0:22:31.038,0:22:33.044 Then very importantly 0:22:33.044,0:22:38.066 we're learning that there is altered[br]gene expression 0:22:38.066,0:22:40.038 and alteration in the 0:22:40.038,0:22:43.073 proteins that are produced, and these may involve 0:22:43.073,0:22:45.669 contractile proteins, 0:22:45.669,0:22:46.068 segmentation 0:22:46.068,0:22:50.071 contraction coupling them, they may involve energy utilization, 0:22:50.071,0:22:53.088 but some abnormal proteins are made 0:22:53.088,0:22:57.053 there's an increase in apoptosis 0:22:57.053,0:23:00.003 in a hypertrophic myocardium 0:23:00.003,0:23:01.519 and, under the influence 0:23:01.519,0:23:06.969 of all of this is actually driven by the various hormonal 0:23:06.969,0:23:09.098 things that i've mentioned 0:23:09.098,0:23:11.469 and with something 0:23:11.469,0:23:15.095 we call remodeling occurs, there's a[br]change in geometry of the ventricle 0:23:15.095,0:23:19.083 which can have implications of tugs on the chordae tendinae of the mitral valve 0:23:19.083,0:23:23.007 the wrong valve, you can get mitral regurgitation, 0:23:23.007,0:23:26.023 it's a disadvantageous thing 0:23:26.023,0:23:30.002 often associated with a lot of fibrosis, that blue-green tissue racing through the myocardium 0:23:30.002,0:23:31.045 0:23:31.045,0:23:35.001 is a fibrosis in the remodeled ventricle 0:23:35.001,0:23:39.011 which causes problems of its own as you[br]can imagine, I don't have to go into any detail 0:23:39.011,0:23:40.015 0:23:40.015,0:23:42.084 So that's a problem 0:23:42.084,0:23:44.078 and there's a problem 0:23:44.078,0:23:48.091 with neurohumoral activation, 0:23:48.091,0:23:50.082 vasoconstriction increases the 0:23:50.082,0:23:54.084 afterload that this poor[br]old failing heart has to pump against. 0:23:54.084,0:23:56.022 It sounds like 0:23:56.022,0:23:59.003 a nice mechanism, but it 0:23:59.003,0:24:00.026 bites the heart 0:24:00.026,0:24:04.072 Various of these humoral[br]substances are 0:24:04.072,0:24:06.001 cardiotoxic 0:24:06.001,0:24:07.028 chronically 0:24:07.028,0:24:09.095 in other words, they are[br]responsible for the increase in apoptosis 0:24:09.095,0:24:14.066 they drive the remodeling and it's a bad thing for the heart 0:24:14.066,0:24:16.003 in the long run, 0:24:16.003,0:24:17.209 and we know about the 0:24:17.209,0:24:21.529 implications of sodium and[br]water retention and how that 0:24:21.529,0:24:24.041 overloads the heart. 0:24:24.041,0:24:26.026 All of these things 0:24:26.026,0:24:26.069 contribute to the downward spiral 0:24:26.069,0:24:29.071 0:24:29.071,0:24:33.052 and I've simplified a very[br]complex business, but 0:24:33.052,0:24:35.016 there are many 0:24:35.016,0:24:38.053 consequences for the[br]peripheral tissues and that's what we're 0:24:38.053,0:24:41.859 really talking about when we talk about[br]heart failure, what's going on 0:24:41.859,0:24:44.299 in the peripheral tissues. 0:24:44.299,0:24:48.007 These consequences we can[br]talk about in a number of ways, we talk 0:24:48.007,0:24:51.058 about sometimes forward failure and backward failure. 0:24:51.058,0:24:53.509 Forward failure being the idea that 0:24:53.509,0:24:58.066 the failing heart does not perfuse the[br]tissues well enough, and 0:24:58.066,0:24:59.669 backward failure you're familiar 0:24:59.669,0:25:03.036 with the idea of passive[br]congestion and we talked about that in class 0:25:03.036,0:25:05.072 so you have a good image of that. 0:25:05.072,0:25:08.929 We speak of left heart failure and[br]right heart failure, 0:25:08.929,0:25:10.028 most processes that cause 0:25:10.028,0:25:12.002 heart failure start out on the left 0:25:12.002,0:25:15.005 but it's a closed plumbing system 0:25:15.005,0:25:20.008 so as the left heart fails, the right heart is going to fail. 0:25:20.008,0:25:21.034 The commonest 0:25:21.034,0:25:25.099 cause of right heart failure then is left heart failure. 0:25:25.099,0:25:29.052 There are some of the examples where the[br]right heart fails primarily and it has to do 0:25:29.052,0:25:31.035 with things happening in the lungs, 0:25:31.035,0:25:37.015 they're relatively less common and you'll[br]hear more about them some other time, 0:25:37.015,0:25:41.043 but the backward consequences[br]of left and right heart failure are very 0:25:41.043,0:25:45.076 familiar to you already, we know that when the left heart fails you get 0:25:45.076,0:25:47.509 pulmonary congestion and edema, 0:25:47.509,0:25:50.053 when the right heart fails, you get 0:25:50.053,0:25:52.066 elevation of hydrostatic 0:25:52.066,0:25:55.034 pressure in a variety of[br]tissues 0:25:55.034,0:25:56.419 with associated 0:25:56.419,0:26:00.389 congestive changes in[br]organs and accumulation of edema 0:26:00.389,0:26:02.007 fluid and this 0:26:02.007,0:26:05.002 is when we start to speak of congestive heart failure. 0:26:05.002,0:26:08.063 We're throwing that adjective very frequently 0:26:08.063,0:26:10.019 0:26:10.019,0:26:14.019 What we're not emphasizing, and I'll just conclude by mentioning this, 0:26:14.019,0:26:15.083 are the forward changes 0:26:15.083,0:26:18.084 associated with left heart[br]failure, in other words, when the left 0:26:18.084,0:26:20.099 heart fails, things begin to 0:26:20.099,0:26:25.559 happen because tissues[br]in a variety of places simply aren't being perfused. 0:26:25.559,0:26:27.027 And you're familiar already with 0:26:27.027,0:26:30.091 the activation of the 0:26:30.091,0:26:32.062 renin-angiotensin-aldosterone system 0:26:32.062,0:26:37.025 from forward failure to 0:26:37.025,0:26:39.099 supply enough blood to the kidney, 0:26:39.099,0:26:45.269 I would point out that as the[br]perfusion drops more and more, 0:26:45.269,0:26:49.096 the kidney can really shut down as far as[br]its excretory function and nitrogenous 0:26:49.096,0:26:52.086 waste can pile up. 0:26:52.086,0:26:54.042 Sometimes they speak, 0:26:54.042,0:26:58.036 people speak, of a cardio-renal syndrome because of this. 0:26:58.036,0:26:59.054 Well many other 0:26:59.054,0:27:04.079 tissues suffer from this lack of perfusion in the same way. 0:27:04.079,0:27:07.075 We've shown you for instance the liver, 0:27:07.075,0:27:11.006 and the liver gets caught in a one-two punch, 0:27:11.006,0:27:12.919 there's resistance to outflow from the liver 0:27:12.919,0:27:16.004 the fact is that the poor old failing left[br]ventricle isn't delivering enough blood 0:27:16.004,0:27:17.002 to this, the central 0:27:17.002,0:27:19.077 lobular area, 0:27:19.077,0:27:22.000 and it undergoes a sort of hemorrhagic 0:27:22.000,0:27:24.007 necrosis which you remember that, you never forget 0:27:24.007,0:27:26.081 that kind of a picture. 0:27:26.081,0:27:31.014 Now something, a little wrinkle that I'll point out here, 0:27:31.014,0:27:31.085 is that the aldosterone 0:27:31.085,0:27:35.309 levels in patients in[br]failure are way way up there 0:27:35.309,0:27:36.096 and part of it 0:27:36.096,0:27:40.023 obviously is because it's been[br]triggered by the production of angiotensin II 0:27:40.023,0:27:42.054 and so forth, but the liver 0:27:42.054,0:27:44.083 when it's in that kind of a state, 0:27:44.083,0:27:48.084 does not catabolize aldosterone the way it should, 0:27:48.084,0:27:52.559 and the patient may end up with a twenty fold increase in aldosterone level partly because 0:27:52.559,0:27:55.041 of synthesis and partly because of 0:27:55.041,0:27:57.033 "non tearing down" 0:27:57.033,0:27:58.063 0:27:58.063,0:27:59.053 by the liver 0:27:59.053,0:28:01.011 0:28:01.011,0:28:02.041 One more example, the gut 0:28:02.041,0:28:04.053 may suffer in very advanced cardiac 0:28:04.053,0:28:06.519 failure, patches of mucosa 0:28:06.519,0:28:09.003 in the bowel may undergo 0:28:09.003,0:28:13.011 necrosis because they're furthest from the blood supply 0:28:13.011,0:28:17.005 and we speak of ischemic colitis, a bit[br]of a misnomer as it is an inflammatory condition, 0:28:17.005,0:28:17.097 0:28:17.097,0:28:18.096 but actually that sort of thing 0:28:18.096,0:28:21.047 can be a problem. 0:28:21.047,0:28:24.929 Other organs and in fact even the[br]central nervous system in very advanced failure 0:28:24.929,0:28:26.018 we see problems 0:28:26.018,0:28:29.002 with CNS function. 0:28:29.002,0:28:32.051 Well I turn the baton over 0:28:32.051,0:28:34.259 to Dr. Matthews 0:28:34.259,0:28:38.012 you just keep some of[br]these images in mind and she will flesh them out, 0:28:38.012,0:28:38.072 0:28:38.072,0:28:40.085 as they say, with the clinical realities 0:28:40.085,0:28:43.031 and with some of the 0:28:43.031,0:28:44.084 therapeutic strategies 0:28:44.084,9:59:59.000 that make sense I hope.