1 00:00:07,069 --> 00:00:10,279 The topic of our conference this afternoon 2 00:00:10,279 --> 00:00:12,409 is is a very important one 3 00:00:12,409 --> 00:00:13,789 namely, heart 4 00:00:13,789 --> 00:00:15,959 failure 5 00:00:15,959 --> 00:00:19,096 and its important, as you'll hear from my colleagues, 6 00:00:19,096 --> 00:00:24,082 for a number of reasons. The sheer prevalence of heart failure in our population 7 00:00:24,082 --> 00:00:25,009 says that 8 00:00:25,009 --> 00:00:29,079 you're going to deal with a tremendous numbers of patients having 9 00:00:29,079 --> 00:00:30,449 related problems. 10 00:00:30,449 --> 00:00:31,769 The associated 11 00:00:31,769 --> 00:00:36,056 morbidity and mortality is very significant and 12 00:00:36,056 --> 00:00:40,095 heart failure, one way or another, consumes a very, very significant 13 00:00:40,095 --> 00:00:43,055 fraction of our health care resources. 14 00:00:43,055 --> 00:00:46,057 So it's a problem that you're going to be dealing with 15 00:00:46,057 --> 00:00:48,092 a lot of the time. 16 00:00:48,092 --> 00:00:51,068 I will spend my time 17 00:00:51,068 --> 00:00:55,008 just introducing the general concept which we've had a little 18 00:00:55,008 --> 00:00:58,044 bit in lecture, but will try to embellish that 19 00:00:58,044 --> 00:01:02,007 and illustrate some of the pathologic anatomy associated with heart 20 00:01:02,007 --> 00:01:03,082 failure one way or another. 21 00:01:03,082 --> 00:01:07,026 Then I'll pass the baton to Dr Matthews 22 00:01:07,026 --> 00:01:11,095 who will make clinical reality out of this 23 00:01:11,095 --> 00:01:16,004 and translate all of this into signs and symptom that the patients manifest 24 00:01:16,004 --> 00:01:16,091 and 25 00:01:16,091 --> 00:01:19,086 appropriate strategies 26 00:01:19,086 --> 00:01:23,034 of medical therapy and then we will conclude the afternoon with 27 00:01:23,034 --> 00:01:25,033 Dr Jonathan Haft 28 00:01:25,033 --> 00:01:28,077 and with the participation of a patient of his 29 00:01:28,077 --> 00:01:32,008 and discuss the treatment of advanced heart failure 30 00:01:32,008 --> 00:01:36,036 with mechanical support and cardiac transplantation. 31 00:01:36,036 --> 00:01:37,044 So that's 32 00:01:37,044 --> 00:01:42,051 the agenda for this afternoon. 33 00:01:42,051 --> 00:01:43,034 Now in its 34 00:01:43,034 --> 00:01:47,098 very simple definition, and there are a lot of ways to define it, the very simple 35 00:01:47,098 --> 00:01:50,018 definition of heart failure 36 00:01:50,018 --> 00:01:53,002 involves the inability of the heart 37 00:01:53,002 --> 00:01:55,729 to meet 38 00:01:55,729 --> 00:02:00,033 to really pump sufficient blood to meet the metabolic needs of 39 00:02:00,033 --> 00:02:02,012 the body. 40 00:02:02,012 --> 00:02:06,056 Now this can happen in a in a variety of ways. 41 00:02:06,056 --> 00:02:10,589 It can come to pass, and this isn't as frequent, that the 42 00:02:10,589 --> 00:02:14,579 heart is putting out a normal or even an excessive amount of blood. 43 00:02:14,579 --> 00:02:16,659 It's really pumping it out there, but it's being 44 00:02:16,659 --> 00:02:18,051 driven by 45 00:02:18,051 --> 00:02:23,009 an increased demand in the peripheral tissues that it just can't keep up with. 46 00:02:23,009 --> 00:02:26,439 This sort of thing we see in thyrotoxicosis. 47 00:02:26,439 --> 00:02:28,059 It used to be seen, 48 00:02:28,059 --> 00:02:31,789 we don't see it much any more thankfully, in beriberi - vitamin deficiency 49 00:02:31,789 --> 00:02:33,659 with vasodilatation 50 00:02:33,659 --> 00:02:36,409 all over the place and the heart just couldn't keep up with 51 00:02:36,409 --> 00:02:37,042 that volume 52 00:02:37,042 --> 00:02:38,139 of the 53 00:02:38,139 --> 00:02:40,209 cardiovascular system. 54 00:02:40,209 --> 00:02:45,839 It's seen occasionally with arteriovenous fistulas 55 00:02:45,839 --> 00:02:49,559 that dump a lot of blood directly from arteries into the veins in the heart 56 00:02:49,559 --> 00:02:52,709 The heart just can't keep up. Or severe anemia. 57 00:02:52,709 --> 00:02:56,499 Those sorts of things will result in what we call a high output sort of failure, 58 00:02:56,499 --> 00:02:57,489 but much more 59 00:02:57,489 --> 00:02:59,119 often, we're dealing with 60 00:02:59,119 --> 00:03:00,085 the problem of 61 00:03:00,085 --> 00:03:03,799 not enough blood being ejected 62 00:03:03,799 --> 00:03:06,269 for one reason or another 63 00:03:06,269 --> 00:03:11,359 from the heart to support even normal demands 64 00:03:11,359 --> 00:03:15,039 and this is a combination really of 65 00:03:15,039 --> 00:03:18,489 the loss of systolic umph, 66 00:03:18,489 --> 00:03:22,069 in other words, the contracting heart just can't get it out there 67 00:03:22,069 --> 00:03:23,059 in the way it should and 68 00:03:23,059 --> 00:03:27,052 often this can be accompanied by 69 00:03:27,052 --> 00:03:29,069 diastolic, 70 00:03:29,069 --> 00:03:34,279 i've listed it here as diastolic failure but it's a difficulty in diastolic filling 71 00:03:34,279 --> 00:03:38,419 which can impair the heart action. If the heart muscle can't relax and is ineffective 72 00:03:38,419 --> 00:03:39,004 it's stiff 73 00:03:39,004 --> 00:03:40,459 it won't 74 00:03:40,459 --> 00:03:41,809 accept 75 00:03:41,809 --> 00:03:44,009 the right volume coming into it and that's going to lead 76 00:03:44,009 --> 00:03:46,989 also to failure. 77 00:03:46,989 --> 00:03:52,229 One way or another, these factors can lead to a constellation 78 00:03:52,229 --> 00:03:54,033 of signs and symptoms, 79 00:03:54,033 --> 00:03:57,009 we'll get to that at the end. 80 00:03:57,009 --> 00:04:00,689 It's really related on the one hand to congestion of organs which you know all 81 00:04:00,689 --> 00:04:02,439 about now after 82 00:04:02,439 --> 00:04:02,095 your 83 00:04:02,095 --> 00:04:08,034 lectures in pathology and hypoprofusion of tissues which 84 00:04:08,034 --> 00:04:10,099 we haven't emphasized as much, but it's a 85 00:04:10,099 --> 00:04:13,068 very important point. 86 00:04:13,068 --> 00:04:18,659 Now, when we look at the causes of heart failure and there are many, many of them, far more 87 00:04:18,659 --> 00:04:20,869 than we can talk about, 88 00:04:20,869 --> 00:04:22,319 but 89 00:04:22,319 --> 00:04:25,819 if we look at those situations where there is 90 00:04:25,819 --> 00:04:28,061 some unusual demand 91 00:04:28,061 --> 00:04:31,041 on the heart, and the heart just can't meet it, they 92 00:04:31,041 --> 00:04:33,229 fall into a number 93 00:04:33,229 --> 00:04:35,319 of categories, and I will 94 00:04:35,319 --> 00:04:37,919 illustrate each of these in a moment, 95 00:04:37,919 --> 00:04:41,028 but one very important category is resistance 96 00:04:41,028 --> 00:04:42,759 to flow, in other words, 97 00:04:42,759 --> 00:04:46,769 if something is keeping the flow of blood from going so 98 00:04:46,769 --> 00:04:50,879 the heart has to work harder to push it past that resistance 99 00:04:50,879 --> 00:04:55,629 it will come to the point where the heart could no longer do it and it fails. 100 00:04:55,629 --> 00:04:59,009 Another problem is what we call regurgitant flow, I mean you like to think of the 101 00:04:59,009 --> 00:05:03,979 blood flowing in one direction through the cardiovascular system, but 102 00:05:03,979 --> 00:05:05,769 sometimes it comes to pass where, at a point, 103 00:05:05,769 --> 00:05:06,007 there's 104 00:05:06,007 --> 00:05:09,089 regurgitation, instead of things pulsing forward, they slosh 105 00:05:09,089 --> 00:05:11,569 backward, and that 106 00:05:11,569 --> 00:05:16,439 imposes a strain on the heart as you will see 107 00:05:16,439 --> 00:05:21,037 and thirdly and very importantly there is disease of various sorts, lots of sorts, 108 00:05:21,037 --> 00:05:25,439 targeting the myocardium itself 109 00:05:25,439 --> 00:05:29,015 so that there's no resistance to flow, there's no regurgitant flow 110 00:05:29,015 --> 00:05:29,999 perhaps, but the 111 00:05:29,999 --> 00:05:32,559 heart muscle is sick. 112 00:05:32,559 --> 00:05:34,019 And finally, we won't talk 113 00:05:34,019 --> 00:05:38,079 at all about this, I won't, about conduction abnormalities 114 00:05:38,079 --> 00:05:40,064 which can also lead to decompensation 115 00:05:40,064 --> 00:05:42,018 of the heart. 116 00:05:42,018 --> 00:05:43,369 Now, I'd like 117 00:05:43,369 --> 00:05:46,619 to illustrate some of these very quickly, don't get lost in the details, 118 00:05:46,619 --> 00:05:47,069 just 119 00:05:47,069 --> 00:05:51,047 let it flow over you, you're going to get these details later on 120 00:05:51,047 --> 00:05:52,097 in the year 121 00:05:52,097 --> 00:05:57,509 later on in your careers, but just for a little orientation, 122 00:05:57,509 --> 00:06:03,011 I'll give you an example first of resistance to flow, 123 00:06:03,011 --> 00:06:04,709 there is a good hallmark for 124 00:06:04,709 --> 00:06:08,309 it, I can't show you hypertension obviously 125 00:06:08,309 --> 00:06:09,179 but think of 126 00:06:09,179 --> 00:06:14,559 the situation when a patient has established significant hypertension, 127 00:06:14,559 --> 00:06:16,081 it means that 24/7 128 00:06:16,081 --> 00:06:19,759 every minute, every beat of the heart 129 00:06:19,759 --> 00:06:24,219 that poor left ventricle is having to force against an increased resistance to flow, 130 00:06:24,219 --> 00:06:25,003 that's what hypertension 131 00:06:25,003 --> 00:06:27,509 is all about. The result 132 00:06:27,509 --> 00:06:28,008 133 00:06:28,008 --> 00:06:32,028 one of the results you see here is is this rather massive 134 00:06:32,028 --> 00:06:34,048 myocardial hypertrophy which i'm sure you all recognize, 135 00:06:34,048 --> 00:06:35,969 so that's one 136 00:06:35,969 --> 00:06:40,036 kind of resistance to flow. Here's another one, this takes a 137 00:06:40,036 --> 00:06:44,919 little explaining, it's an unusual plane of section of the heart, 138 00:06:44,919 --> 00:06:48,289 but what attracts your attention right away is that the left ventricle 139 00:06:48,289 --> 00:06:51,009 is immensely hypertrophied, very thick 140 00:06:51,009 --> 00:06:52,819 and very heavy, and the reason 141 00:06:52,819 --> 00:06:56,479 for it is not terribly well shown here 142 00:06:56,479 --> 00:07:00,849 but here is the aortic outflow, this is the aorta here, and this would be the aortic valve 143 00:07:00,849 --> 00:07:03,005 which you can't get a good view of, but 144 00:07:03,005 --> 00:07:08,043 a common lesion is stenosis of the aortic valve, 145 00:07:08,043 --> 00:07:13,024 and obviously, in that situation, it's very analogous to hypertension, every time 146 00:07:13,024 --> 00:07:16,159 the ventricle contracts, it's got to push that blood 147 00:07:16,159 --> 00:07:18,449 through a stenotic valve 148 00:07:18,449 --> 00:07:20,269 and it's a lot of work. 149 00:07:20,269 --> 00:07:23,839 I'll show you one of these valves from above, this is an interesting one, 150 00:07:23,839 --> 00:07:27,849 this is a pretty typical example of aortic stenosis, 151 00:07:27,849 --> 00:07:31,004 you're standing in the ascending aorta, looking back 152 00:07:31,004 --> 00:07:33,859 towards the left ventricle, and 153 00:07:33,859 --> 00:07:39,939 you're aware from your gross anatomy that this should be a three cusp valve 154 00:07:39,939 --> 00:07:42,033 and you're seeing a couple of things here, 155 00:07:42,033 --> 00:07:45,129 first of all this is only two cusps 156 00:07:45,129 --> 00:07:47,009 and that was a congenital problem 157 00:07:47,009 --> 00:07:50,279 and it's a fairly frequent one in our population, there are probably a 158 00:07:50,279 --> 00:07:51,499 couple of so-called 159 00:07:51,499 --> 00:07:53,699 bicuspid valves in this room 160 00:07:53,699 --> 00:07:55,499 and 161 00:07:55,499 --> 00:07:57,009 whatever the case 162 00:07:57,009 --> 00:08:01,021 the aortic valve is very susceptible to calcification 163 00:08:01,021 --> 00:08:04,119 and stiffening with age, and if you 164 00:08:04,119 --> 00:08:07,969 plot it against the aging population, we see an increasing 165 00:08:07,969 --> 00:08:09,409 incidence of stenotic 166 00:08:09,409 --> 00:08:11,319 aortic valves even if they're not 167 00:08:11,319 --> 00:08:15,409 bicuspid, if they're congenitally bicuspid like this they get wrecked 168 00:08:15,409 --> 00:08:16,689 very frequently 169 00:08:16,689 --> 00:08:18,609 earlier on so that 170 00:08:18,609 --> 00:08:21,959 instead of maybe in the seventies or eighties, it might be in the 171 00:08:21,959 --> 00:08:24,049 fifties and sixties that the patient would suffer from such stenosis. 172 00:08:24,049 --> 00:08:25,006 But you can see 173 00:08:25,006 --> 00:08:26,919 that every time 174 00:08:26,919 --> 00:08:30,004 the ventricle is trying to push blood through that orifice, and it's really like brick 175 00:08:30,004 --> 00:08:31,619 it doesn't move. 176 00:08:31,619 --> 00:08:32,082 It's going to be a 177 00:08:32,082 --> 00:08:37,024 tremendous load on the left ventricle. 178 00:08:37,024 --> 00:08:41,047 here's another valve stenosis for you, we don't see this as much anymore, 179 00:08:41,047 --> 00:08:45,093 it's a result usually of old rheumatic fever in childhood, but the mitral valve 180 00:08:45,093 --> 00:08:50,001 here is reduced to a fish mouth, it's all puckered up 181 00:08:50,001 --> 00:08:54,035 and scarred, and frequently calcified, 182 00:08:54,035 --> 00:08:55,649 and the valve leaflets 183 00:08:55,649 --> 00:08:57,026 can't move at all, 184 00:08:57,026 --> 00:08:59,096 so that the blood coming out of the lungs into the 185 00:08:59,096 --> 00:09:01,059 into the left atrium trying to get through 186 00:09:01,059 --> 00:09:04,039 into the left ventricle, you're looking down towards the left ventricle, 187 00:09:04,039 --> 00:09:08,072 it's got to pass by that stenotic slit. 188 00:09:08,072 --> 00:09:10,009 The result is damming back, 189 00:09:10,009 --> 00:09:15,043 very obviously you know about passive congestion, you can see this immensely dilated 190 00:09:15,043 --> 00:09:16,017 left atrium 191 00:09:16,017 --> 00:09:17,003 and you can imagine 192 00:09:17,003 --> 00:09:20,007 what was happening in the lungs 193 00:09:20,007 --> 00:09:21,669 behind that sort of obstruction. 194 00:09:21,669 --> 00:09:22,082 Now as far as 195 00:09:22,082 --> 00:09:25,094 regurgitant flow, hold on with me 196 00:09:25,094 --> 00:09:30,035 and i'll try to explain it, here is another mitral valve, we've chopped off the 197 00:09:30,035 --> 00:09:32,004 the atrium and you're looking right at the 198 00:09:32,004 --> 00:09:34,088 mitral valve, and 199 00:09:34,088 --> 00:09:38,023 think about what you saw in gross anatomy, the mitral valve leaflets usually come together 200 00:09:38,023 --> 00:09:41,003 like that and keep the blood, during systole, 201 00:09:41,003 --> 00:09:45,023 keep the blood from flowing back into the atrium so all the blood goes out 202 00:09:45,023 --> 00:09:47,044 the aorta like it should. 203 00:09:47,044 --> 00:09:49,071 Here, 204 00:09:49,071 --> 00:09:54,084 and this happens for a variety of reasons, but here this leaflet of the valve 205 00:09:54,084 --> 00:09:57,043 is sort of pooched up and 206 00:09:57,043 --> 00:10:02,071 and with every ventricular systole, blood is able to force its way back 207 00:10:02,071 --> 00:10:04,048 into the atrium, which means 208 00:10:04,048 --> 00:10:08,015 the poor old left ventricle is pumping some of that blood more than once 209 00:10:08,015 --> 00:10:11,063 in other words it's putting part of it out the aorta, part of it back up the atrium, 210 00:10:11,063 --> 00:10:12,044 and that comes 211 00:10:12,044 --> 00:10:14,047 sloshing down for the next 212 00:10:14,047 --> 00:10:16,028 beat of the heart 213 00:10:16,028 --> 00:10:18,084 and it consists, 214 00:10:18,084 --> 00:10:22,649 it induces a volume overload on the valve 215 00:10:22,649 --> 00:10:24,075 and 216 00:10:24,075 --> 00:10:26,059 on the ventricle 217 00:10:26,059 --> 00:10:29,016 and it may fail. 218 00:10:29,016 --> 00:10:33,026 Now when you get to the realm of myocardial abnormality per se, in other words disease of the myocardium 219 00:10:33,026 --> 00:10:34,098 220 00:10:34,098 --> 00:10:36,022 there are lots 221 00:10:36,022 --> 00:10:42,012 and lots of examples, and the most frequent one and most important one is myocardial ischemic disease 222 00:10:42,012 --> 00:10:46,098 in other words, the result of coronary artery disease, atherosclerosis 223 00:10:46,098 --> 00:10:50,062 and its complications, and what happens when the myocardium 224 00:10:50,062 --> 00:10:52,001 becomes ischemic. 225 00:10:52,001 --> 00:10:55,075 Clearly many patients who have a myocardial infarct, an acute heart attack 226 00:10:55,075 --> 00:10:56,095 will go into 227 00:10:56,095 --> 00:11:01,012 acute failure if enough of the myocardium is involved right then and there in the 228 00:11:01,012 --> 00:11:04,023 emergency room. 229 00:11:04,023 --> 00:11:06,097 But chronically it can become a big problem even when the 230 00:11:06,097 --> 00:11:11,057 situation heals. Here, for example, 231 00:11:11,057 --> 00:11:15,045 a slice of a heart, this is left ventricle over here, 232 00:11:15,045 --> 00:11:19,012 and this individual sustained a myocardial infarct, I don't know how long ago, 233 00:11:19,012 --> 00:11:20,089 it could be years ago, 234 00:11:20,089 --> 00:11:25,014 months ago, and you see a lot of scar 235 00:11:25,014 --> 00:11:28,022 throughout the ventricular wall, a little bit back there, a little bit in the septum, 236 00:11:28,022 --> 00:11:31,005 but a tremendous scar here 237 00:11:31,005 --> 00:11:36,399 and when this involves enough of the ventricular myocardium, it puts a strain 238 00:11:36,399 --> 00:11:39,056 on what's left of viable myocardium, because this 239 00:11:39,056 --> 00:11:43,000 obviously doesn't contract. 240 00:11:43,000 --> 00:11:47,005 Patients can sustain a lot of myocardial infarcts, 241 00:11:47,005 --> 00:11:52,025 here's serial sections of the same heart, and you can see at least a couple of infarcts 242 00:11:52,025 --> 00:11:52,809 that involve 243 00:11:52,809 --> 00:11:54,015 a tremendous 244 00:11:54,015 --> 00:11:55,072 fraction of the 245 00:11:55,072 --> 00:11:56,024 left ventricle 246 00:11:56,024 --> 00:11:57,093 and again when 247 00:11:57,093 --> 00:11:59,639 that happens, the rest of 248 00:11:59,639 --> 00:12:02,048 this can't keep up with it, and the left 249 00:12:02,048 --> 00:12:04,083 ventricle fails. 250 00:12:04,083 --> 00:12:06,059 Here is a heart that was 251 00:12:06,059 --> 00:12:09,093 was removed from a patient who was still alive 252 00:12:09,093 --> 00:12:12,071 happy and well as far as i know 253 00:12:12,071 --> 00:12:15,073 This is an explant to the heart, in other words, taken out of the time of transplantation 254 00:12:15,073 --> 00:12:16,889 and this was also 255 00:12:16,889 --> 00:12:19,239 ischemic disease, and this 256 00:12:19,239 --> 00:12:22,459 individual had scraped through 257 00:12:22,459 --> 00:12:26,083 with this much of the heart converted into 258 00:12:26,083 --> 00:12:29,085 what amounted to a fibrous sack, totally 259 00:12:29,085 --> 00:12:32,021 non-contractile 260 00:12:32,021 --> 00:12:36,006 and you can see there's even a clot in there because it wasn't moving 261 00:12:36,006 --> 00:12:37,002 and that had 262 00:12:37,002 --> 00:12:41,018 produced failure of the remaining myocardium. 263 00:12:41,018 --> 00:12:42,093 So that's a 264 00:12:42,093 --> 00:12:45,002 good sample of 265 00:12:45,002 --> 00:12:46,012 ischemic 266 00:12:46,012 --> 00:12:49,021 disease leading to chronic failure of the left ventricle. 267 00:12:49,021 --> 00:12:49,679 268 00:12:49,679 --> 00:12:51,084 Now, beyond 269 00:12:51,084 --> 00:12:55,017 ischemic disease there are a whole lot of them, don't worry about the details 270 00:12:55,017 --> 00:12:58,092 I'll show you this as an example of an inflammatory process targeted at 271 00:12:58,092 --> 00:13:01,013 the myocardium. We see this 272 00:13:01,013 --> 00:13:05,049 with certain viral infections, certain protozoan infections, 273 00:13:05,049 --> 00:13:06,074 with bacterial 274 00:13:06,074 --> 00:13:11,004 infections, but you can get inflammation of the myocardium 275 00:13:11,004 --> 00:13:13,076 and you can almost literally hear 276 00:13:13,076 --> 00:13:16,018 these cells chewing at the myocytes 277 00:13:16,018 --> 00:13:18,025 and obviously 278 00:13:18,025 --> 00:13:22,059 obviously that can produce failure. 279 00:13:22,059 --> 00:13:25,049 We see that not infrequently, 280 00:13:25,049 --> 00:13:29,048 then the heart can be involved in a variety of systemic diseases, in other words 281 00:13:29,048 --> 00:13:32,097 you can have something going on affecting many tissues in 282 00:13:32,097 --> 00:13:36,041 the body, but that something may affect the heart and produce 283 00:13:36,041 --> 00:13:37,669 failure. Here's an example 284 00:13:37,669 --> 00:13:39,093 now I don't know 285 00:13:39,093 --> 00:13:44,021 if I want to dart in the auditorium completely to show you this 286 00:13:44,021 --> 00:13:49,093 did you discuss hemochromatosis in genetics? Yes? Not a complete blank. 287 00:13:49,093 --> 00:13:52,025 288 00:13:52,025 --> 00:13:56,016 It's an ineffective storage disease because the body absorbs too much iron 289 00:13:56,016 --> 00:13:56,083 from the gut, 290 00:13:56,083 --> 00:13:58,003 and the iron 291 00:13:58,003 --> 00:14:01,087 gets stored in a variety of issues and one of the tissues it gets stored in 292 00:14:01,087 --> 00:14:03,066 is the heart, 293 00:14:03,066 --> 00:14:07,024 and you recognize instantly that this is myocardium 294 00:14:07,024 --> 00:14:11,021 and as you stare at it a little bit, you'll pick out some nice golden brown pigment 295 00:14:11,021 --> 00:14:16,045 there and there and there, you see a little more over there, and little bit down there and over there. 296 00:14:16,045 --> 00:14:18,071 and one of the pigments 297 00:14:18,071 --> 00:14:21,088 you'd think of in the heart, someone asked me a question about this last week, 298 00:14:21,088 --> 00:14:25,052 it would be lipofuscin (wear and tear pigment) 299 00:14:25,052 --> 00:14:30,066 but another pigment you got to think about is iron, and this is stored iron 300 00:14:30,066 --> 00:14:31,989 in this myocardium. Here is 301 00:14:31,989 --> 00:14:33,038 that blue 302 00:14:33,038 --> 00:14:37,099 Prussian blue iron stain, tremendous iron 303 00:14:37,099 --> 00:14:38,096 load, iron is bad for you 304 00:14:38,096 --> 00:14:44,024 if it gets deposited in certain tissues. This can produce myocardial failure. 305 00:14:44,024 --> 00:14:46,089 This was from a relatively young man who presented with 306 00:14:46,089 --> 00:14:49,004 very advanced heart failure 307 00:14:49,004 --> 00:14:51,013 because of his unrecognized 308 00:14:51,013 --> 00:14:52,004 hemochromatosis. 309 00:14:52,004 --> 00:14:54,056 310 00:14:54,056 --> 00:14:55,009 One other that you will hear about 311 00:14:55,009 --> 00:14:58,045 probably next year 312 00:14:58,045 --> 00:15:01,026 is amyloidosis. Amyloid 313 00:15:01,026 --> 00:15:02,109 314 00:15:02,109 --> 00:15:06,058 is an abnormal protein that could get deposited in a number of tissues 315 00:15:06,058 --> 00:15:08,082 for a number of reasons, which I won't go into. 316 00:15:08,082 --> 00:15:10,149 But all of this 317 00:15:10,149 --> 00:15:15,002 sort of translucent, gray stuff surrounding the 318 00:15:15,002 --> 00:15:19,066 myocytes, you're looking at a cross-sectional view of myocardium, 319 00:15:19,066 --> 00:15:23,049 and you can see that each myocyte is enveloped in this 320 00:15:23,049 --> 00:15:24,062 casing 321 00:15:24,062 --> 00:15:26,035 of amyloid. 322 00:15:26,035 --> 00:15:27,063 And this is 323 00:15:27,063 --> 00:15:31,007 a marvelous example of something that renders the heart rigid 324 00:15:31,007 --> 00:15:31,093 and unable to 325 00:15:31,093 --> 00:15:34,074 expand diastolically, and it can be 326 00:15:34,074 --> 00:15:36,063 a cause of heart failure. 327 00:15:36,063 --> 00:15:38,092 Finally, 328 00:15:38,092 --> 00:15:41,061 this is not a complete list, I'm just showing 329 00:15:41,061 --> 00:15:43,006 the examples, there are 330 00:15:43,006 --> 00:15:47,082 a number of genetic diseases of the heart muscle itself, where from 331 00:15:47,082 --> 00:15:49,078 the get go, because of 332 00:15:49,078 --> 00:15:51,087 abnormal genetic endowment 333 00:15:51,087 --> 00:15:52,046 334 00:15:52,046 --> 00:15:53,085 the heart is 335 00:15:53,085 --> 00:15:56,003 made wrong. Here's an example 336 00:15:56,003 --> 00:16:00,021 of something we call hypertrophic cardiomyopathy. 337 00:16:00,021 --> 00:16:06,012 Cardiomyopathy means heart muscle disease. 338 00:16:06,012 --> 00:16:09,083 This particular heart was immensely hypertrophic, you can see that left ventricle 339 00:16:09,083 --> 00:16:11,086 it's really tremendous with no 340 00:16:11,086 --> 00:16:14,009 valve disease, no hypertension to explain that, 341 00:16:14,009 --> 00:16:17,001 but look at the 342 00:16:17,001 --> 00:16:19,063 goofy muscle, you know 343 00:16:19,063 --> 00:16:23,031 what myocardium is supposed to look like, and the histology people never show you 344 00:16:23,031 --> 00:16:24,001 the kind of 345 00:16:24,001 --> 00:16:27,055 disarray and criss-crossing of fibers like that. 346 00:16:27,055 --> 00:16:33,056 This is the result of the genetic abnormality of this myocardium. 347 00:16:33,056 --> 00:16:37,004 All right, these are just a few examples of the things that can go wrong 348 00:16:37,004 --> 00:16:40,013 349 00:16:40,013 --> 00:16:41,093 and most frequently, 350 00:16:41,093 --> 00:16:46,000 if I had to pick from this whole list, I'd say hypertension and 351 00:16:46,000 --> 00:16:47,062 ischemic disease 352 00:16:47,062 --> 00:16:52,062 are the big actors at least in our population. 353 00:16:52,062 --> 00:16:55,052 Whatever the cause, as the heart is 354 00:16:55,052 --> 00:16:56,086 overburdened, 355 00:16:56,086 --> 00:17:00,005 there are certain compensatory mechanisms that kick in 356 00:17:00,005 --> 00:17:02,091 for a while, in other words, enable the heart to keep up 357 00:17:02,091 --> 00:17:05,042 with the abnormal strain, 358 00:17:05,042 --> 00:17:08,077 and some of these you know about, you've heard about I'm sure about the Frank Starling 359 00:17:08,077 --> 00:17:10,179 mechanism, 360 00:17:10,179 --> 00:17:11,000 361 00:17:11,000 --> 00:17:11,066 362 00:17:11,066 --> 00:17:17,005 where the myocyte is stretched by increased filling pressure, it's stretched 363 00:17:17,005 --> 00:17:19,002 and contracts then 364 00:17:19,002 --> 00:17:20,094 with greater vigor, 365 00:17:20,094 --> 00:17:23,429 in other words, it can put out more UMPH 366 00:17:23,429 --> 00:17:27,069 if it starts from a slight stretch. The trouble with that mechanism is that it fails. 367 00:17:27,069 --> 00:17:28,209 In other words, for a while 368 00:17:28,209 --> 00:17:31,085 it's adaptive, you get more and more UMPH for each 369 00:17:31,085 --> 00:17:34,017 contraction and then it peters out 370 00:17:34,017 --> 00:17:37,003 for a variety of reasons. 371 00:17:37,003 --> 00:17:40,039 A second compensation is hypertrophy, 372 00:17:40,039 --> 00:17:44,049 and you know about this, we talked about it last summer I guess. 373 00:17:44,049 --> 00:17:46,159 It's a situation where the same number 374 00:17:46,159 --> 00:17:49,149 of muscle cells are there 375 00:17:49,149 --> 00:17:51,071 but more sarcomeres are added 376 00:17:51,071 --> 00:17:54,089 and the muscle cells enlarge the whole 377 00:17:54,089 --> 00:17:56,074 tissue grossly 378 00:17:56,074 --> 00:17:59,001 enlarges and there's more UMPH. 379 00:17:59,001 --> 00:18:00,089 I mean it's very definitely 380 00:18:00,089 --> 00:18:03,097 a compensatory mechanism. 381 00:18:03,097 --> 00:18:05,001 A third compensation 382 00:18:05,001 --> 00:18:08,023 mechanism I've listed 383 00:18:08,023 --> 00:18:11,061 is activation of neuro-humoral systems and we're not going to go into that 384 00:18:11,061 --> 00:18:13,649 in much detail, just enough detail 385 00:18:13,649 --> 00:18:15,002 so you know that 386 00:18:15,002 --> 00:18:17,006 they are there. 387 00:18:17,006 --> 00:18:19,083 Now here's hypertrophy! 388 00:18:19,083 --> 00:18:22,051 Normal size myocytes you see over here 389 00:18:22,051 --> 00:18:25,092 and each one is on the average just a little bit thicker 390 00:18:25,092 --> 00:18:27,007 than the normal 391 00:18:27,007 --> 00:18:28,038 392 00:18:28,038 --> 00:18:32,051 That's because of addition of sarcomeres, not much change in the number of cells 393 00:18:32,051 --> 00:18:36,005 and you can imagine these cells having more UMPH like a weight lifter, 394 00:18:36,005 --> 00:18:41,095 imagine that, like a weight lifters arm 395 00:18:41,095 --> 00:18:44,389 This is maybe what we see 396 00:18:44,389 --> 00:18:48,789 grossly, there's an increase in the muscle, increase in the weight of the heart, 397 00:18:48,789 --> 00:18:49,071 and sometimes 398 00:18:49,071 --> 00:18:53,093 we see concentric hypertrophy, meaning 399 00:18:53,093 --> 00:18:58,039 the chamber is not enlarged, it may even be a little smaller, gross thickening of the walls 400 00:18:58,039 --> 00:18:59,098 and its 401 00:18:59,098 --> 00:19:00,077 concentric. 402 00:19:00,077 --> 00:19:03,048 We see that usually with pressure overload. 403 00:19:03,048 --> 00:19:06,039 With a volume overload, we may see 404 00:19:06,039 --> 00:19:07,052 what looks like no hypertrophy 405 00:19:07,052 --> 00:19:10,058 at all except that's a lot more muscle 406 00:19:10,058 --> 00:19:13,046 than there is normal, it's just that it's dilated. 407 00:19:13,046 --> 00:19:16,015 That also happens in very advanced failure 408 00:19:16,015 --> 00:19:19,005 from any cause, you see this sort of eccentric picture. 409 00:19:19,005 --> 00:19:20,038 410 00:19:20,038 --> 00:19:24,009 When it comes to the neuro-humoral mechanisms, I'm just going to race through these now, 411 00:19:24,009 --> 00:19:25,053 there is 412 00:19:25,053 --> 00:19:28,021 first of all 413 00:19:28,021 --> 00:19:30,001 414 00:19:30,001 --> 00:19:32,077 all of these things tend to be triggered by pressure and 415 00:19:32,077 --> 00:19:36,409 stretch receptors that are scattered through the heart 416 00:19:36,409 --> 00:19:38,789 the aorta, the carotids, 417 00:19:38,789 --> 00:19:41,031 and the kidney even there is such sensing. 418 00:19:41,031 --> 00:19:45,074 When the cardiac output begins to drop, these receptors say UH OH 419 00:19:45,074 --> 00:19:50,015 and they trigger a number of things, one of the things they trigger is 420 00:19:50,015 --> 00:19:51,093 a central nervous system, 421 00:19:51,093 --> 00:19:54,035 i'm sorry, the sympathetic nervous system 422 00:19:54,035 --> 00:19:57,559 with release of norepinephrine 423 00:19:57,559 --> 00:19:59,005 and this can produce 424 00:19:59,005 --> 00:20:02,056 a contractile boost for the heart 425 00:20:02,056 --> 00:20:04,029 426 00:20:04,029 --> 00:20:07,086 this can produce an increased heart rate 427 00:20:07,086 --> 00:20:11,094 these things will help meet an abnormal load 428 00:20:11,094 --> 00:20:16,005 and also this will produce vasoconstriction peripherally. 429 00:20:16,005 --> 00:20:18,061 This is designed, 430 00:20:18,061 --> 00:20:20,053 this evolved this way presumably to 431 00:20:20,053 --> 00:20:26,006 to make sure that blood gets shunted to essential organs 432 00:20:26,006 --> 00:20:29,026 so there's peripheral vasoconstriction 433 00:20:29,026 --> 00:20:33,549 which increase, well we'll talk about what the bad things it does. 434 00:20:33,549 --> 00:20:35,219 Vasopressin is released 435 00:20:35,219 --> 00:20:38,091 from the hypothalamus, that's also a vasoconstrictor, 436 00:20:38,091 --> 00:20:41,017 and we talked in class previously about 437 00:20:41,017 --> 00:20:44,092 the renin-angiotension-aldosterone system. 438 00:20:44,092 --> 00:20:45,095 439 00:20:45,095 --> 00:20:51,549 The kidney senses the decreased flow that's coming to it, secretes renin which 440 00:20:51,549 --> 00:20:56,005 acts on angiotensinogen which is circulating protein 441 00:20:56,005 --> 00:20:56,095 442 00:20:56,095 --> 00:20:58,093 forms angiotensin I 443 00:20:58,093 --> 00:21:02,004 and then there's angiotensin converting enzyme which takes angiotensin II 444 00:21:02,004 --> 00:21:03,038 that in turn 445 00:21:03,038 --> 00:21:05,001 stimulates the production 446 00:21:05,001 --> 00:21:10,018 in the adrenals of aldosterone. 447 00:21:10,018 --> 00:21:11,005 448 00:21:11,005 --> 00:21:14,859 The importance of all of this is first of all angiotensin II 449 00:21:14,859 --> 00:21:18,064 is also a vasoconstrictor 450 00:21:18,064 --> 00:21:20,047 and 451 00:21:20,047 --> 00:21:24,083 between angiotensin II and aldosterone, there is 452 00:21:24,083 --> 00:21:29,038 sodium retention, salt retention, sodium retention and water retention 453 00:21:29,038 --> 00:21:30,067 and that has 454 00:21:30,067 --> 00:21:33,083 some important consequences. 455 00:21:33,083 --> 00:21:38,061 I just listed, I don't have time to go into it, the natriuretic peptides 456 00:21:38,061 --> 00:21:42,085 secreted by the heart which tend to counteract the renin-angiotensin-aldosterone 457 00:21:42,085 --> 00:21:45,087 system to some extent. 458 00:21:45,087 --> 00:21:49,058 Unfortunately, all of these 459 00:21:49,058 --> 00:21:52,036 mechanisms 460 00:21:52,036 --> 00:21:56,000 are limited in how much help they can provide and there's a downside 461 00:21:56,000 --> 00:21:57,033 to a lot of them. 462 00:21:57,033 --> 00:21:58,069 Now 463 00:21:58,069 --> 00:22:02,028 problems with hypertrophy, it just gets bigger and 464 00:22:02,028 --> 00:22:04,004 bigger and bigger muscle, 465 00:22:04,004 --> 00:22:08,051 it doesn't work out that way because the capillary network in the muscle 466 00:22:08,051 --> 00:22:11,269 does not increase in parallel and you 467 00:22:11,269 --> 00:22:15,259 end up with perfusion problems so there's a limit to how much hypertrophy 468 00:22:15,259 --> 00:22:18,039 the tissue can stand. 469 00:22:18,039 --> 00:22:21,064 Same is true for the ratio between mitochondria and 470 00:22:21,064 --> 00:22:27,033 and contractile protein, so to speak, the mitochondria-to-meat ratio 471 00:22:27,033 --> 00:22:31,038 does not keep up to what it should be so the energy is a problem. 472 00:22:31,038 --> 00:22:33,044 Then very importantly 473 00:22:33,044 --> 00:22:38,066 we're learning that there is altered gene expression 474 00:22:38,066 --> 00:22:40,038 and alteration in the 475 00:22:40,038 --> 00:22:43,073 proteins that are produced, and these may involve 476 00:22:43,073 --> 00:22:45,669 contractile proteins, 477 00:22:45,669 --> 00:22:46,068 segmentation 478 00:22:46,068 --> 00:22:50,071 contraction coupling them, they may involve energy utilization, 479 00:22:50,071 --> 00:22:53,088 but some abnormal proteins are made 480 00:22:53,088 --> 00:22:57,053 there's an increase in apoptosis 481 00:22:57,053 --> 00:23:00,003 in a hypertrophic myocardium 482 00:23:00,003 --> 00:23:01,519 and, under the influence 483 00:23:01,519 --> 00:23:06,969 of all of this is actually driven by the various hormonal 484 00:23:06,969 --> 00:23:09,098 things that i've mentioned 485 00:23:09,098 --> 00:23:11,469 and with something 486 00:23:11,469 --> 00:23:15,095 we call remodeling occurs, there's a change in geometry of the ventricle 487 00:23:15,095 --> 00:23:19,083 which can have implications of tugs on the chordae tendinae of the mitral valve 488 00:23:19,083 --> 00:23:23,007 the wrong valve, you can get mitral regurgitation, 489 00:23:23,007 --> 00:23:26,023 it's a disadvantageous thing 490 00:23:26,023 --> 00:23:30,002 often associated with a lot of fibrosis, that blue-green tissue racing through the myocardium 491 00:23:30,002 --> 00:23:31,045 492 00:23:31,045 --> 00:23:35,001 is a fibrosis in the remodeled ventricle 493 00:23:35,001 --> 00:23:39,011 which causes problems of its own as you can imagine, I don't have to go into any detail 494 00:23:39,011 --> 00:23:40,015 495 00:23:40,015 --> 00:23:42,084 So that's a problem 496 00:23:42,084 --> 00:23:44,078 and there's a problem 497 00:23:44,078 --> 00:23:48,091 with neurohumoral activation, 498 00:23:48,091 --> 00:23:50,082 vasoconstriction increases the 499 00:23:50,082 --> 00:23:54,084 afterload that this poor old failing heart has to pump against. 500 00:23:54,084 --> 00:23:56,022 It sounds like 501 00:23:56,022 --> 00:23:59,003 a nice mechanism, but it 502 00:23:59,003 --> 00:24:00,026 bites the heart 503 00:24:00,026 --> 00:24:04,072 Various of these humoral substances are 504 00:24:04,072 --> 00:24:06,001 cardiotoxic 505 00:24:06,001 --> 00:24:07,028 chronically 506 00:24:07,028 --> 00:24:09,095 in other words, they are responsible for the increase in apoptosis 507 00:24:09,095 --> 00:24:14,066 they drive the remodeling and it's a bad thing for the heart 508 00:24:14,066 --> 00:24:16,003 in the long run, 509 00:24:16,003 --> 00:24:17,209 and we know about the 510 00:24:17,209 --> 00:24:21,529 implications of sodium and water retention and how that 511 00:24:21,529 --> 00:24:24,041 overloads the heart. 512 00:24:24,041 --> 00:24:26,026 All of these things 513 00:24:26,026 --> 00:24:26,069 contribute to the downward spiral 514 00:24:26,069 --> 00:24:29,071 515 00:24:29,071 --> 00:24:33,052 and I've simplified a very complex business, but 516 00:24:33,052 --> 00:24:35,016 there are many 517 00:24:35,016 --> 00:24:38,053 consequences for the peripheral tissues and that's what we're 518 00:24:38,053 --> 00:24:41,859 really talking about when we talk about heart failure, what's going on 519 00:24:41,859 --> 00:24:44,299 in the peripheral tissues. 520 00:24:44,299 --> 00:24:48,007 These consequences we can talk about in a number of ways, we talk 521 00:24:48,007 --> 00:24:51,058 about sometimes forward failure and backward failure. 522 00:24:51,058 --> 00:24:53,509 Forward failure being the idea that 523 00:24:53,509 --> 00:24:58,066 the failing heart does not perfuse the tissues well enough, and 524 00:24:58,066 --> 00:24:59,669 backward failure you're familiar 525 00:24:59,669 --> 00:25:03,036 with the idea of passive congestion and we talked about that in class 526 00:25:03,036 --> 00:25:05,072 so you have a good image of that. 527 00:25:05,072 --> 00:25:08,929 We speak of left heart failure and right heart failure, 528 00:25:08,929 --> 00:25:10,028 most processes that cause 529 00:25:10,028 --> 00:25:12,002 heart failure start out on the left 530 00:25:12,002 --> 00:25:15,005 but it's a closed plumbing system 531 00:25:15,005 --> 00:25:20,008 so as the left heart fails, the right heart is going to fail. 532 00:25:20,008 --> 00:25:21,034 The commonest 533 00:25:21,034 --> 00:25:25,099 cause of right heart failure then is left heart failure. 534 00:25:25,099 --> 00:25:29,052 There are some of the examples where the right heart fails primarily and it has to do 535 00:25:29,052 --> 00:25:31,035 with things happening in the lungs, 536 00:25:31,035 --> 00:25:37,015 they're relatively less common and you'll hear more about them some other time, 537 00:25:37,015 --> 00:25:41,043 but the backward consequences of left and right heart failure are very 538 00:25:41,043 --> 00:25:45,076 familiar to you already, we know that when the left heart fails you get 539 00:25:45,076 --> 00:25:47,509 pulmonary congestion and edema, 540 00:25:47,509 --> 00:25:50,053 when the right heart fails, you get 541 00:25:50,053 --> 00:25:52,066 elevation of hydrostatic 542 00:25:52,066 --> 00:25:55,034 pressure in a variety of tissues 543 00:25:55,034 --> 00:25:56,419 with associated 544 00:25:56,419 --> 00:26:00,389 congestive changes in organs and accumulation of edema 545 00:26:00,389 --> 00:26:02,007 fluid and this 546 00:26:02,007 --> 00:26:05,002 is when we start to speak of congestive heart failure. 547 00:26:05,002 --> 00:26:08,063 We're throwing that adjective very frequently 548 00:26:08,063 --> 00:26:10,019 549 00:26:10,019 --> 00:26:14,019 What we're not emphasizing, and I'll just conclude by mentioning this, 550 00:26:14,019 --> 00:26:15,083 are the forward changes 551 00:26:15,083 --> 00:26:18,084 associated with left heart failure, in other words, when the left 552 00:26:18,084 --> 00:26:20,099 heart fails, things begin to 553 00:26:20,099 --> 00:26:25,559 happen because tissues in a variety of places simply aren't being perfused. 554 00:26:25,559 --> 00:26:27,027 And you're familiar already with 555 00:26:27,027 --> 00:26:30,091 the activation of the 556 00:26:30,091 --> 00:26:32,062 renin-angiotensin-aldosterone system 557 00:26:32,062 --> 00:26:37,025 from forward failure to 558 00:26:37,025 --> 00:26:39,099 supply enough blood to the kidney, 559 00:26:39,099 --> 00:26:45,269 I would point out that as the perfusion drops more and more, 560 00:26:45,269 --> 00:26:49,096 the kidney can really shut down as far as its excretory function and nitrogenous 561 00:26:49,096 --> 00:26:52,086 waste can pile up. 562 00:26:52,086 --> 00:26:54,042 Sometimes they speak, 563 00:26:54,042 --> 00:26:58,036 people speak, of a cardio-renal syndrome because of this. 564 00:26:58,036 --> 00:26:59,054 Well many other 565 00:26:59,054 --> 00:27:04,079 tissues suffer from this lack of perfusion in the same way. 566 00:27:04,079 --> 00:27:07,075 We've shown you for instance the liver, 567 00:27:07,075 --> 00:27:11,006 and the liver gets caught in a one-two punch, 568 00:27:11,006 --> 00:27:12,919 there's resistance to outflow from the liver 569 00:27:12,919 --> 00:27:16,004 the fact is that the poor old failing left ventricle isn't delivering enough blood 570 00:27:16,004 --> 00:27:17,002 to this, the central 571 00:27:17,002 --> 00:27:19,077 lobular area, 572 00:27:19,077 --> 00:27:22,000 and it undergoes a sort of hemorrhagic 573 00:27:22,000 --> 00:27:24,007 necrosis which you remember that, you never forget 574 00:27:24,007 --> 00:27:26,081 that kind of a picture. 575 00:27:26,081 --> 00:27:31,014 Now something, a little wrinkle that I'll point out here, 576 00:27:31,014 --> 00:27:31,085 is that the aldosterone 577 00:27:31,085 --> 00:27:35,309 levels in patients in failure are way way up there 578 00:27:35,309 --> 00:27:36,096 and part of it 579 00:27:36,096 --> 00:27:40,023 obviously is because it's been triggered by the production of angiotensin II 580 00:27:40,023 --> 00:27:42,054 and so forth, but the liver 581 00:27:42,054 --> 00:27:44,083 when it's in that kind of a state, 582 00:27:44,083 --> 00:27:48,084 does not catabolize aldosterone the way it should, 583 00:27:48,084 --> 00:27:52,559 and the patient may end up with a twenty fold increase in aldosterone level partly because 584 00:27:52,559 --> 00:27:55,041 of synthesis and partly because of 585 00:27:55,041 --> 00:27:57,033 "non tearing down" 586 00:27:57,033 --> 00:27:58,063 587 00:27:58,063 --> 00:27:59,053 by the liver 588 00:27:59,053 --> 00:28:01,011 589 00:28:01,011 --> 00:28:02,041 One more example, the gut 590 00:28:02,041 --> 00:28:04,053 may suffer in very advanced cardiac 591 00:28:04,053 --> 00:28:06,519 failure, patches of mucosa 592 00:28:06,519 --> 00:28:09,003 in the bowel may undergo 593 00:28:09,003 --> 00:28:13,011 necrosis because they're furthest from the blood supply 594 00:28:13,011 --> 00:28:17,005 and we speak of ischemic colitis, a bit of a misnomer as it is an inflammatory condition, 595 00:28:17,005 --> 00:28:17,097 596 00:28:17,097 --> 00:28:18,096 but actually that sort of thing 597 00:28:18,096 --> 00:28:21,047 can be a problem. 598 00:28:21,047 --> 00:28:24,929 Other organs and in fact even the central nervous system in very advanced failure 599 00:28:24,929 --> 00:28:26,018 we see problems 600 00:28:26,018 --> 00:28:29,002 with CNS function. 601 00:28:29,002 --> 00:28:32,051 Well I turn the baton over 602 00:28:32,051 --> 00:28:34,259 to Dr. Matthews 603 00:28:34,259 --> 00:28:38,012 you just keep some of these images in mind and she will flesh them out, 604 00:28:38,012 --> 00:28:38,072 605 00:28:38,072 --> 00:28:40,085 as they say, with the clinical realities 606 00:28:40,085 --> 00:28:43,031 and with some of the 607 00:28:43,031 --> 00:28:44,084 therapeutic strategies 608 00:28:44,084 --> 99:59:59,999 that make sense I hope.