Circulation May 2, 2017 Issue

Dr Carolyn
Lam:               
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. I'm Doctor
Carolyn Lam, associate editor for the National Heart Center and
Duke National University of Singapore. Our feature paper today
presents the first information on the impact of cardiovascular
health in middle age and the burden of mobility in older age.
This exciting data is from the Chicago Heart Association study.
First, let me give you your summary of this week's journal.


                                               
The first study tells us that patients with long QT syndrome type
II are at increased risk of hypoglycemia. First author, Doctor
Hilton Cavallius, co-corresponding authors Doctor Tarakov and
Hanson from University of Copenhagen, Denmark, noticed that loss
of function mutations in HERG, which encodes the voltage gate at
potassium channel 11.1, causes long QT syndrome II, but that the
specific voltage gate at potassium channels are also present in
pancreatic alpha and beta cells and intestinal L and K cells,
which secrete glucagon, insulin, and the incretins, glucagon-like
peptide one or GLP1, and glucose-dependent insulinotropic
polypeptide, or GIP.


                                               
All these hormones are crucial for glucose regulation. The
authors therefore hypothesize that patients with long QT syndrome
II may have increased incretin and beta cell, but decreased alpha
cell function and thus, lower glucose levels. To test this
hypothesis, they measured secretion of these hormones and cardiac
repolarization in response to a six-hour, 75 gram oral glucose
tolerance test in 11 patients with long QT syndrome II with
functional mutations in HERG with 22 matched healthy
participants.


                                               
They found that following glucose ingestion, patients with long
QT syndrome II displayed exaggerated incretin and endocrine
pancreatic function with more than 50% increased levelsq of
circulating insulin, GLP1 , and GIP and defective glucagon
secretion, causing low plasma glucose levels and thus, increased
risk of symptomatic reactive hypoglycemia following the glucose
load.


                                               
Furthermore, in rats, pharmacological blockade of these voltage
gate at potassium channel 11.1 with [inaudible 00:02:43] had
similar effects and inhibition of HERG in beta and L cells
increased insulin and GLP1  secretion up to 50%. Finally,
glucose ingestion aggravated cardiac repolarization disturbances
in patients with long QT syndrome II with a 122% greater increase
in QT interval in these patients compared to controls. The take
home message is that clinicians should be more aware of the risk
of hypoglycemia with glucose ingestion in patients with long QT
II syndrome and also recognize that this reactive hypoglycemia
can further increase the risk of malignant arrhythmia in these
patients.


                                               
The next paper is the first study to describe the risk of
myocardial infarction after discontinuation of thienopyridine
therapy in the DAPT study, or dual antiplatelet therapy study. As
a reminder, in this trial, after PCI and 12 months of clopidogrel
or prasugrel plus aspirin, eligible patients remained on aspirin
and were randomized to continue thienopyridine  versus
placebo for 18 months. At 30 months, patients stopped the study
drug and were observed for three months. In the current study by
first author Doctor Schmidt, corresponding author Doctor Mauri,
and colleagues from Brigham and Women's Hospital in Boston,
Massachusetts. The authors looked at cumulative incidents of
myocardial infarction assessed over three months after
randomization and three months after study drug discontinuation.
They found that discontinuing thienopyridine after either 12 or
30 months was associated with an early increase in myocardial
infarction risk, mainly unrelated though to stent thrombosis. The
magnitude of risk was highest in the early time frame and lower
in patients not treated with the [inaudible 00:04:47] eluting
stents.


                                               
The authors further compared pateints with DAPT scores above or
below 2, and showed that both groups had lower rates of
myocardial infarction with continued thienopyridine . Thus, while
higher DAPT scores identify patients with a greater absolute
ischemic benefit relative to bleeding with continued
thienopyridine therapy, discontinuation at 12 months increases
the myocardial infarction hazard regardless of DAPT score group.


                                               
The next paper describes the impact of depression treatment on
one year mortality following acute myocardial infarction. Doctor
[inaudible 00:05:28] and colleagues from the University of
Missouri School of Medicine in Kansas City looked at the TRIUMPH
study, which is an observational multicenter cohort study that
enrolled more than 4000 patients with acute myocardial infarction
between 2005 and 2008 from 24 US hospitals.


                                               
Patients were administered the patient health questionnaire 9
during the index myocardial infarction admission and depression
was defined by a score of 10 or above. This was categorized as
treated if there was a documentation of a discharged diagnosis,
medication prescribed for depression, or referral for counseling,
and is untreated if none of these three criteria were documented.
Overall, 18.7% of patients met criteria for depression and 30.4%
were treated. Compared without depression, patients with treated
depression had one year mortality rates that were not different.
However, patients with untreated depression had a higher one year
mortality when compared to patients without depression. In
summary, this study really shows that the association between
depression following myocardial infarction and increased
mortality differs by depression treatment status at the time of
the index myocardial infarction. Patients with untreated
depression have a 70 to 90% higher risk of dying at one year
after the myocardial infarction than patients without depression
or patients with treated depression. These findings should
therefore encourage further research to examine the impact of
depression recognition and treatment at the time of an acute
myocardial infarction.


                                               
The final study provides insight into the paradox that folate
deficiency is an independent risk factor for congenital heart
disease, yet the maternal plasma folate level is paradoxically
not a good diagnostic marker of this risk. In the current study
by first author Doctor Wang, co corresponding authors Doctors
Chow and Wang, from Fudan University, Shanghai, China. The
authors examined six folate related polymorphisms in three
independent case control groups comprising 1489 patients with
congenital heart disease and 1745 healthy individuals from the
Han Chinese population. They found that a specific fidgetin
intronic 4 variant was associated with decreased circulating
folate levels and increased protection against congenital heart
disease. They further showed that increased fidgetin expression
inhibited proteasomal degradation of reduced folate carrier 1 and
dihydrofolate reductase, thus facilitating [inaudible 00:08:29]
uptake and metabolism of folate. Their results therefore
demonstrated that folate utilization, rather than the circulating
folate levels, determined the preventive effects of folate
against congenital heart disease. These findings provide new
insights into the relationship of circulating folate levels with
congenital heart disease and potentially other folate associated
diseases.


                                               
Well, that wraps it up for your summaries. Now, for our feature
discussion.


                                               
Today's feature paper really represents the first data we have
that tells us what our cardiovascular health in middle age is
doing to us in older age, in terms of both morbidity and
longevity. To discuss this paper today, I'm so happy to have the
first and corresponding author, Doctor Norrina Allen from
Northwestern University in Chicago and Doctor Jarett Berry,
associate editor from UT Southwestern. Welcome, both.


Dr Norrina
Allen:             
Thank you very much.


Dr Jarett
Berry:                
Thanks, Carolyn.


Dr Carolyn
Lam:               
Norrina, could I start with you? This represents the 40 year
follow up of the Chicago Heart Association detection project and
industry. Could you maybe start by telling us a little bit about
the Chicago Heart Association study?


Dr Norrina
Allen:             
The Chicago Heart Association study was a large study that
recruited almost 40,000 individuals who were employed in Chicago.
They did a baseline exam between 1967 and 1973. After that
baseline exam, we followed those individuals for over 40 years
using their Medicare records, so we've been able to monitor their
healthcare utilization and the incidence of disease across their
lifetime up through 2010.


Dr Carolyn
Lam:               
Then you measured their cardiovascular health by specific
measurements, right? Could you tell us how that was defined and
then also how was morbidity burden defined?


Dr Norrina
Allen:             
Of course. We really think the overall burden of cardiovascular
health tells us something more than looking at individual risk
factors, so we classified each of the CHA participants into one
of four groups, and each of those groups was defined by the level
of main cardiovascular risk factors, including blood pressure,
BMI, diabetes, smoking, and cholesterol level. We identified
people who had favorable levels of all of those risk factors,
individuals who had one elevated but not clinically of those high
risk factors, individuals who had one high level, or individuals
who had two or more high levels. That was based on their baseline
exam. Overall we found that about 6% of the CHA participants had
favorable levels of all of the risk factors at baseline, 19% had
one or more that was elevated, 40% had one high, and 35% had two
or more high risk factors, and again this was at the baseline
exam when they were young to middle aged.


                                               
We then followed them, as I mentioned, using Medicare data and we
identified the burden of whole morbidity based on the ICD9 codes
in their Medicare record, and we identified the level of
morbidity for each year of age, from entry into Medicare,
[inaudible 00:11:54] all the way to their death.


Dr Carolyn
Lam:               
And now, drum roll, your findings, they were pretty stunning.


Dr Norrina
Allen:             
Yeah. As you mentioned when you introduced the study, this study
is really the first to look at the whole of an individual's later
life, meaning not just looking at the incidence of disease or
longevity but taking those both into account. What we were
particularly interested in was looking at the cumulative burden
of morbidity in older age and the relative proportion of life
that people live with cardiovascular or all cause morbidity. What
we found was that individuals, who at baseline in young and
middle age and favorable levels of all major cardiovascular risk
factors, lived longer by almost four years but they also delayed
the onset of all cause and cardiovascular morbidity by 4 and a
half and almost 7 years respectively. What that means is that the
proportion of their life that they live with morbidity was much
shorter, they lived longer and healthier as compared to
individuals who had one or two more high risk factors.


Dr Carolyn
Lam:               
What an important public health message. Jarett, this concept of
morbidity compression, tell us your thoughts.


Dr Jarett
Berry:                
This is a really important paper. We've known for a long time, of
course, that low risk individuals live longer, but the question
of whether or not low risk individuals lived better throughout
their life has been incompletely understood. The problem is that
because low risk individuals live longer, the question that many
have asked is that when we live longer is there a so-called
expansion of misery, which some have talked about? That we live
longer, but we have the same burden of disease or is that
extended time horizon with the extended life span ... is the
burden of morbidity compressed into a shorter period of time? In
order to do that you need a couple things. You need a very large
study that's followed for a very long time. Importantly, not just
follow them for a long period of time, but follow enough
individuals all the way until death so you know not just the
first part of the story but we know the end of the story.


                                               
It really wasn't until [inaudible 00:15:18] paper, with not only
the very large sample side but the very long term follow up until
death, that we've been able to understand that actually low risk
status in middle age does actually compress morbidity. This
question of morbidity compression is not just an academic
question but it actually has potential implications for cost
savings and how we think about health care costs in our health
care system. It'd be nice to hear [inaudible 00:15:18] thoughts
about that as well, what else she found in regard to the Medicare
costs.


Dr Norrina
Allen:             
Right. As Jarett mentioned, not only from an individual
perspective but at a societal level, what we're interested in is
whether being in favorable cardiovascular health actually lowers
healthcare costs at the same time as increasing an individual's
health and longevity. What we found was that not only do the
individuals in favorable health live longer and healthier, but
they also have lower cumulative and annual healthcare costs,
meaning that from a societal standpoint the compression of
morbidity results in healthcare savings. We really think this is
a strong method that provides support for earlier prevention
efforts not only to improve an individual's quality of life but
to reduce the healthcare costs associated with later life
morbidity.


Dr Carolyn
Lam:               
Indeed, what an important message to live longer and better and
to save societal cost we need to get healthier cardiovascularly
in middle age. Now, what really scares me though, is the
statistic you told us a bit earlier. Only 6% of the individuals
that you studied had a favorable level of all factors. What do
you think this implies? What do you think needs to be done?


Dr Norrina
Allen:             
Unfortunately, at this point, it's relatively rare in our
population to reach middle age, 40 to 50 years of age, with
favorable levels of all major cardiovascular risk factors. I
think ... my research is really focused on trying to identify
ways and times to intervene, to really help promote
cardiovascular health early in life. I really think that we need
to work hard to prevent the occurrence of these risk factors and
the elevation of these risk factors much earlier in life. That
means, even before the age of 40 and much earlier than that, we
really need to be focusing on preserving cardiovascular health so
that by the time individuals reach later life they can have a
good quality of life and a longer, healthier life.


Dr Jarett
Berry:                
I think the issue of the fact that low risk status is rare is
that's a challenge that we continue to wrestle with as a society
and as investagators interested in this are and how to improve
that. When you look at your data, Norrina, I guess one silver
lining here is we do see that ... when you look across the strata
of risk groups ... it wasn't just the low risk individuals that
seemed to benefit. It seemed that there was a little bit of a
dose response. The goal obviously is to promote low risk status,
but if we could limit the prevalence of those at the highest risk
and shift them down a little bit, that could also have potential
implications. I'd be interested to hear your thoughts about that.


Dr Norrina
Allen:             
I think that's very accurate. There really is kind of a dose
response level, so that every risk factor that's favorable adds a
benefit and the more we can do to reduce the high risk factors
over time, the better the long term outcomes are likely to be. I
do really think prevention doesn't only have to exist before the
development of the risk factors, but also there's a benefit to
reducing risk factors that may have already developed or are
elevated, and to try and reduce their level. I would say that I
think that's an interesting next step that we really want to look
at and try and think about how best to intervene even at middle
age and help improve outcomes much later in life.


Dr Carolyn
Lam:               
Thank you, listeners, for joining us today. I'm sure you agree,
it's such an important message. Share it with your friends and
tune in next week.