Circulation January 7, 2020 Issue

Dr Greg Hundley: Well listeners, this is Dr Greg Hundley from the
VCU Pauley Heart Center in Richmond this week, who is sadly
missing his dear friend, Dr Carolyn Lam, who is away for just a
week or two. I hope you've experienced a wonderful holiday season
and are able to embrace the new year with joy and hope.


In our feature article this week, Dr Marcelo Di Carli and
colleagues are going to discuss the role of coronary
microvascular dysfunction assessed with cardiac stress during
PET, as well as left ventricular remodeling assessed with
echocardiography and how both of those relate to clinical
outcomes in patients with chronic kidney impairment. But first,
let's have a coffee and chat about other articles in this issue.


We have four original manuscripts, two or more clinical papers,
and two from the world of basic science. So let's go to the
clinical papers first. And the first emanates from our own
associate editor, Dr Sana Al-Khatib from Duke University. Her
paper comes from the ARISTOTLE trial, a randomized study of
18,201 participants that compared apixaban with warfarin in
patients with atrial fibrillation at increased risk of stroke.
And so this sub study included 17,423 patients in ARISTOTLE
without severe renal or liver disease. And the authors evaluated
the risk of bleeding and major cardiovascular outcomes in
patients with atrial fibrillation taking either NSAIDs with
therapixaban or warfarin. The authors found that those with NSAID
use at baseline, so before starting into the study or incident
NSAID use, that is they began an NSAID after initiating this
study were more likely, both groups were more likely to have a
history of bleeding, nearly a quarter of the patients to a fifth
of the patients versus only 15% that had never used NSAIDs either
before or after entering the study.


In addition, the safety and efficacy of apixaban versus warfarin
appeared not to significantly be altered by NSAID use. That is
whether you were taking apixaban or whether you're taking
warfarin, the impact of NSAID use was not different between
either of those anticoagulants.


The second original clinical article comes from Dr Audrey Blewer,
also from Duke University, and evaluates the variation in
bystander cardiopulmonary resuscitation delivery and subsequent
survival from out of hospital cardiac arrest based on
neighborhood level ethnic characteristics.


As background for this research, bystander cardiopulmonary
resuscitation delivery and survival from out of hospital cardiac
arrest varies at the neighborhood level, was generally lower
survival seen in neighborhoods predominantly with individuals
from black race. Despite Hispanics being the fastest growing
minority population in the United States, few studies have
assessed whether the proportion of Hispanics in a neighborhood is
also associated with delivery of bystander CPR or subsequent
survival for an out of hospital cardiac arrest. Accordingly, the
authors in this study assessed whether bystander CPR rates and
survival buried by neighborhood level ethnicity. And they
hypothesized that neighborhoods with a higher proportion of
Hispanics would have lower bystander CPR rates and overall lower
survival.


This study was a retrospective cohort and use data from the
Resuscitations Outcome Consortium, or ROC Epistry across the
United States. So in this study, the authors identified 18,900
cardiac arrests. And they excluded pediatric arrests, EMS
witnessed arrests, or arrest occurring in a healthcare or an
institutional facility. And they found overall that bystander CPR
was administered in 37% of these out-of-hospital arrests. Among
neighborhoods with less than 25% Hispanic residents, bystander
CPR was administered in 39% of the events, while it was
administered in only 27% of the events in those neighborhoods
with greater than 75% Hispanic residents. Also, lower rates of
survival occurred in neighborhoods with greater than 75% Hispanic
residents. And so the authors conclude that these findings
suggest there's an important need to understand the underlying
disparities in CPR delivery and an unmet CPR training need among
Hispanic communities.


Well now let's shift to our two original articles that come from
the world of basic science. And the first is from Dr Ying Shen
from Baylor College of Medicine and reports on the critical role
of cytosolic DNA and its sensing adapters sting in aortic
degeneration, dissection and rupture. So as some background for
this study, recent evidence has indicated that cytosolic DNA and
abnormal activation of the cytosolic DNA sensing it after sting,
a stimulator of interferon genes, plays a critical role in
vascular inflammation and destruction. And so in this paper, the
authors examine the involvement of this mechanism in aortic
degeneration and sporadic aortic aneurysm and dissections. Just
like with our other basic science papers, the authors perform
both studies in a small animal model, mice, and also in human
subjects. So what did they find?


The authors found that in human sporadic aortic dissection
tissues, they observe the presence of cytosolic DNA in smooth
muscle cells and macrophages. And they had significant activation
of this sting pathway. In a mouse model, sting deficient mice
showed significant reduction in challenged induced aortic
enlargement, dissection and rupture in both the thoracic and
abdominal aortic regions. Additional single cell transcriptome
analyses were performed and provided some mechanistic
understanding for the author's findings.


So in summary, for this very interesting paper from the world of
basic science, the author's findings indicate that the presence
of cytosolic DNA and subsequent activation of cytosolic DNA
sensing it after, or sting signaling, is a key mechanism in
aortic degeneration. And therefore future studies, perhaps
targeting sting, may be performed to see if they could prevent
sporadic aortic aneurysm dissection development.


The second basic original article in this issue is entitled In
Vivo CRISPR CAS9-mediated gene editing and how that ameliorates
atherosclerosis in familial hypercholesterolemia. It comes to us
from Dr Bin Zhou from the Chinese Academy of Sciences.


So as background for this study, mutations in the low-density
lipoprotein receptor are one of the main causes of familial
hypercholesterolemia. The clustered regularly interspace short
palindromic repeats of CRISPR and caspase-9 system is an
effective tool for gene editing to correct gene mutations and
thus ameliorate the disease.


So these authors tested whether in vivo sematic cell gene editing
through the CRISPR CAS based nine system delivered by adeno
associated virus could treat familial hypercholesterolemia caused
by the LDLr mutant in a mouse model. Well, the authors ... As
Carolyn would ask, so what did they find, Greg? Well, the authors
observed some really exciting results. They found that the LDLr
mutation was corrected in a subset of hepatocytes after the
CRISPR CAS based nine treatment with LDLr protein expression
partially restored. Compared with control animals, the CRISPR CAS
based nine targeted SGRNA group had significant reductions in
total cholesterol, total triglyceride, and LDL cholesterol in the
serum while the aorta had smaller atherosclerotic plaques and a
lower degree of macrophage infiltration. So this study really
implicates perhaps not only a mechanism of disease, but a
potential treatment. But with the relatively small numbers in
this study, more research is needed to confirm and substantiate
the findings from this group.


So great original articles in this issue. What else is in the
issue? And let's move to those. We have a global rounds feature.
Remember, global rounds are investigating how cardiovascular
disease is assessed and managed in countries from all over the
world. Well, in this global rounds feature Professor Ali Oto from
Memorial and Cairo Hospital provides a quick reference to the
control and management of cardiovascular disease in Turkey. And
the next article, an on my mind piece, Dr Milton Packer explorers
whether the conditions of atrial fibrillation and heart failure
with preserved ejection fraction are two separate diseases that
occur frequently together in patients or alternatively, whether
these two adverse clinical syndromes may be parallel
manifestations of the same underlying myocardial disease with
atrial fibrillation affecting the left atrium and heart failure
preserved ejection fraction afflicting the left ventricle.


In our what's in the mailbag series, Professor Nicholas Mills
from the University of Edinburgh shares in a research letter the
relationship between exercise intensity and duration on cardiac
troponin release in 10 physically active healthy volunteers
averaging 34 years in age. A great read for our readership that
is actively exercising. And it looks like in this letter,
intensity of exercise matters when evaluating post-exercise serum
troponin values. I really encourage everyone to take a look at
that letter.


And then finally, there's a letter to the editors from Dr
Abdallah Fayssoil from the Raymond Poincare Hospital in Garches,
France regarding a prior publication related to nutrition and
functional tricuspid regurgitation.


Well, listeners, that sums up our summary. And I hope you had a
great coffee or if you're running on your treadmill, a great run.
And let's now move on to our feature discussion with Dr Di Carli.
Welcome everyone to our feature discussion and we have Dr Marcelo
Di Carli from Brigham and Women's Hospital who's going to be
discussing with us a manuscript relating to the measurements of
coronary micro circulatory function and how they may impact
patients with chronic kidney disease. Also discussing today, we
have our own associate editor, Dr Victoria Delgado from Leiden in
the Netherlands. Well, welcome Marcelo and Victoria. We're so
glad to have the opportunity to speak with you. And Marcelo,
could you tell us a little bit about what was the hypothesis and
some of the background of why you wanted to perform this study?


Dr Marcelo Di Carli: Chronic kidney disease represents a
relatively large segment of the population. In the US alone, it's
estimated that around 50 million people have the diagnosis of
chronic kidney disease. And it's a disease that we all know is
associated with a high risk of cardiovascular events. Even in the
absence of obstructive coronary disease, it's been shown that the
incidents of cardiomyopathy and the absence of obstructive
disease, of coronary disease, is pretty high and that associates
with a high risk of heart failure and death.


The mechanisms related to cardiomyopathy in patients with chronic
kidney disease have been debated for a long time. This has been
associated with LVH incidents of non-transmittal or
non-ST-elevation MIs, also with microvascular disease as a
measure of ischemic heart disease, but there's no clear
association with how do these features of chronic kidney disease
link to each other. And so our objective was to look at the
associations between LV remodeling, coronary microvascular
disease and adverse events. And we hypothesized that coronary
microvascular dysfunction as a more integrative marker of
myocardial ischemia and injury would associate with changes in
cardiac structure and function and with increased risk of adverse
cardiovascular events.


Dr Greg Hundley: Very nice. So tell us a little bit, Marcelo,
about your study population and your study design.


Dr Marcelo Di Carli: Well, this is a cross sectional analysis of
a cohort that is well-characterized in our registries. And so it
consisted of a consecutive group of patients who underwent both
PET scanning for measuring coronary vascular function and
echocardiography within 90 days of each other. Could it not have
evidence of overt obstructive coronary disease as defined by a
history of prior revascularization, prior AMI or an abnormal PET
scan indicating presence of obstructive disease.


We also excluded patients with severe valvular disease, cancer,
severe LV disfunction to try to avoid confounding elements in the
associations where we're trying to study. We used
echocardiography to assess quantitatively the changes in LV
geometry, diastolic function and subclinical systolic
dysfunction. Most of our patients have relatively preserved LV
function, LV ejection fraction. And so we looked at peak
longitudinal strain, global radial strain and circumferential
strain as indicators of systolic dysfunction. And of course we
also looked at changes in LV mass. Patients were followed a
little over four years for the occurrence of death,
hospitalization for heart failure or myocardial infarction. And
all of these myocardial infarctions were non-ST-elevation MIs, or
people might call it type two MIs.


Dr Greg Hundley: Tell us a little bit about the results. But
before you get to that, how old were these patients and what was
their breakdown in terms of race and gender?


Dr Marcelo Di Carli: Yeah, so we had a population of 352
patients. The mean age was mid-sixties. not surprisingly, 60% of
the patients were female. And this is because we obviously
excluded obstructive coronary disease that would be more
prevalent in male. They have about a 40% incidence of diabetes, a
high percentage of them had hypertension. These are all the
features that would typically be associated with chronic kidney
disease. The rate of obesity was actually lower in patients with
CKD. And we call CKD here as a GFR less than 60. That's the
population we're targeting here. And so that's essentially the
cohort.


Dr Greg Hundley: And what did you find?


Dr Marcelo Di Carli: Well, there were essentially three or four
main findings. Number one and not very surprisingly, patients
with CKD had worse myocardial mechanics that is worse diastolic
function and worse systolic strain. In multi-variable models,
fully adjusted for a number of clinical covariates as well as
ejection fraction, we found that these abnormalities in
myocardial mechanics were relatively strongly associated with
abnormal coronary microvascular function as defined by PET. So
this sort of suggests that the variability that we see in
diastolic and systolic function are explained largely by
microvascular disease, but not necessarily directly linked to GFR
as a mediator.


The second finding was that patients with CKD, again, not
surprisingly, it showed a higher incidence of MACE, including
especially death and heart failure, more than triple the rate of
death and doubled the rate of heart failure compared to those
without CKD. And in multi-variable analysis, again, MACE was
associated with coronary flow reserve as a measure of
microvascular dysfunction but not glomerular filtration rate. And
there was no interaction between coronary flow reserve and GFR.
Interestingly, when we looked at the adverse events subgroup by
measures of LV remodeling and we picked three measures. One is
changes in LV geometry, diastolic dysfunction, and impaired
global longitudinal strain, we found that the incidence of both
mace as well as heart failure and myocardial infarction were
significantly higher when both abnormal LV mechanics or
remodeling were present and the patients also had microvascular
disease. So in the absence of either one, the rate of mace was
relatively low, indicating that there is a clear interaction
between abnormalities in cardiac structure and function and
microvascular disease.


And then lastly, we looked at mediation analysis to try to
investigate a plausible pathway between impaired renal function
and events and we hypothesized that coronary microvascular
dysfunction might actually mediate at least part of that
relationship. And indeed we found that about a third of the
relationship was explained by the presence of microvascular
disease. Very nice,


Dr Greg Hundley: Very nice. Very important work. So now we'll
turn to our own associate editor, Victoria Delgado. Victoria,
help us put this into perspective for what we know about patients
with chronic kidney disease. How does the results of this study
really move the field forward?


Dr Victoria Delgado: I think that this article brings new
evidence on phenotyping of these patients and the factors that
influence the cardiac abnormalities that we may see. There are
not many studies including patients with chronic kidney disease.
These patients are usually underrepresented in randomized control
trials. And we know that these patients are associated with an
increased mortality and morbidity and mainly heart failure
hospitalizations. And I think that this study is showing another
piece in the person that can help us understand why these
patients are associated with much higher cardiovascular morbidity
and mortality. I think that relating the coronary microvascular
dysfunction is an important piece and important knowledge because
then we may think how to improve the microvascular dysfunction on
these patients and see if by improving these microvascular
dysfunction, these abnormalities that have been described in
terms of a structure and function can be reversed and see how
these impacts on the outcome of these patients.


Dr Greg Hundley: So Marcelo, just briefly, what do you think is
the next study that needs to be performed in this area of
science?


Dr Marcelo Di Carli: I think that obviously our study has some
limitations and the causation. Cause and effect cannot be
inferred from our study. So I think the next steps will be to try
to demonstrate whether indeed modifying microvascular dysfunction
leads to improved outcomes. And I think this will be best done by
intervention studies that can be targeted towards improving
microvascular dysfunction. We can think of novel therapies as
well that have been initially associated with improved renal
outcomes. I'm talking about for example, SGLT2 inhibitors that
can be potentially of benefit not only on renal outcomes but
potentially on cardiovascular outcomes as has been shown in
populations largely without CKD.


Dr Greg Hundley: Victoria, anything to add in terms of how
noninvasive imaging could play a role in some of those next
future studies?


Dr Victoria Delgado: I think that the point that Marcelo raise on
the use of SGLT2 inhibitors is very timely and very appealing
because we know that for patients with diabetes who have renal
dysfunction and you have EGFR below 35, they may not be eligible
for these therapies. But as you can see in this study, the mean
EGFR of the patients with renal dysfunction was 41. So there is a
wide range of patients that could be eligible for these
therapies. How imaging can help to see or to detect the patients
that may benefit from these therapies and see how these therapies
may improve the structure and the function of the heart.


Dr Greg Hundley: Well, listeners, we've had a great discussion
today with Dr Marcelo Di Carli from Brigham and Women's Hospital
and Dr Victoria Delgado from Leiden. And really trying to
understand some noninvasive markers of both micro circulatory
dysfunction as well as abnormal echocardiographic assessments of
both diastolic function as well as systolic dysfunction and how
they forecast adverse events in patients with chronic kidney
disease.


I want to wish you all a great week and on behalf of Carolyn and
myself, I hope to see you next week. Take care now.


This program is copyright the American Heart Association 2020.