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Confidential: For Review Only
In Hospital Outcomes and Prevalence of Comorbidities in
patients with Infective Endocarditis with and without Heart
Blocks – Insight from National Inpatient Sample
Journal:
Journal of Investigative Medicine
Manuscript ID
jim-2020-001501.R2
Article Type:
Original research
Date Submitted by the
Author:
03-Sep-2020
Complete List of Authors:
Jamal, Shakeel; Central Michigan University, Internal Medicine
Kichloo, Asim; CMU Medical Education Partners,
Albosta, Michael; Central Michigan University, Internal Medicine
Bailey, Beth; Central Michigan University, Internal Medicine
Singh, Jagmeet; Geisinger Commonwealth School of Medicine
Wani, Farah; Samaritan Medical Center
Shah zaib, Muhammad; Central Michigan University, Internal Medicine
Ahmad, Muhammad; Central Michigan University, Internal Medicine
Khan, Muhammad; Central Michigan University, Internal Medicine
Soni, Ronak; University of Toledo, Cardiovascular Medicine
Aljadah, Michael; Medical College of Wisconsin, Internal Medicine
Khan, Hafiz; Michigan State University
Khan, Mahin; Michigan State University
Khan, Muhammad; West Virginia University
Keywords:
Endocarditis, Heart Block
https://mc.manuscriptcentral.com/jinvestigativemed
Journal of Investigative Medicine
Confidential: For Review Only
Infective Endocarditis and Heart Block
In Hospital Outcomes and Prevalence of Comorbidities in patients with Infective Endocarditis with and
without Heart Blocks – Insight from National Inpatient Sample
Shakeel Jamal, MD1, Asim Kichloo, MD1, Michael Albosta, MD1, Beth Bailey, PhD1, Jagmeet Singh, MD5
Farah Wani, MD6, Muhammad Shah Zaib, MD1, Muhammad Ahmad, MD1, Muhammad Dilawar Khan,
MD1, Ronak Soni, MD2, Michael Aljadah, MD3, Hafiz Waqas Khan, MD4, Mahin R Khan, MD4, Muhammad
Z Khan, MD7
1. Central Michigan University, College of Medicine, Saginaw, Michigan. USA.
2. University of Toledo, College of Medicine, Toledo, Ohio. USA.
3. Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
4. McLaren-Flint/Michigan State University, Flint, Michigan, USA.
5. Geisinger Commonwealth School of Medicine, Scranton, Pennsylvania. USA.
6. Samaritan Medical Center, Watertown, NY, USA.
7. West Virginia University, Morgantown, West Virginia, USA.
Word Count: 3169
Corresponding Author: Kichloo Asim M.D.
Address: 1000 Houghton Avenue, Saginaw, Michigan, 48602
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Telephone: 989-746-7500
Email address: kichlooasim@gmail.com
Abstract
Infective Endocarditis (IE) complicated by heart block can have adverse outcomes and usually requires
immediate surgical and cardiac interventions. Data on outcomes and trends in patients with IE with
concurrent heart block is lacking. Patients with a primary diagnosis of IE with or without heart block
were identified by querying the Healthcare Cost and Utilization (HCUP) database, specifically, the
National Inpatient Sample for the years 2013 and 2014 based on ICD9 codes. During 2013 and 2014, a
total of 18,733 patients were admitted with primary diagnosis of IE, including 867 with concurrent heart
blocks. There was an increased in-hospital mortality (13% vs 10.3%), length of stay (19 vs 14 days), and
cost of care ($282,573 vs $223,559) for patients with IE complicated by heart block. Additionally, these
patients were more likely to develop cardiogenic shock (8.9% vs 3.2%), acute kidney injury (40.1% vs
32.6%), hematologic complications (19.3 vs 15.2%), and require placement of a pacemaker (30.6% vs
0.9%). Infective endocarditis and concurrent heart block resulted in increased requirement for aortic
(25.7 vs 6.1%) and mitral (17.3% vs 4.2%) valvular replacements. Conclusion was made that, IE with
concurrent heart block worsens in-hospital mortality, length of stay, and cost for patients. Our analysis
demonstrates an increase in cardiac procedures, specifically aortic and/or mitral valve replacements,
and ICD/CRT/PPM placement in IE with concurrent heart block. A close tele monitoring system and
prompt interventions may represent a significant mitigation strategy to avoid the adverse outcomes
observed in this study.
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Significance of this study:
Heart Blocks predict worse outcomes in patients with infective endocarditis.
What is already known about this subject?
Infective endocarditis can cause valve abscess.
Infective endocarditis can result in atrioventricular node blockage
Poor outcomes in patients with Infective endocarditis include old age, prosthetic valve
endocarditis, heart failure, paravalvular complications.
What are the new findings?
Infective endocarditis with concurrent heart block worsens the mortality.
Infective endocarditis with concurrent heart block increases length and cost of stay.
Infective endocarditis with concurrent heart block increases the requirement of pacemaker
insertion.
How might these results change the focus of research or clinical practice?
Patients with infective endocarditis and comorbid heart block are at high risk of worse outcomes
and immediate surgical intervention should be considered.
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Introduction
Infective endocarditis (IE) is an infection of a native or prosthetic heart valve, endocardial surface, or
indwelling cardiac device.[1,2] It occurs at an incidence of approximately 3 to 9 cases per 100,000
people per year.[3] In the developing world, rheumatic heart disease is the number one risk factor for
the development of IE.[1,2] However, in developed countries, rheumatic heart disease is extremely rare
and risk factors for the development of IE include diabetes, cancer, IV drug abuse, degenerative heart
valve disease, and congenital heart disease.[2] Although IE is rare, it is among the most common life-
threatening infectious syndromes along with pneumonia, intra-abdominal abscess, and sepsis.[4] In a
large prospective cohort study, it was found that the most common presenting symptoms include fever,
development of a new murmur, or worsening of an old murmur.[5] Less commonly, patients presented
with symptoms such as vascular embolic events, splenomegaly, Janeway lesions, Osler’s nodes, Roth
spots, and splinter hemorrhages.[5] Complications of IE include the development of embolism, stroke,
intracardiac abscess, congestive heart failure, and new conduction abnormalities.[5] Despite advances in
care, the mortality rates of IE have remained stable over the past 20 years, with rates approaching 30%
at 1 year after diagnosis.[6]
The high morbidity and mortality associated with infective endocarditis warrants further investigation
into the patterns, clinical course, and outcomes associated with development of this infectious process.
Heart block is a complication of IE that suggests the potential need for early surgical management.[4]
According to one study, complete heart block may occur in as many as 14% of cases of IE.[7] Current
data is limited regarding trends and outcomes in patients with IE developing heart block as a
complication. Using data from the National Inpatient Sample databases, we performed a cross sectional
analysis to evaluate several outcomes associated with the development of heart block along with IE.
Through this study, we hope to provide further information regarding the impact of developing heart
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block along with IE and to determine whether this can be used as a predictor of clinical course and
outcome in these patients.
Methods
Data source
The National Inpatient Sample has been elaborated in detail in prior studies.[8] National Inpatient
Sample is the largest publicly available database in United States, which falls under Healthcare Cost and
Utilization project (HCUP) and is maintained by the Agency for Health Care Quality and Research
(AHQR). It is one of the most useful databases for studying outcomes and trends of various procedures
and diseases. It is comprised of deidentified data collected from 20% of community hospitals in 46 states
in the United States. Each hospitalization is representative of one primary diagnosis, up to 29 secondary
diagnoses and 15 procedures using the International Clinical Modification Codes (ICD9 and ICD10). The
data includes admission status, demographics, admitting diagnosis, comorbidities, healthcare facility
status (rural vs. urban), discharge diagnosis, outcomes, length of stay and cost during hospitalization.
We examined all adult patients who were hospitalized during the years 2013 and 2014 with the
diagnosis of infective endocarditis with and without comorbid heart block using the National Inpatient
Sample. Patients were filtered using International Classification of Diseases, ninth revision, clinical
modification codes. ICD9 codes for IE were validated based on previous studies and codes that were
included were; 4210, 4211, 4212, 4219, 03642, 09884, 11281 and 1154.[9] ICD9 codes used to identify
first, second and third degree heart blocks were; 426.11, 426.12, 426.13 and 426.0. We excluded any
hospitalizations with missing demographics, i.e. age, gender, admission or discharge diagnosis and
mortality data. We utilized NIS variables to identify patients’ age, gender, race, county location, income,
and hospital bed size. Race was divided into three categories; African-American, White and Hispanic.
Baseline comorbidities taken into consideration were hypertension, diabetes mellitus, chronic kidney
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disease, atrial fibrillation, anemia, and peripheral arterial disease using the ICD9 codes. ICD codes for
outcomes have been included as a supplementary file.
Primary and secondary outcomes
Our objective was to assess the primary and secondary outcomes in patients with the principle diagnosis
of infective endocarditis with and without heart block. The primary outcomes to be analyzed were
mortality, length of stay, and cost for all hospitalizations due to IE with and without comorbid heart
blocks. Secondary outcomes to be assessed were; stroke, acute kidney injury (with and without new
hemodialysis), aortic and mitral valve replacement, cardiac arrest, cardiogenic shock, pacemaker
implantation, hematologic (thrombocytopenia/coagulopathy) and hepatic complications (hepatic
necrosis/hepatic encephalopathy/hepatitis), cardiac tamponade, sepsis, acquired pneumonia,
tracheostomy and gastrostomy. The ICD9 codes for these outcomes are included as a supplementary
file.
Statistical analysis
We used survey analyses to stratify and cluster encounters for all continuous and categorical variables.
SPSS software was used to perform statistical analyses. We used Chi-square test or analyses of variance
(ANOVA) to identify differences in categorical variables and two sample t-test for analysis of continuous
variables. Logistic regression model was used to calculate the odds ratio (OR) for the outcomes between
the two study groups. This was followed by multivariate analyses to account for any confounders
between the groups in the form of comorbidities mentioned in Table 1 (i.e. atrial fibrillation and
peripheral arterial disease). P value of <0.05 was considered statistically significant. We audited the
analyses using the checklist provided by NIS to assess and ensure data analyses is as per rules
recommended by NIS. (https://www.hcupus.ahrq.gov/db/nation/nis/nischecklist.jsp)
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Results
We identified a total of 14,191,325 hospitalizations during the years 2013 and 2014. Further, we
identified 18,733 in-patient hospitalizations for IE. Out of these, 867 had concurrent heart block. Our
final sample had two study groups: IE without heart block (n=17,866) and IE with heart block (n=867).
Table 1 shows background characteristics by study group. We found that patients with IE and heart
block were older, with a mean age of 58.6 ± 18.6 (p = 0.054). Patients with IE without heart block were
more likely to be female compared to those with IE with heart block (39.6% vs 31.6%; p<.001).
Prevalence of atrial fibrillation (27.9% vs 23.3%, p = 0.002) and peripheral arterial disease (22.4% vs
15.6%; p <0.001) was significantly higher in patients with IE and heart blocks.
Characteristics
Infective
endocarditis
without heart
block
Infective
endocarditis
with heart block
Number of Patients
17,866
867
P-Value
Age- mean (SD), y
57.3 ± 19.4
58.6 ± 18.6
.054
Female
39.6%
31.6%
<.001
Race
White
72.0%
70.1%
Black
14.8%
17.1%
Hispanic
8.3%
7.7%
.312
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Table 1. Baseline demographics and characteristics
Note: Statistically significant variables age, gender, atrial fibrillation, peripheral arterial disease, and
paying mode are adjusted in Table 2
Table 2 summarizes the results of logistic regression analyses used to calculated adjusted odds ratio (a-
OR) to control for variables in table 1. IE with heart block had higher mortality [a-OR 1.02 (1.01-1.02)],
increased length of stay [a-OR 2.23(1.95-2.56)] and higher cost of stay [a-OR 3.52(3.05-4.05)]. IE patients
with heart block had higher odds of stroke [a-OR = 1.32(1.10-1.59)], acute kidney injury [a-OR 1.36(1.18-
Hypertension
27.9%
27.8%
.938
Diabetes Mellitus
15.7%
15.5%
.867
Chronic kidney disease
5.7%
5.2%
.490
Atrial Fibrillation
23.3.%
27.9%
.002
Anemia
18.7%
17.2%
.250
Peripheral arterial disease
15.6%
22.4%
<.001
Teaching Hospital
30.1%
29.6%
.298
Rural Location
37.1%
37.4%
.611
Large Hospital bed size
25.8%
25.2%
.368
Primary Payer
Medicare / Medicaid
69.0%
66.9%
Private Insurance
20.7%
24.3%
.022
0-25th Percentile Income
30.7%
29.0%
.150
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1.57)], aortic valve replacement [a-OR 5.09(4.30-6.02)], mitral valve replacement [a-OR 4.70(3.87-5.70)],
pacemaker implantation [a-OR 48.55(39.14-60.24)], cardiogenic shock [a-OR 2.81(2.19-3.60)], cardiac
arrest [a-OR 3.48(2.64-4.57), hematologic complications [a-OR = 1.33 (1.12-1.59)], hepatic complications
[a-OR 1.40(1.03-1.91)], vascular complications [a-OR 2.26(1.62-3.15)] and cardiac tamponade [a-OR
2.20(1.14—4.25)]. After controlling for confounding variables in Table 1 with statistically significant
difference i.e. gender, atrial fibrillation, peripheral arterial disease and primary payer, the severity of
outcomes was significantly higher in IE with heart block for all variables except for acute kidney injury
leading to hemodialysis [a-OR 1.15 (0.96-1.39)], acquired pneumonia [a-OR 0.95(0.74-0.98)], and sepsis
[a-OR 0.85(0.74-0.98)]. Percentages of outcomes between the two groups is included in Figures 1 and 2.
In-Hospital Outcomes
Infective
Infective
a-OR
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endocarditis
without heart
block
endocarditis
with heart
block
In-Hospital Death
10.3%
13.0%
1.02(1.01-1.02)
Stroke
13.7%
17.2%
1.32(1.10-1.59)
Acute Kidney Injury
32.6%
40.1%
1.36(1.18-1.57)
Aortic valve replacement
6.1%
25.7%
5.09(4.30-6.02)
Mitral Valve replacement
4.2%
17.3%
4.70(3.87-5.70)
New Dialysis
14.8%
16.6%
1.15(.96-1.39)
Pacemaker Implantation
0.9%
30.6%
48.55(39.14-60.24)
Cardiogenic shock
3.2%
8.9%
2.81(2.19-3.60)
Cardiac arrest
2.2%
7.4%
3.48(2.64-4.57)
Hematologic complications
15.2%
19.3%
1.33(1.12-1.59)
Hepatic complications
3.95
5.2%
1.40(1.03-1.91)
Metabolic acidosis
11.7%
15.6%
1.41(1.16-1.70)
Vascular Complications
2.1%
4.7%
2.26(1.62-3.15)
Unplanned Vascular Surgery
1.3%
4.4%
3.54(2.49-5.03)
Cardiac Tamponade
0.5%
1.2%
2.20(1.14-4.25)
Acquired Pneumonia
14.4%
13.5%
.95(.78-1.16)
Sepsis
44.6%
40.0%
.85(.74-.98)
Tracheostomy
2.3%
3.1%
1.46(.98-2.17)
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Table 2. Clinical Outcomes of IE with and without heart block with adjusted Odds ratio
Note: Adjusted for age, gender, payor, atrial fibrillation, and peripheral artery disease
a Predicting length of stay greater 2 weeks
b Predicting cost greater than $150,000
Discussion
The primary and secondary outcomes were assessed after adjusting for variables that were statistically
significant in table 1, i.e. age, gender, atrial fibrillation, peripheral arterial disease, and paying mode. We
identified a significant increase in in-hospital mortality when IE is complicated by the development of
heart block (a-OR = 1.02). This could be explained by the pathophysiology of heart block in IE. The
development of heart block usually signifies that the infection has spread beyond the valve annulus and
into the local tissue.[4] Because of the proximity of the aortic and mitral valves to the conduction system
and AV node, extension of infection beyond the valve annulus and development of myocardial abscess
may impinge on these critical structures, leading to the development of heart block and arrythmias.[10]
This contiguous spread of infection could signify more advanced disease, therefore explaining the
increased mortality seen in these patients. We also found that patients with heart block had statistically
significant increases in stroke (a-OR = 1.32), acute kidney injury (a-OR = 1.36), and vascular
complications (a-OR = 2.26). This could also explain the increased mortality seen in these patients, as
patients with heart block are more likely to have multiple organ complications as demonstrated here.
Acute kidney injury could be due to potentially low cardiac output states in heart block leading to low
Gastrostomy
2.1%
1.6%
.78(.45-1.33)
Length of stay
13.8±15.4
18.9±16.8
2.23(1.95-2.56)a
Mean Cost ($)
$146,769±
$223,559
$274,481±
$282,573
3.52(3.05-4.05)b
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renal perfusion and kidney dysfunction. Further, septic embolization, which is closely correlated to the
size of the vegetation and the degree of vegetation spread beyond the annulus, are larger in size and
can embolize easily to the kidneys as well as the brain.[4] Lastly, vascular complications may be related
to embolization as well. An interesting finding is that the incidence of sepsis was less common in
patients suffering from IE with heart block (a-OR = .85). This is unusual, as the data is suggesting that
patients with complications secondary to an infectious process are less frequently developing sepsis
than in patients without this same complication. One hypothesis for this finding could be that due to the
increased incidence of multiple severe comorbid conditions in patients with IE and heart block (ex. valve
replacement, pacemaker placement, stroke, cardiogenic shock, cardiac arrest), it is possible that the
presence of sepsis is being overlooked and thus coded less frequently. Further research may be
necessary to expand upon this finding.
Patients with IE and heart block were more likely to require replacement of both the aortic and mitral
valves, with a-OR of 5.09 and 4.70 respectively. This is likely due to the fact that in order for heart block
to develop, the infection must spread beyond the valve annulus via damage to the affected valve.[4]
Adhesion of bacterium to the heart valve leads to damage to the endothelium, and the subsequent
development of an infected thrombus.[1] This leads to an inflammatory response and the release of
cytokines, integrins, and tissue factor thus further propagating valve leaflet distortion and
destruction.[1] The destruction may be due to the development of abscess, fistula, valve tears or holes,
and prosthetic valve detachment, all of which require surgical reconstruction of the valve.[11] When
considering that aortic valve replacement was more common than mitral valve replacement, it is worth
noting that the aortic valve is more commonly involved in IE than the mitral valve.[12,13] In addition,
the proximity of the aortic valve to the left and right bundle branches means that extension of infection
through the aortic valve has a greater likelihood of development of high-grade heart block compared to
mitral valve involvement.[13] Lastly, studies have shown that early surgical intervention is associated
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with reduced mortality and reduced risk of embolic events compared to medical management in
patients with endocarditis.[14,15] One multicenter cohort study has demonstrated that surgery
conveyed a significant benefit in mortality in patients with S. Aureus endocarditis, the most common
bacterium indicated in IE today.[15] Because of this proven benefit, nearly 50% of patients with IE are
now undergoing surgical intervention.[4] According the American Heart Association, heart block is an
indication for early surgical intervention in cases of IE, thus explaining the increase in valvular
replacement in patients with more severe complications such as heart block.[4] It is also worth noting
that patients with heart block likely require operations of greater magnitude. For example, surgical
management of patients with heart block secondary to periannular extension often involves drainage of
abscess cavities, excising necrotic tissue, and closure of any fistula tracts that may have developed
secondary to bacterial infection.[16] Reitz et al. attempted to treat patients with aortic annular abscess
via translocation of the aortic valve, closure of the coronary ostia, and saphenous venous bypass grafting
to the coronary vessels.[17] Van Hooser et al. found success in treating the same complication in a small
cohort of patients (n=3) through the use of composite prosthetic valve-woven Dacron tube graft
reconstruction of the aortic root.[18] Lastly, Navia et al. describe the need for reconstruction of the
intervalvular fibrosa with double valve replacement for patients with invasive double-valve IE, a very
challenging operation that may provide the only chance for cure in patients with significantly advanced
IE.[19] In their study, it was found that patients undergoing reconstruction of the intervalvular fibrosa
along with double valve replacement had post-operative in hospital death rates as high as 20%, often
due to post-operative sepsis related multiorgan failure. [19] The greater magnitude of the procedures
necessary to treat patients with the development of periannular extension and heart block is likely also
a contributing factor to poorer prognosis in these patients.
An additional finding that warrants discussion is the increased need for pacemaker implantation in
patients with IE complicated by heart block (a-OR = 48.55). In order to better understand this
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phenomenon, it is important to recognize that the cardiac conduction system is located within the right
atrium as well as the membranous septum. The left bundle branch is often located within the base of
the membranous septum, or along the left side of the interventricular septum in most cases.[7] The non-
coronary sinus of Valsalva, is in close proximity to the superior interventricular septum which contains
the bundle of HIS.[7] Finally, the mitral valve is within close proximity to the AV node.[10] Extension of
the infectious process into surrounding tissues in the form of an abscess may lead to interruption of the
conduction system due to direct impingement or inflammation.[20] One study by DiNubile et al.
demonstrated that of 211 patients with IE, 20 developed unstable conduction abnormalities.[20] Those
with unstable conduction abnormalities were more likely to have aortic valve involvement, consistent
with the anatomical proximity of the aortic valve to the conduction system.[21] Patients with AV
conduction abnormalities are at risk for the development of serious symptoms related to bradycardia or
ventricular arrythmias, which may also explain the increase in risk of cardiogenic shock and cardiac
arrest seen in our study. According to the American College of Cardiology, implantation of a permanent
pacemaker should be performed in adults with symptomatic third-degree AV block, type 2 second-
degree AV block, and even some cases of type 1 second-degree AV block and first-degree AV block to
prevent these complications from occurring.[21]
In the current study, it was found that women were less likely than men to develop heart block as a
complication of IE. This is consistent with data seen in previous studies. DiNubile et al. found that
patients with IE and unstable conduction abnormalities were more likely to be male (p = 0.04).[20]
Furthermore, Wang et al. found that when examining the records of 142 patients with bacterial
endocarditis, 6 developed complete heart block.[22] Of those 6 developing complete heart block, 5 of
them were males.[22] There are several reasons as to why women are less likely to develop heart block.
First, it has been hypothesized that higher levels of estrogen in women may play a protective role
against endothelial damage and inflammation.[23] Second, studies have shown that women are less
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likely than men to have aortic valve involvement, which as discussed previously, is known to be
associated with higher risk of developing heart block. Sombala et al. studied the differences between
men and women with IE, and found that 46% of men with IE had aortic valve involvement compared to
only 31% of women.[24] Further, 52% of women had mitral valve involvement compared to 36% of
men.[24] Castillo et al. demonstrated similar findings, with mitral valve involvement being seen in 54%
of women compared to 39% in men, and aortic valve involvement more common in men than women
(50% vs 29%).[25] It is likely that the differences in valvular involvement between sexes plays a
significant role in the development of heart block in these patients. Additional findings that were not of
statistical significance, but that may be of clinical significance are the increased incidence of IE and
comorbid heart block in African American patients (17.1% vs. 14.8%) and in rural hospitals (37.4 vs.
37.1%). The incidence was slightly less in patients with hypertension (27.8% vs. 27.9%), diabetes mellitus
(15.5% vs. 15.7%), and chronic kidney disease (5.2% vs. 5.7%).
Finally, patients with IE complicated by heart block were more likely to have increased length of stay as
well as increased mean cost compared to patients without heart block. This is likely due to an increased
need for surgical intervention, valvular replacement, and pacemaker implantation in patients with heart
block. The need for these interventions will prolong hospitalization and increased cost for patients due
to the cost of the procedures as well as additional costs accrued during the prolonged inpatient course.
Moreover, patients with heart block were more likely to develop complications such as stroke, acute
kidney injury, hematologic complications, hepatic complications, vascular complication and metabolic
acidosis. This increased likelihood of multi-organ involvement likely plays a significant role in increased
length and cost of hospitalization.
Limitations:
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There are limitations to utilization of the Healthcare Utilization Project database, including errors in
relation to the ICD9 and ICD10 coding system. In order to prevent this, we have utilized codes that have
been validated in previous studies. We have performed a retrospective analysis and give insight into an
association between two conditions rather than proving causation between these conditions and the
studied outcomes. An additional limitation is that the ICD coding system is unable to identify when
patients are readmitted with the same condition. Because of this, every admission is considered a
separate case and therefore a new patient encounter. A final limitation of the paper is that the model
used for data analysis was performed using statistically significant variables as confounders, as opposed
to a full comorbidity adjustment.
Conclusion
The development of heart block in patients with IE worsens in-hospital mortality, length of
hospitalization and cost of stay. Patients with IE and heart block are more likely to require surgical
interventions including valvular replacement and pacemaker implantation. In addition, these patients
are more likely to develop multiple organ dysfunction which likely contributes to the increased mortality
as well as length/cost of hospitalization. Patients with IE should be closely monitored with telemetry in
order to recognize the development of heart block. Doing so may lead to more prompt recognition of
the conduction abnormality as well as earlier intervention to avoid the adverse outcomes observed in
our study.
CONFLICT OF INTEREST
The authors report no conflict of interest.
Ethical Approval
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Our institution does not require ethical approval NIS data base studies.
FUNDING SOURCES
None
AUTHORSHIP STATEMENT
Shakeel Jamal and Asim Kichloo are credited with substantial contribution to the design of the work,
acquisition and interpretation of the data, drafting the manuscript, revision of important intellectual
content, final approval of the version published, and agreement of accountability for all aspects of the
work. Michael Albosta is credited with substantial contribution to interpretation of data, literature
review of all sections discussed, drafting of the manuscript, final approval of the version published, and
agreement of accountability for all aspects of the work. Beth Bailey is credited with substantial
contribution to acquisition, analysis, and interpretation of the data, revision of critically important
intellectual content, final approval of the version to be published, and agreement of accountability for
all aspects of the work. Jagmeet Singh, Farah Wani, Muhammad Shah Zaib, Muhammad Ahmad, and
Muhammad Dilawar Khan are credited with interpretation of the data, literature review of all sections,
revision of important intellectual content, final approval of the version published, and agreement of
accountability of all aspects of the work. Ronak Soni, Michael Aljadah, Hafiz Waqas Khan, Mahin R. Khan,
and Muhammad Z Khan are credited with interpretation of data, literature review, specifically for the
discussion section, revision of the work for critically important intellectual content, final approval of the
version published, and agreement of accountability for all aspects of the work.
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References:
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7. Kopelman HA, Graham BS, Forman MB. Myocardial abscess with complete heart block
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8. Voruganti DC, Shantha G, Dugyala S, et al. Temporal trends and factors associated with
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11. Lalani T, Cabell CH, Benjamin DK, et al. Analysis of the impact of early surgery on in-
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and Predictors of Mortality in 360 Consecutive Patients. Med Sci Monit. Jul
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13. Carpenter JL. Perivalvular extension of infection in patients with infectious endocarditis.
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19. Navia JL, Elgharably H, Hakim AH, et al. Long-term Outcomes of Surgery for Invasive
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20. DiNubile MJ, Calderwood SB, Steinhaus DM, Karchmer AW. Cardiac conduction
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21. Gregoratos G, Cheitlin MD, Conill A, et al. ACC/AHA Guidelines for Implantation of
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Guidelines (Committee on Pacemaker Implantation). Circulation. Apr 1998;97(13):1325-
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22. Wang K, Gobel F, Gleason DF, Edwards JE. Complete heart block complicating bacterial
endocarditis. Circulation. Nov 1972;46(5):939-47. doi:10.1161/01.cir.46.5.939
23. Farhat MY, Lavigne MC, Ramwell PW. The vascular protective effects of estrogen.
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24. Sambola A, Fernández-Hidalgo N, Almirante B, et al. Sex differences in native-valve
infective endocarditis in a single tertiary-care hospital. Am J Cardiol. Jul 2010;106(1):92-
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25. Castillo JC, Anguita MP, Delgado M, et al. [Clinical characteristics and prognosis of
infective endocarditis in women]. Rev Esp Cardiol. Jan 2008;61(1):36-40.
Figure 1. Outcomes of Infective Endocarditis with heart block (y-axis denotes percentage; p<0.05)
Figure 2. Outcome of Infective Endocarditis with heart block (y-axis denotes percentage; p<0.05)
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Figure 1. Outcomes of Infective Endocarditis with heart block (y-axis denotes percentage; p<0.05)
98x57mm (300 x 300 DPI)
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Figure 2. Outcome of Infective Endocarditis with heart block (y-axis denotes percentage; p<0.05)
97x58mm (300 x 300 DPI)
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ICD9 codes for secondary outcomes
1. Aortic valve replacement
35.21 Replacement of aortic valve with tissue graft
35.22 Other replacement of aortic valve
2. Mitral valve replacement
35.23 Replacement of mitral valve with tissue graft
35.24 Other replacement of mitral valve
3. Vascular Complications
868.04 Retroperitoneal hematoma
997.2 Peripheral vascular complications, NOS
997.7 Vascular complications of other vessels
999.2 Vascular complications, NEC
447.0 Arteriovenous fistula, acquired
901.0 Injury to thoracic aorta
902.0 Injury to abdominal aorta
904.0 Injury to common femoral artery
998.11 Hemorrhage complicating a procedure
998.12 Hematoma complicating a procedure
998.2 Accidental laceration during a procedure
7. Vascular Complications Requiring Surgery
39.31 Suture of artery
39.41 Control of hemorrhage
39.49 Other revision of vascular procedure
39.52 Repair of aneurysm
39.53 Repair of arteriovenous fistula
39.56 Repair of vessel with tissue patch
39.57 Repair of vessel with synthetic patch
39.58 Repair of vessel with unspecified patch
39.59 Repair of vessel, unspecified
8. Cardiogenic shock
785.51
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9. Cardiac arrest
427.5
10. Stroke
434.91 Cerebral artery occlusion, unspecified with cerebral infarction
430 Subarachnoid hemorrhage
431 Intracerebral hemorrhage
432.0 Nontraumatic extradural hemorrhage
432.1 Subdural hemorrhage
432.9 Unspecified intracranial hemorrhage
433.01 Cerebral thrombus with infarction
433.11 Occlusion of carotid artery, with cerebral infarction
433.21 Occlusion of vertebral artery with cerebral infarction
433.31 Occlusion of bilateral precerebral arteries with infarction
433.81 Occlusion of other precerebral arteries with cerebral infarction
433.91 Occlusion of unspecified precerebral arteries with infarction
434.00 Cerebral infarction without mention of cerebral infarction
434.01 Cerebral infarction with cerebral infarction
434.10 Cerebral embolism without mention of cerebral infarction
434.11 Cerebral embolism with cerebral infarction
436 Acute cerebral vascular disease, ill-defined
997.02 Iatrogenic cerebral infarction
11. Acute Kidney Injury
584.5 Acute Kidney Injury with tubular necrosis
584.6 Acute Kidney Injury with lesion of renal cortical necrosis
584.6 Acute Kidney Injury with lesion of renal cortical necrosis
584.8 Acute Kidney Injury, other specified pathological lesion in kidney
584.9 Acute Kidney Injury, unspecified
12. Acute Kidney Injury Requiring Dialysis
39.95 Hemodialysis (in addition to acute kidney injury)
585.6 End stage renal disease – excluded
13. Pacemaker Implantation
00.50 Implantation of CRT-P, total system
00.51 Implantation of CRT-D, total system
00.52 Implantation of coronary sinus lead
00.53 Implantation of CRT-P generator only
00.54 Implantation of CRT-D generator only
37.70 Initial insertion of lead, NOS
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37.71 Initial insertion of lead, ventricle
37.72 Initial insertion of lead, ventricle and atrium
37.73 Initial insertion of lead, atrium
37.80 Initial insertion of permanent pacemaker, NOS
37.81 Initial insertion of single-chamber pacemaker
37.82 Initial insertion of single-chamber pacemaker, rate responsive
37.83 Initial insertion of dual-chamber pacemaker
37.94 Implantation of ICD, total system
37.96 Implantation of ICD, generator only
14. Blood Transfusion CCS diagnosis
222 Blood transfusion
15. Cardiac Tamponade
423.3 Cardiac tamponade
16. Acquired Pneumonia
486 Pneumonia, organism unspecified
481 Pneumococcal pneumonia
482.8 Pneumonia due to other specified bacteria
482.3 Pneumonia due to streptococcus
17. Urinary Tract Infection
599.0 Urinary tract infection, site not specified
590.9 Infection of kidney, unspecified
18. Sepsis
995.91 Sepsis
038 Septicemia.
995.92 Severe sepsis
996.64 Infection and inflammatory reaction due to indwelling urinary catheter
999.31 Other and unspecified infection due to central venous catheter
999.32 Bloodstream infection due to central venous catheter
19. Mechanical Ventilation
96.72 Invasive mechanical ventilation
20. Tracheostomy
311 Temporary tracheostomy
31.21 Mediastinal tracheostomy
31.29 Other permanent tracheostomy
21. Gastrostomy
43.11 Percutaneous [endoscopic] Gastrostomy [PEG]
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43.19 Other gastrostomy
22. Hepatic
570 hepatic necrosis
572.2 Hepatic encephalopathy
573.3 unspecified hepatitis
23. Hematologic
287.3, 287.4, 287.5 Thrombocytopenia
286.9 Coagulopathy
24. Metabolic/lactic acidosis
276.2
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In Hospital Outcomes and Prevalence of Comorbidities in patients with Infective Endocarditis with and
without Heart Blocks – Insight from National Inpatient Sample
Shakeel Jamal, MD1, Asim Kichloo, MD1, Michael Albosta, MD1, Beth Bailey, PhD1, Jagmeet Singh, MD5
Farah Wani, MD6, Muhammad Shah Zaib, MD1, Muhammad Ahmad, MD1, Muhammad Dilawar Khan,
MD1, Ronak Soni, MD2, Michael Aljadah, MD3, Hafiz Waqas Khan, MD4, Mahin R Khan, MD4, Muhammad
Z Khan, MD7
1. Central Michigan University, College of Medicine, Saginaw, Michigan. USA.
2. University of Toledo, College of Medicine, Toledo, Ohio. USA.
3. Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
4. McLaren-Flint/Michigan State University, Flint, Michigan, USA.
5. Geisinger Commonwealth School of Medicine, Scranton, Pennsylvania. USA.
6. Samaritan Medical Center, Watertown, NY, USA.
7. West Virginia University, Morgantown, West Virginia, USA.
Word Count: 3169
Corresponding Author: Kichloo Asim M.D.
Address: 1000 Houghton Avenue, Saginaw, Michigan, 48602
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Telephone: 989-746-7500
Email address: kichlooasim@gmail.com
Abstract
Introduction: Infective Endocarditis (IE) complicated by heart block can have adverse outcomes and
usually requires immediate surgical and cardiac interventions. Data on outcomes and trends in patients
with IE with concurrent heart block is lacking. Patients with a primary diagnosis of IE with or without
heart block were identified by querying the Healthcare Cost and Utilization (HCUP) database,
specifically, the National Inpatient Sample for the years 2013 and 2014 based on ICD9 codes. During
2013 and 2014, a total of 18,733 patients were admitted with primary diagnosis of IE, including 867 with
concurrent heart blocks. There was an increased in-hospital mortality (13% vs 10.3%), length of stay (19
vs 14 days), and cost of care ($282,573 vs $223,559) for patients with IE complicated by heart block.
Additionally, these patients were more likely to develop cardiogenic shock (8.9% vs 3.2%), acute kidney
injury (40.1% vs 32.6%), hematologic complications (19.3 vs 15.2%), and require placement of a
pacemaker (30.6% vs 0.9%). Infective endocarditis and concurrent heart block resulted in increased
requirement for aortic (25.7 vs 6.1%) and mitral (17.3% vs 4.2%) valvular replacements. Conclusion was
made that, IE with concurrent heart block worsens in-hospital mortality, length of stay, and cost for
patients. Our analysis demonstrates an increase in cardiac procedures, specifically aortic and/or mitral
valve replacements, and ICD/CRT/PPM placement in IE with concurrent heart block. A close tele
monitoring system and prompt interventions may represent a significant mitigation strategy to avoid
the adverse outcomes observed in this study.
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Significance of this study:
Heart Blocks predict worse outcomes in patients with infective endocarditis.
What is already known about this subject?
Infective endocarditis can cause valve abscess.
Infective endocarditis can result in atrioventricular node blockage
Poor outcomes in patients with Infective endocarditis include old age, prosthetic valve
endocarditis, heart failure, paravalvular complications.
What are the new findings?
Infective endocarditis with concurrent heart block worsens the mortality.
Infective endocarditis with concurrent heart block increases length and cost of stay.
Infective endocarditis with concurrent heart block increases the requirement of pacemaker
insertion.
How might these results change the focus of research or clinical practice?
Patients with infective endocarditis and comorbid heart block are at high risk of worse outcomes
and immediate surgical intervention should be considered.
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Introduction
Infective endocarditis (IE) is an infection of a native or prosthetic heart valve, endocardial surface, or
indwelling cardiac device.[1,2] It occurs at an incidence of approximately 3 to 9 cases per 100,000
people per year.[3] In the developing world, rheumatic heart disease is the number one risk factor for
the development of IE.[1,2] However, in developed countries, rheumatic heart disease is extremely rare
and risk factors for the development of IE include diabetes, cancer, IV drug abuse, degenerative heart
valve disease, and congenital heart disease.[2] Although IE is rare, it is among the most common life-
threatening infectious syndromes along with pneumonia, intra-abdominal abscess, and sepsis.[4] In a
large prospective cohort study, it was found that the most common presenting symptoms include fever,
development of a new murmur, or worsening of an old murmur.[5] Less commonly, patients presented
with symptoms such as vascular embolic events, splenomegaly, Janeway lesions, Osler’s nodes, Roth
spots, and splinter hemorrhages.[5] Complications of IE include the development of embolism, stroke,
intracardiac abscess, congestive heart failure, and new conduction abnormalities.[5] Despite advances in
care, the mortality rates of IE have remained stable over the past 20 years, with rates approaching 30%
at 1 year after diagnosis.[6]
The high morbidity and mortality associated with infective endocarditis warrants further investigation
into the patterns, clinical course, and outcomes associated with development of this infectious process.
Heart block is a complication of IE that suggests the potential need for early surgical management.[4]
According to one study, complete heart block may occur in as many as 14% of cases of IE.[7] Current
data is limited regarding trends and outcomes in patients with IE developing heart block as a
complication. Using data from the National Inpatient Sample databases, we performed a cross sectional
analysis to evaluate several outcomes associated with the development of heart block along with IE.
Through this study, we hope to provide further information regarding the impact of developing heart
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block along with IE and to determine whether this can be used as a predictor of clinical course and
outcome in these patients.
Methods
Data source
The National Inpatient Sample has been elaborated in detail in prior studies.[8] National Inpatient
Sample is the largest publicly available database in United States, which falls under Healthcare Cost and
Utilization project (HCUP) and is maintained by the Agency for Health Care Quality and Research
(AHQR). It is one of the most useful databases for studying outcomes and trends of various procedures
and diseases. It is comprised of deidentified data collected from 20% of community hospitals in 46 states
in the United States. Each hospitalization is representative of one primary diagnosis, up to 29 secondary
diagnoses and 15 procedures using the International Clinical Modification Codes (ICD9 and ICD10). The
data includes admission status, demographics, admitting diagnosis, comorbidities, healthcare facility
status (rural vs. urban), discharge diagnosis, outcomes, length of stay and cost during hospitalization.
We examined all adult patients who were hospitalized during the years 2013 and 2014 with the
diagnosis of infective endocarditis with and without comorbid heart block using the National Inpatient
Sample. Patients were filtered using International Classification of Diseases, ninth revision, clinical
modification codes. ICD9 codes for IE were validated based on previous studies and codes that were
included were; 4210, 4211, 4212, 4219, 03642, 09884, 11281 and 1154.[9] ICD9 codes used to identify
first, second and third degree heart blocks were; 426.11, 426.12, 426.13 and 426.0. We excluded any
hospitalizations with missing demographics, i.e. age, gender, admission or discharge diagnosis and
mortality data. We utilized NIS variables to identify patients’ age, gender, race, county location, income,
and hospital bed size. Race was divided into three categories; African-American, White and Hispanic.
Baseline comorbidities taken into consideration were hypertension, diabetes mellitus, chronic kidney
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disease, atrial fibrillation, anemia, and peripheral arterial disease using the ICD9 codes. ICD codes for
outcomes have been included as a supplementary file.
Primary and secondary outcomes
Our objective was to assess the primary and secondary outcomes in patients with the principle diagnosis
of infective endocarditis with and without heart block. The primary outcomes to be analyzed were
mortality, length of stay, and cost for all hospitalizations due to IE with and without comorbid heart
blocks. Secondary outcomes to be assessed were; stroke, acute kidney injury (with and without new
hemodialysis), aortic and mitral valve replacement, cardiac arrest, cardiogenic shock, pacemaker
implantation, hematologic (thrombocytopenia/coagulopathy) and hepatic complications (hepatic
necrosis/hepatic encephalopathy/hepatitis), cardiac tamponade, sepsis, acquired pneumonia,
tracheostomy and gastrostomy. The ICD9 codes for these outcomes are included as a supplementary
file.
Statistical analysis
We used survey analyses to stratify and cluster encounters for all continuous and categorical variables.
SPSS software was used to perform statistical analyses. We used Chi-square test or analyses of variance
(ANOVA) to identify differences in categorical variables and two sample t-test for analysis of continuous
variables. Logistic regression model was used to calculate the odds ratio (OR) for the outcomes between
the two study groups. This was followed by multivariate analyses to account for any confounders
between the groups in the form of comorbidities mentioned in Table 1 (i.e. atrial fibrillation and
peripheral arterial disease). P value of <0.05 was considered statistically significant. We audited the
analyses using the checklist provided by NIS to assess and ensure data analyses is as per rules
recommended by NIS. (https://www.hcupus.ahrq.gov/db/nation/nis/nischecklist.jsp)
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Results
We identified a total of 14,191,325 hospitalizations during the years 2013 and 2014. Further, we
identified 18,733 in-patient hospitalizations for IE. Out of these, 867 had concurrent heart block. Our
final sample had two study groups: IE without heart block (n=17,866) and IE with heart block (n=867).
Table 1 shows background characteristics by study group. We found that patients with IE and heart
block were older, with a mean age of 58.6 ± 18.6 (p = 0.054). Patients with IE without heart block were
more likely to be female compared to those with IE with heart block (39.6% vs 31.6%; p<.001).
Prevalence of atrial fibrillation (27.9% vs 23.3%, p = 0.002) and peripheral arterial disease (22.4% vs
15.6%; p <0.001) was significantly higher in patients with IE and heart blocks.
Characteristics
Infective
endocarditis
without heart
block
Infective
endocarditis
with heart block
Number of Patients
17,866
867
P-Value
Age- mean (SD), y
57.3 ± 19.4
58.6 ± 18.6
.054
Female
39.6%
31.6%
<.001
Race
White
72.0%
70.1%
.312
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Table 1. Baseline demographics and characteristics
Black
14.8%
17.1%
Hispanic
8.3%
7.7%
Hypertension
27.9%
27.8%
.938
Diabetes Mellitus
15.7%
15.5%
.867
Chronic kidney disease
5.7%
5.2%
.490
Atrial Fibrillation
23.3.%
27.9%
.002
Anemia
18.7%
17.2%
.250
Peripheral arterial disease
15.6%
22.4%
<.001
Teaching Hospital
30.1%
29.6%
.298
Rural Location
37.1%
37.4%
.611
Large Hospital bed size
25.8%
25.2%
.368
Primary Payer
Medicare / Medicaid
69.0%
66.9%
Private Insurance
20.7%
24.3%
.022
0-25th Percentile Income
30.7%
29.0%
.150
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Note: Statistically significant variables age, gender, atrial fibrillation, peripheral arterial disease, and
paying mode are adjusted in Table 2
Table 2 summarizes the results of logistic regression analyses used to calculated adjusted odds ratio (a-
OR) to control for variables in table 1. IE with heart block had higher mortality [a-OR 1.02 (1.01-1.02)],
increased length of stay [a-OR 2.23(1.95-2.56)] and higher cost of stay [a-OR 3.52(3.05-4.05)]. IE patients
with heart block had higher odds of stroke [a-OR = 1.32(1.10-1.59)], acute kidney injury [a-OR 1.36(1.18-
1.57)], aortic valve replacement [a-OR 5.09(4.30-6.02)], mitral valve replacement [a-OR 4.70(3.87-5.70)],
pacemaker implantation [a-OR 48.55(39.14-60.24)], cardiogenic shock [a-OR 2.81(2.19-3.60)], cardiac
arrest [a-OR 3.48(2.64-4.57), hematologic complications [a-OR = 1.33 (1.12-1.59)], hepatic complications
[a-OR 1.40(1.03-1.91)], vascular complications [a-OR 2.26(1.62-3.15)] and cardiac tamponade [a-OR
2.20(1.14—4.25)]. After controlling for confounding variables in Table 1 with statistically significant
difference i.e. gender, atrial fibrillation, peripheral arterial disease and primary payer, the severity of
outcomes was significantly higher in IE with heart block for all variables except for acute kidney injury
leading to hemodialysis [a-OR 1.15 (0.96-1.39)], acquired pneumonia [a-OR 0.95(0.74-0.98)], and sepsis
[a-OR 0.85(0.74-0.98)]. Percentages of outcomes between the two groups is included in Figures 1 and 2.
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In-Hospital Outcomes
Infective
endocarditis
without heart
block
Infective
endocarditis
with heart
block
a-OR
In-Hospital Death
10.3%
13.0%
1.02(1.01-1.02)
Stroke
13.7%
17.2%
1.32(1.10-1.59)
Acute Kidney Injury
32.6%
40.1%
1.36(1.18-1.57)
Aortic valve replacement
6.1%
25.7%
5.09(4.30-6.02)
Mitral Valve replacement
4.2%
17.3%
4.70(3.87-5.70)
New Dialysis
14.8%
16.6%
1.15(.96-1.39)
Pacemaker Implantation
0.9%
30.6%
48.55(39.14-60.24)
Cardiogenic shock
3.2%
8.9%
2.81(2.19-3.60)
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Table 2. Clinical Outcomes of IE with and without heart block with adjusted Odds ratio
Note: Adjusted for age, gender, payor, atrial fibrillation, and peripheral artery disease
a Predicting length of stay greater 2 weeks
b Predicting cost greater than $150,000
Cardiac arrest
2.2%
7.4%
3.48(2.64-4.57)
Hematologic complications
15.2%
19.3%
1.33(1.12-1.59)
Hepatic complications
3.95
5.2%
1.40(1.03-1.91)
Metabolic acidosis
11.7%
15.6%
1.41(1.16-1.70)
Vascular Complications
2.1%
4.7%
2.26(1.62-3.15)
Unplanned Vascular Surgery
1.3%
4.4%
3.54(2.49-5.03)
Cardiac Tamponade
0.5%
1.2%
2.20(1.14-4.25)
Acquired Pneumonia
14.4%
13.5%
.95(.78-1.16)
Sepsis
44.6%
40.0%
.85(.74-.98)
Tracheostomy
2.3%
3.1%
1.46(.98-2.17)
Gastrostomy
2.1%
1.6%
.78(.45-1.33)
Length of stay
13.8±15.4
18.9±16.8
2.23(1.95-2.56)a
Mean Cost ($)
$146,769±
$223,559
$274,481±
$282,573
3.52(3.05-4.05)b
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Discussion
The primary and secondary outcomes were assessed after adjusting for variables that were statistically
significant in table 1, i.e. age, gender, atrial fibrillation, peripheral arterial disease, and paying mode. We
identified a significant increase in in-hospital mortality when IE is complicated by the development of
heart block (a-OR = 1.02). This could be explained by the pathophysiology of heart block in IE. The
development of heart block usually signifies that the infection has spread beyond the valve annulus and
into the local tissue.[4] Because of the proximity of the aortic and mitral valves to the conduction system
and AV node, extension of infection beyond the valve annulus and development of myocardial abscess
may impinge on these critical structures, leading to the development of heart block and arrythmias.[10]
This contiguous spread of infection could signify more advanced disease, therefore explaining the
increased mortality seen in these patients. We also found that patients with heart block had statistically
significant increases in stroke (a-OR = 1.32), acute kidney injury (a-OR = 1.36), and vascular
complications (a-OR = 2.26). This could also explain the increased mortality seen in these patients, as
patients with heart block are more likely to have multiple organ complications as demonstrated here.
Acute kidney injury could be due to potentially low cardiac output states in heart block leading to low
renal perfusion and kidney dysfunction. Further, septic embolization, which is closely correlated to the
size of the vegetation and the degree of vegetation spread beyond the annulus, are larger in size and
can embolize easily to the kidneys as well as the brain.[4] Lastly, vascular complications may be related
to embolization as well. An interesting finding is that the incidence of sepsis was less common in
patients suffering from IE with heart block (a-OR = .85). This is unusual, as the data is suggesting that
patients with complications secondary to an infectious process are less frequently developing sepsis
than in patients without this same complication. One hypothesis for this finding could be that due to the
increased incidence of multiple severe comorbid conditions in patients with IE and heart block (ex. valve
replacement, pacemaker placement, stroke, cardiogenic shock, cardiac arrest), it is possible that the
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presence of sepsis is being overlooked and thus coded less frequently. Further research may be
necessary to expand upon this finding.
Patients with IE and heart block were more likely to require replacement of both the aortic and mitral
valves, with a-OR of 5.09 and 4.70 respectively. This is likely due to the fact that in order for heart block
to develop, the infection must spread beyond the valve annulus via damage to the affected valve.[4]
Adhesion of bacterium to the heart valve leads to damage to the endothelium, and the subsequent
development of an infected thrombus.[1] This leads to an inflammatory response and the release of
cytokines, integrins, and tissue factor thus further propagating valve leaflet distortion and
destruction.[1] The destruction may be due to the development of abscess, fistula, valve tears or holes,
and prosthetic valve detachment, all of which require surgical reconstruction of the valve.[11] When
considering that aortic valve replacement was more common than mitral valve replacement, it is worth
noting that the aortic valve is more commonly involved in IE than the mitral valve.[12,13] In addition,
the proximity of the aortic valve to the left and right bundle branches means that extension of infection
through the aortic valve has a greater likelihood of development of high-grade heart block compared to
mitral valve involvement.[13] Lastly, studies have shown that early surgical intervention is associated
with reduced mortality and reduced risk of embolic events compared to medical management in
patients with endocarditis.[14,15] One multicenter cohort study has demonstrated that surgery
conveyed a significant benefit in mortality in patients with S. Aureus endocarditis, the most common
bacterium indicated in IE today.[15] Because of this proven benefit, nearly 50% of patients with IE are
now undergoing surgical intervention.[4] According the American Heart Association, heart block is an
indication for early surgical intervention in cases of IE, thus explaining the increase in valvular
replacement in patients with more severe complications such as heart block.[4] It is also worth noting
that patients with heart block likely require operations of greater magnitude. For example, surgical
management of patients with heart block secondary to periannular extension often involves drainage of
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abscess cavities, excising necrotic tissue, and closure of any fistula tracts that may have developed
secondary to bacterial infection.[16] Reitz et al. attempted to treat patients with aortic annular abscess
via translocation of the aortic valve, closure of the coronary ostia, and saphenous venous bypass grafting
to the coronary vessels.[17] Van Hooser et al. found success in treating the same complication in a small
cohort of patients (n=3) through the use of composite prosthetic valve-woven Dacron tube graft
reconstruction of the aortic root.[18] Lastly, Navia et al. describe the need for reconstruction of the
intervalvular fibrosa with double valve replacement for patients with invasive double-valve IE, a very
challenging operation that may provide the only chance for cure in patients with significantly advanced
IE.[19] In their study, it was found that patients undergoing reconstruction of the intervalvular fibrosa
along with double valve replacement had post-operative in hospital death rates as high as 20%, often
due to post-operative sepsis related multiorgan failure. [19] The greater magnitude of the procedures
necessary to treat patients with the development of periannular extension and heart block is likely also
a contributing factor to poorer prognosis in these patients.
An additional finding that warrants discussion is the increased need for pacemaker implantation in
patients with IE complicated by heart block (a-OR = 48.55). In order to better understand this
phenomenon, it is important to recognize that the cardiac conduction system is located within the right
atrium as well as the membranous septum. The left bundle branch is often located within the base of
the membranous septum, or along the left side of the interventricular septum in most cases.[7] The non-
coronary sinus of Valsalva, is in close proximity to the superior interventricular septum which contains
the bundle of HIS.[7] Finally, the mitral valve is within close proximity to the AV node.[10] Extension of
the infectious process into surrounding tissues in the form of an abscess may lead to interruption of the
conduction system due to direct impingement or inflammation.[20] One study by DiNubile et al.
demonstrated that of 211 patients with IE, 20 developed unstable conduction abnormalities.[20] Those
with unstable conduction abnormalities were more likely to have aortic valve involvement, consistent
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with the anatomical proximity of the aortic valve to the conduction system.[21] Patients with AV
conduction abnormalities are at risk for the development of serious symptoms related to bradycardia or
ventricular arrythmias, which may also explain the increase in risk of cardiogenic shock and cardiac
arrest seen in our study. According to the American College of Cardiology, implantation of a permanent
pacemaker should be performed in adults with symptomatic third-degree AV block, type 2 second-
degree AV block, and even some cases of type 1 second-degree AV block and first-degree AV block to
prevent these complications from occurring.[21]
In the current study, it was found that women were less likely than men to develop heart block as a
complication of IE. This is consistent with data seen in previous studies. DiNubile et al. found that
patients with IE and unstable conduction abnormalities were more likely to be male (p = 0.04).[20]
Furthermore, Wang et al. found that when examining the records of 142 patients with bacterial
endocarditis, 6 developed complete heart block.[22] Of those 6 developing complete heart block, 5 of
them were males.[22] There are several reasons as to why women are less likely to develop heart block.
First, it has been hypothesized that higher levels of estrogen in women may play a protective role
against endothelial damage and inflammation.[23] Second, studies have shown that women are less
likely than men to have aortic valve involvement, which as discussed previously, is known to be
associated with higher risk of developing heart block. Sombala et al. studied the differences between
men and women with IE, and found that 46% of men with IE had aortic valve involvement compared to
only 31% of women.[24] Further, 52% of women had mitral valve involvement compared to 36% of
men.[24] Castillo et al. demonstrated similar findings, with mitral valve involvement being seen in 54%
of women compared to 39% in men, and aortic valve involvement more common in men than women
(50% vs 29%).[25] It is likely that the differences in valvular involvement between sexes plays a
significant role in the development of heart block in these patients. Additional findings that were not of
statistical significance, but that may be of clinical significance are the increased incidence of IE and
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comorbid heart block in African American patients (17.1% vs. 14.8%) and in rural hospitals (37.4 vs.
37.1%). The incidence was slightly less in patients with hypertension (27.8% vs. 27.9%), diabetes mellitus
(15.5% vs. 15.7%), and chronic kidney disease (5.2% vs. 5.7%).
Finally, patients with IE complicated by heart block were more likely to have increased length of stay as
well as increased mean cost compared to patients without heart block. This is likely due to an increased
need for surgical intervention, valvular replacement, and pacemaker implantation in patients with heart
block. The need for these interventions will prolong hospitalization and increased cost for patients due
to the cost of the procedures as well as additional costs accrued during the prolonged inpatient course.
Moreover, patients with heart block were more likely to develop complications such as stroke, acute
kidney injury, hematologic complications, hepatic complications, vascular complication and metabolic
acidosis. This increased likelihood of multi-organ involvement likely plays a significant role in increased
length and cost of hospitalization.
Limitations:
There are limitations to utilization of the Healthcare Utilization Project database, including errors in
relation to the ICD9 and ICD10 coding system. In order to prevent this, we have utilized codes that have
been validated in previous studies. We have performed a retrospective analysis and give insight into an
association between two conditions rather than proving causation between these conditions and the
studied outcomes. An additional limitation is that the ICD coding system is unable to identify when
patients are readmitted with the same condition. Because of this, every admission is considered a
separate case and therefore a new patient encounter. A final limitation of the paper is that the model
used for data analysis was performed using statistically significant variables as confounders, as opposed
to a full comorbidity adjustment.
Conclusion
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The development of heart block in patients with IE worsens in-hospital mortality, length of
hospitalization and cost of stay. Patients with IE and heart block are more likely to require surgical
interventions including valvular replacement and pacemaker implantation. In addition, these patients
are more likely to develop multiple organ dysfunction which likely contributes to the increased mortality
as well as length/cost of hospitalization. Patients with IE should be closely monitored with telemetry in
order to recognize the development of heart block. Doing so may lead to more prompt recognition of
the conduction abnormality as well as earlier intervention to avoid the adverse outcomes observed in
our study.
CONFLICT OF INTEREST
The authors report no conflict of interest.
Ethical Approval
Our institution does not require ethical approval NIS data base studies.
FUNDING SOURCES
None
AUTHORSHIP STATEMENT
Shakeel Jamal and Asim Kichloo are credited with substantial contribution to the design of the work,
acquisition and interpretation of the data, drafting the manuscript, revision of important intellectual
content, final approval of the version published, and agreement of accountability for all aspects of the
work. Michael Albosta is credited with substantial contribution to interpretation of data, literature
review of all sections discussed, drafting of the manuscript, final approval of the version published, and
agreement of accountability for all aspects of the work. Beth Bailey is credited with substantial
contribution to acquisition, analysis, and interpretation of the data, revision of critically important
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intellectual content, final approval of the version to be published, and agreement of accountability for
all aspects of the work. Jagmeet Singh, Farah Wani, Muhammad Shah Zaib, Muhammad Ahmad, and
Muhammad Dilawar Khan are credited with interpretation of the data, literature review of all sections,
revision of important intellectual content, final approval of the version published, and agreement of
accountability of all aspects of the work. Ronak Soni, Michael Aljadah, Hafiz Waqas Khan, Mahin R. Khan,
and Muhammad Z Khan are credited with interpretation of data, literature review, specifically for the
discussion section, revision of the work for critically important intellectual content, final approval of the
version published, and agreement of accountability for all aspects of the work.
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Figure 1. Outcomes of Infective Endocarditis with heart block (y-axis denotes percentage; p<0.05)
Figure 2. Outcome of Infective Endocarditis with heart block (y-axis denotes percentage; p<0.05)
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