04-Back to the Future_ of Fevers and Failures

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Future Cardiology
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Back to the Future: of Fevers and Failures
Farouk Mookadam & Jamil Tajik
To cite this article: Farouk Mookadam & Jamil Tajik (2010) Back to the Future: of Fevers and
Failures, Future Cardiology, 6:5, 567-569, DOI: 10.2217/fca.10.79
To link to this article: https://doi.org/10.2217/fca.10.79
Published online: 08 Oct 2010.
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567ISSN 1479-6678Future Cardiol. (2010) 6(5), 567–569
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10.2217/FCA.10.79 © 2010 Future Medicine Ltd 
On 7 October 1896, 114 years ago in Sir 
William Osler’s address to the American Medical 
Association in Atlanta (GA, USA) he famously 
declared: ‘Humanity has but three great enemies: 
fever, famine and war ... of these by far the most 
terrible is fever’ [1]. This was an era where Osler 
and his contemporaries spent their energy battling 
fevers and infectious diseases. The microbiologi­
cal basis for infections and the biochemical basis 
for the febrile response were poorly understood.
Galileo in 1595 invented the first water thermo­
meter and the mercury­based thermo meter was 
presented by Fahrenheit in 1714 [2]. Typhoid, 
tuberculosis and pneumonia were the rogues of 
the day.
“...114 years ago ... [humanity had] but 
three great enemies: fever, famine and 
war ... of these by far the most terrible 
is fever...”
In the 21st century, it can be declared with 
Oslerian mimicry that the modern humanity has 
but three great enemies: congestive heart failure 
(CHF), famine and war. It is a sad commentary 
of humanity that over a century later, that two of 
the three Oslerian enemies, namely famine and 
war are still rampant in this 21st century. The 
scourge of fever has now been replaced by the 
scourge of heart failure (HF). The not infrequent 
final ‘discharge’ diagnosis on patients chart of 
‘fever of unknown origin or FUO’ has in modern 
practice been replaced by the frequent discharge 
diagnosis of CHF or simply HF, a nebulous term. 
In similitude then, just as the pharmacopeia of 
antipyretics emerged to subvert the inflamma­
tory and pyrogenic processes underlying fever, 
so too in the 20th century pharmacother­
apy is being used to subvert activation of the 
renin–angiotensin–aldosterone system (RAAS). 
The scourge of fever was eventually conquered 
by improvements in public hygiene, vaccination 
and aseptic technique to the point where ‘fever of 
unknown origin’ may soon be assigned a status 
among the ‘maladies of relic’. Advances in the 
management of CHF have been modest since 
the advent of diuretics and digitalis. Drugs and 
device therapy have both provided, at best, a 
modest relative risk reduction in the region of 
20% when the RAAS is interrupted. Recent 
studies, in an attempt to discover the holy grail 
for CHF, have been met with limited success. 
This is akin to fever, which may have a specific 
microbiologic etiology and hence, can be accu­
rately targeted with therapeutic antimicrobi­
als, such as antibiotics, antivirals, antifungals, 
antiparasitic or antiprotozoals for infection or 
antimitotic agents for cancers that may present 
with fever. These specific targeted strategies lead 
to success. Similarly, should there not be targeted 
therapy for CHF?
“...In the 21st century, it can be 
declared with Oslerian mimicry that the 
modern humanity has but three great 
enemies: congestive heart 
failure ... famine and war...”
The etiology of fever is protean, as is the 
etiology of CHF. Heart failure, like fever or 
anemia is not a diagnosis but a conglomerate of 
signs and symptoms. Heart failure represents the 
final common pathway of all forms of heart dis­
ease . Successful treatment therefore mandates 
targeted therapy toward the disparate etiologies 
of CHF. Furthermore, the broad categories of 
CHF have identical etiologies but vastly dif­
ferent therapeutic strategies. The conventional 
culprits of systolic HF (CAD, hypertension, 
Type II diabetes mellitus, and dyslipidemia) 
Ed
ito
ria
l
Keywords
n clinical trials n diastolic heart 
failure n failure n fever
n heart failure prevention
n systolic heart failure
Back to the future: 
of fevers and failures
“...the broad categories of CHF have 
identical etiologies but vastly different 
therapeutic strategies.”
Farouk Mookadam† & Jamil Tajik1
1Aurora St Lukes, Mount Sinai Cardiovascular Specialists, 2801 W Kinnickinnic River Pkwy, Milwaukee, WI 
53215-3678, USA 
†Author for correspondence: College of Medicine, Mayo Clinic Arizona, 13400 East Shea Blvd, 
Mayo Building Concourse, Scottsdale, Arizona, AZ, USA n Tel.: +1 480 301 6801 n Fax: +1 480 301 8018 
n mookadam.farouk@mayo.edu
For reprint orders, please contact: reprints@futuremedicine.com
Future Cardiol. (2010) 6(5)568 future science group
also cause diastolic HF. In addition, hyper­
tension, obstructive sleep apnea, obesity and 
the metabolic syndrome can be implicated in 
the etiology of diastolic HF. The true success in 
the management paradigm of CHF by necessity 
then must incorporate preventive strategies or 
hygienic methods as it relates to caloric restric­
tion, regular aerobic exercise and weight main­
tenance, among others. CHF having progressed 
owing either to failure of preventive strategies or 
targeted treatments then requires specific treat­
ment strategies targeted at the specific etiology 
of that CHF, in cases of valvular heart disease 
the treatment is surgical repair or replacement; 
coronary artery disease by revascularization, 
percutaneously or by surgical technique; and 
end­stage systolic HF by cardiac transplanta­
tion, ventricular assist device or total artificial 
heart. Critical to this paradigm is the timing of 
the intervention, for example, fixing advanced 
mitral regurgitation or late aortic stenosis, 
while it helps the hemodynamic state of the 
afflicted valve by relieving the valvular prob­
lem, it leaves in its wake a pump problem that 
no amount of medication can easily manage, 
namely that of poor LV systolic function (with 
diastolic dysfunction of variable degree) in cases 
of mitral regurgitation and advanced diastolic 
dysfunction in cases of severe aortic stenosis.
“The etiology of fever is protean, as is 
the etiology of CHF. Heart failure such as 
anemia is not a ‘diagnosis’ but a sign or 
a conglomerate of signs 
(and symptoms).”
Recent clinical trials have little impact on 
the management of CHF because disparate 
etiologies of CHF are all lumped together as 
if they all had a common etiology and offered 
a homogenized treatment strategy of ‘one size 
fits all’. Ischemic cardiomyopathy may behave 
differently in response to pharmacotherapeu­
tics when compared with nonischemic cardio­
myopathy as noted from the PRAISE II study. 
Valvular heart disease is a mechanical problem 
and hence ideally requires a mechanical solution 
in a timely manner to avoid the LV dysfunction 
in late valve repair. Ischemic cardiomyopathy 
with revascularization percutaneously may leave 
the patient incompletely treated if there is con­
comitant malfunctioning valvular disease that 
is left untreated. 
Incorporating such patients into CHF trials 
is unlikely to result in robust success. 
“Recent clinicaltrials have little impact 
on the management of CHF because 
disparate etiologies of CHF are being 
offered a homogenized 
treatment strategy.”
Even among the group with diastolic HF or 
HF with preserved ejection fraction, there is 
a gradation of severity and mortality as well as 
varied etiology. Outcomes in terms of death were 
demonstrated in two recent studies by Owan 
and Bhatia with high mortality rates [3,4]. The 
more recent I­PRESERVE study [5] shows a 34% 
event rate among this group. It is well recognized 
that the higher the grade of severity of diastolic 
dysfunction, the higher the mortality. Tailored 
therapy towards each category with meticulous 
attention to assessing diastolic dysfunction by 
echocardiographic technique as described in the 
literature is more likely to demonstrate a difference 
in outcomes. 
The time has come for clinical trials directed 
at specific etiologies of CHF or LV dysfunction, 
the grab­bag approach to this disease is unlikely 
to yield positive results.
 
“The time has come for clinical trails 
directed at specific etiologies of CHF or 
LV dysfunction. The grab bag approach 
to this disease is unlikely to yield 
positive results.”
Lessons from fever in the days of Osler should 
be applied to present day problems with HF. 
It is axiomatic that treatment strategies based 
on the specific etiology of the fever, eliminated 
the ‘FUO’ designation resulting in improved 
outcomes for patients with fever. It is also axi­
omatic that emulating a similar etiologic and 
pathophysiologic­based strategy will eventually 
lead to conquest of F or CHF. Lessons from 
fever in the days of Osler should be applied to 
present day problems of heart failure. 
Financial & competing interests disclosure
The authors have no relevant affiliations or financial 
involvement with any organization or entity with a 
financial interest in or financial conflict with the sub-
ject matter or materials discussed in the manuscript. 
This includes employment, consultancies, honoraria, 
stock ownership or options, expert testimony, grants or 
patents received or pending, or royalties.
No writing assistance was utilized in the production 
of this manuscript.
Editorial Mookadam & Tajik
www.futuremedicine.com 569future science group
Bibliography
1. Osler W: The study of the fevers in the south. 
JAMA 1896(26), 999–1004 (1896).
2. Estes JW: Quantitative observations on fever 
and its treatment before the advent of short 
clinical thermometers. Med. Hist. 35(2), 
189–216 (1991).
3. Packer M, O’Connor CM, 
Ghali JK, Pressler ML et al.: Effect of 
amlodipine on morbidity and mortality in 
severe chronic heart failure. Prospective 
Randomized Amlodipine Survival Evaluation 
Study Group. N. Engl. J. Med. 335(15), 
1107–1114 (1996).
4. Owan TE, Hodge DO, Herges RM, 
Jacobsen SJ, Roger VL, Redfield MM: Trends 
in prevalence and outcome of heart failure 
with preserved ejection fraction. 
N. Engl. J. Med. 355(3), 1256–1259 (2008).
5. Bhatia RS, Tu JV, Lee DS et al.: Outcome of 
heart failure with preserved ejection fraction in 
a population­based study. N. Eng. J. Med. 
355(3), 260–269 (2006).
Back to the future: of fevers & failures Editorial