CPC

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CPC 4 A Case of the Swollen Organ
Bridging the Gap. Where Clinical and Basic
Sciences Meet

• Maximiliano Arroyo, MD
• Fellow, Cardiovascular Diseases

Louisa Balazs, MD, PhD Associate Professor of
Pathology
Karl T. Weber, MD Professor of Medicine
2
Undaunted by the heat and humidity offered on
this Wednesday, January, 14, 1970, the streets of
São Paulo were filled with confident rhetoric
about Brasils football team. Despite its
absence from the finals of the World Cup in 1966,
this years team was felt to have an excellent
chance to again reign as champion.
3
The Cup would be held in Mexico this June and
Mario Zagalo, former member of the 1958 and 1962
championship teams, would serve as coach. And
this time around there would be Pelé, who because
of injury had missed his teams 31 victory over
Czechoslovakia on June 17, 1962, in Santiago.
Busy rounding on the medical service of this
famous University hospital was Nick de Carvelho,
second-year resident in internal medicine. As
usual, the ward was filled to capacity and his
patients represented a remarkable diversity of
illnesses.
4
This morning 3 patients in particular posed
several mysteries that he wished to solve. Mr.
H., a 53-year-old businessman, was convalescing
with strict bed rest after his myocardial
infarction (MI) 14 days earlier and which had
been complicated by acute pulmonary edema, but
which had resolved spontaneously.
5
Miss F., a 16-year-old, who presented to the
emergency room with a history of painless edema
of the left palpebrae and periocular tissue
(Figure) followed by malaise, fever, facial edema
and signs and symptoms of heart failure. A
presumptive diagnosis of acute Chagas disease
with Trypanosoma cruzi infestation had been made.
6
Mr. S., a 35-year-old agricultural worker who
just yesterday had been bitten on the hand when
he startled a viper in the weeds.
7
The snake was likely Bothrops jararaca, the most
frequent venomous species seen in southern
Brasil. This included Rio Grande do Sul, São
Paulo and Rio de Janeiro.
8
At the Hospital Vital Brasil of the Instituto
Butantan, venomous snakebites have long posed a
serious health problem. From 19021945, there
were 6001 reported cases with B. jararaca
accounting for 52 while between 19541965 a
total of 15,709 cases were seen and of those
poisonous, 36 were related to this viper.
9
Mr. S. had presented to the emergency room
several hours after the bite with a painful and
swollen hand. Unlike more serious bites Nick had
seen, there was no bleeding from the gums, nose,
or internal organs. Antivenin had been
administereda treatment that had substantially
reduced mortality from such bites.
10
As Nick prepared for rounds with his attending,
he pondered about similarities between these
three cases. He reflected back on lectures given
during sophomore year pathology, where the
initial exudative and inflammatory phases of
wound healing were noted to be followed by
cicatrization.
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And while etiologic factors were distinctive for
each entity, the same early phases of healing
that eventuated in a swollen organ had to be
operative. Was this fanciful or was Nick right
to correlate the inflammation-healing paradigm in
each of these disparate entities?
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Mr. H

• Acute Myocardial Infarction
• Myocardial Interstitial Edema with increase in
  wall stiffness
• Pulmonary Edema

Increase in pulmonary venous pressure
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Miss.FChagas Myocarditis

• Major Cardiovascular manifestation is an
  extensive myocarditis that typically becomes
  evident years after the initial infection.
• Acute During this phase it can be transmitted to
  humans through the bite of a reduviid bug. It
  harbors the parasite in the GI tract.

14

• The bug often bites the person around the eyes
  and later infects when parasites in the animals
  feces gain entry through abraded skin or
  conjunctivae. Occasionally this results in
  unilateral periorbital edema and swelling of the
  eyelid, termed the Romaña sign, whereas entry
  through the skin my result in a lesion called
  chagoma

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• Metacyclic trypomastigotes are effective forms of
  T. cruzi that pass from the insect's hindgut in
  the fecal matter and burrow into the skin, either
  through the bite site or skin abrasions.
• After metacyclic tryps pass through the skin,
  they briefly travel in the blood stream and then
  colonize muscle and neuron tissue, areas less
  vulnerable to attack, where they encyst and form
  amastigotes

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Mr.SSnake Bite

• Bothrops is distributed in most parts of Latin
  America and the southern parts of the Caribbean
  area. The genus holds a variety of poisonous
  species.

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Inflammation
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Snake Venom and ACE-I

• The venom of the Bothrops jararaca induces
  systemic vasodilatation. Ferreiras, et al.
  search for the active component of the venom led
  to the discovery of bradykinin-potentiating
  factor.
• Bradykinin-potentiating peptides prevent the
  conversion of BK into inactive metabolites,
  therefore, were inhibitors of kininase II. They
  also would prevent the conversion of Angiotensin
  I to Ang II, therefore, considered ACE
  inhibitors.
• Inhibition of ACE was subsequently found to also
  reduce the degradation of other substances,
  including substance P and enkephalins, which are
  mediators of inflammation.

Weber KT, Wound Healing in Cardiovascular
Disease, 1995
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Weber KT, Wound Healing in Cardiovascular
Disease, 1995
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Seaweed and Chemical Mediators of Inflammation

• The release of BK and Prostaglandins is
  associated with immediate sustained response in
  vascular hyperpermeability and accompanies the
  injection of a polysaccharide derivative of
  seaweed, Chondrus crispus, (CARR).

Weber KT, Wound Healing in Cardiovascular
Disease, 1995
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Weber KT, Wound Healing in Cardiovascular
Disease, 1995
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• An ACE inhibitor will attenuate kininase II
  activity and thereby increase local
  concentrations of BK and potentiate its effects.
• Captopril increased CARR-induced paw edema the
  same was true for kininase II inhibitor
  phenanthroline.

Weber KT, Wound Healing in Cardiovascular
Disease, 1995
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Conclusions

• The heart, skin and other tissues respond to
  injury and infection in a similar way.
• BK is an essential component of the reaction seen
  in the heart and skin following seaweed
  injection, infection or infarction.
• BK causes initial vasodilatation, followed by
  vascular hyperpermeability interstitial
  edema
• Swollen Organ

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Inflammation

• Pathomechanism and physiology

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Stimuli for acute inflammation

• Infections (bacterial, viral, parasitic)
• Trauma (blunt, penetrating)
• Physical and chemical agents
• Tissue necrosis
• Foreign bodies
• Hypersensitivity reactions

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Changes in vascular flow and caliber

• Vascular dilation (effect of histamine, nitric
  oxide on smooth muscle), blood flow increased
• Increased permeability, outflow of protein rich
  fluid (vasoactive amines, bradykinin)
• Stasis
• Leukocyte adhesion and migration

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Vascular Leakage

• Reduced intravascular and increased extra
  vascular osmotic pressure -EDEMA
• Formation of intravascular gaps
• Direct endothelial injury
• Leukocyte dependent injury
• Increased transcytosis
• New blood vessel formation

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Formation of endothelial gaps

• Effects venules (20-60 microm)
• Elicited by histamine, bradykinin, leukotrienes,
  neuropeptide substance P
• Phosphorylation of contractile and cytoskeletal
  proteins
• Contraction of endothelial cells and separation
  of intercellular junctions

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Insect bite, increased blood flow (rubor)
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Insect bite, edema
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Acute dermatitis
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Acute myocardial infarct
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Interstitial edema, acute myocardial infarct
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Outcome of acute inflammation

• Resolution (clearance, replacement, normal
  function)
• Pus formation (precedes healing)
• Fibrosis (healing, loss of function)
• Progression (chronic inflammation, followed by
  healing)

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Myocardial infarct, cellular reaction
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Insect bite - chronic phase
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Myocardial fibrosis

39
In February, 1901, the Institute Butantan
officially opened with Dr. Vital Brazil, a
pioneer in the development of serotherapy against
snakebite and the specificity of antivenins,
named its director. By 1970, chemical mediators
of inflammation following snakebite or
subcutaneous injection of foreign substance
(e.g., seaweed) had received considerable
interest.
40
This included the famous laboratory of Rocha e
Silva in the Department of Biochemistry and
Pharmacodynamics, Instituto Biologico, São Paolo.
41
Silvas laboratory found venom extract caused a
gradual contraction of guinea pig ileum compared
to rapid contraction by histamine. He therefore
named this substance bradykinin.
42
Edema in the heart, as seen after infarction or
trypanosome infestation, can account for abnormal
myocardial stiffness. A bradykinin potentiating
factor is present in snake venom. It is known
today as a kininase II inhibitor (alternatively
an angiotensin I converting enzyme inhibitor) and
was reported by Ferriera from São Paolo in 1970.
43
Indeed, the heart, skin and other tissues respond
to injury and infection in a rather similar
fashion. Depending on the nature of the
stimulus, chemical mediators of inflammation,
such as histamine, serotonin, bradykinin and
prostaglandins, are released. Bradykinin is
central to the response seen in the heart and
skin following infarction, infection or seaweed
injection. Its initial vasodilatory properties
are followed by vascular hyperpermeability with
interstitial edemathe swollen organ.