Amenophis IV, Lincoln, Paganini, and Rachmaninov

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Amenophis IV, Lincoln, Paganini, and
Rachmaninov
Shadwan Alsafwah, MD
Cardiology Fellow
Staff
Support Dr. Richard Davis
The University of Tennessee at
Memphis
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Case

• 21 YO AAM presented to the ED with headache, neck
  pain, and N/V for 2 days getting worse with time.
  The family noticed him to be starting to develop
  mental status changes with lethargy and
  difficulty following commands.
• In ER, LP was done, was found later to have viral
  meningitis and was admitted to MICU, and started
  on IV Acyclovir.
• He had significant improvement, and transferred
  to the floor.
• on the 3rd hospital day he developed mild
  pleuretic CP on ambulation, so repeat ECG showed
  significant changes in comparison to admit ECG,
  so Cardiology consult requested, transferred to
  telemetry, and CEs checked.

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Case

• PMH none
• PSH Skin graft to LLQ (burn)
• SH previous smoker, previous Marijuana, none
• recently
• No ETOH
• FH Aunt with DM
• Meds Acetaminophen, IV Acyclovir
• Allergies none
• ROS positive for N/V, HA, neck pain, and chills
• negative for SOB, visual complaints
• excellent exercise tolerance prior to
  this admit

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Case

• PE on the 3rd hospital stay
• General mildly lethargic, H 6 00, W 132
  LBS
• Vitals 110/60, 45, 16, 100, 97 on RA
• Neck no JVD, mild nuchal rigidity
• Chest CTAB
• CVS Bradycardic, RRR, no S3 or S4, mid
  systolic click
• heard widely all over the
  precordium that moved
• toward S2 with squatting, and
  toward S1 with
• standing. There was also II/VI
  early decrescendo diastolic
• murmur at LSB
• Abdomen Soft, NT, ND, NABS, graft scar
• Ext no edema, clubbing, cyanosis
• Muskeloskeletal system without gross
  abnormalities
• Neuro mildly lethargic, but oriented x3, no
  focal deficits

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Labs and Diagnostic Imaging

• UDS negative
• Head CT negative
• MRI of head and whole spine was negative
• CEs obtained when the ECG changes were noted
• 1st 2nd 3rd
  
• CKMB 6.6 4.0 2.2
• CKMB index 0.8 0.8 1.3
• Trop-I 0.07 0.07 0.02
• With the positive CEs, 2D echo was requested to
  assist in the diagnosis

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2D Echocardiogram

• Chambers Normal LV size and systolic function,
  EF is 65-70
• Mild mitral valve prolapse with mild mitral
  regurgitation
• Annuloaortic ectasia with aortic valve prolapse
  and moderate aortic insufficiency
• No evidence of aortic dissection
• Findings consistent with connective tissue
  disorder such as Marfans syndrome

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Marfan Syndrome (MFS)Outline

• Incidence
• Historic Background
• Genetic Background
• Pathogenesis
• Clinical Manifestations
• Diagnosis
• Marfan Related Disorders

• Overlap Heritable Connective Tissue Disorder
• Prognosis
• Management
• Pregnancy
• Conclusion

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Incidence

• In the US it affects 1 in 10,000
• At least 200,000 people in the US have MFS or a
  related connective tissue disorder
• This makes MFS one of the most common single-gene
  malformation syndromes
• May be diagnosed prenatally, at birth, or well
  into adulthood
• Internationally, no geographic predilection is
  known
• It is pan-ethnic
• No gender predilection is known

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Historic Background

• In 1896 Marfan described the case of 5-year old
  patient Gabriel P.
• Weve in 1931 described its autosomal dominant
  inheritance
• Dietz in 1991 described FBN1 gene mutation as the
  cause of Marfan syndrome

Antoine Marfan, MD 1858-1942
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Amenophis IV
Lincoln
Paganini
Rachmaninov
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Genetic Background

• Inherited connective tissue disorder transmitted
  as an autosomal dominant trait
• 75 of patients have an affected parent
• The other 25 is due to new mutations
• Most of the time results from molecular defects
  in the fibrillin-1 (FBN1) gene located on
  chromosome 15q21.1

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FBN1 Gene
FBN1 is a large gene composed of 9000 nucleotides
dispersed in 65 exones
located at chromosome 15q-21.1
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Genetic Background

• Different mutations involving FBN1 gene, but
  associated with similar phenotypes have been
  demonstrated
• However, FBN1 mutations occur across a wide range
  of milder phenotypes that overlap the classic
  Marfan phenotype
• In a minority of cases of typical MFS, a mutation
  in FBN1 is not identified. In some of these cases
  an inactivating mutation in a gene encoding a
  receptor for transforming growth factor-beta
  (TGFR2) may be responsible for up to 10 of
  Marfan syndrome

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Genetic Background

• The first report of an FBN1 mutation was in 1991
• By 1998 a total of 137 FBN1 mutations has been
  characterized in patients MFS
• The majority of these occur as isolated mutations
  throughout the gene
• To date, no correlation between the specific type
  of FBN1 mutation and the clinical phenotype has
  been recognized
• Mutation analysis can identify the exact mutation
  in the fibrilin gene, and linkage analysis can
  track an abnormal fibrilin gene in a family.
  However, no molecular diagnosis is currently
  available commercially. No single gene probe or
  group of probes is available to detect most FBN1
  mutations

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Pathogenesis

• The fibrillin-1 (FBN1) gene encodes the
  glycoprotein fibrillin, a major building block of
  microfibrils
• The microfibrils constitute the structural
  components of the suspensory ligaments of the
  lens, and serve as a substrates for elastin in
  the aorta and the other connective tissues

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The Functions of Microfibrils

• They act as a scaffolding for the elastic fiber
  formation
• They are extensible, and may contribute to the
  mechanical properties of the mature elastic
  tissues by means of load redistribution between
  individual elastic fibers
• They provide structural anchorage in non-elastic
  tissues, such as ciliary zonules
• They may serve to anchor endothelial cells and
  epithelial cells to elastic fibers of the ECM via
  cell binding domains
• A role for the microfibrils in the provision of a
  flexible mechanical anchor at epithelial-mesenchym
  al basement membrane interfaces, has been
  proposed

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Pathogenesis

• Production of abnormal fibrillin-1 monomers from
  the mutated gene disrupts the multimerization of
  fibrillin-1 and prevents microfibril formation
• This pathogenetic mechanism has been termed
  dominant-negative because the mutant fibrillin-1
  disrupts microfibril formation even though normal
  fibrillin is being encoded on the other fibrillin
  gene
• This leads to fragmentation and disorganization
  of the elastic fibers in the aortic media and
  other connective tissues (inappropriately called
  cystic medial necrosis)

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Pathogenesis

• Mucin stain of the wall of the aorta demonstrates
  cystic medial necrosis, typical for Marfan's
  syndrome and causes the connective tissue
  weakness that explains the aortic dissection.
  Pink elastic fibers, instead of running in
  parallel arrays, are disrupted by pools of blue
  mucinous (mucopolysaccharide) ground substance,
  these accumulations are the so-called cysts of
  cystic medial necrosis.

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Manifestations

• Wide range of clinical severity associated with
  MFS
• Classically it has muskeloskeletal, occular, and
  cardiovascular abnormalities
• MFS patients also demonstrate significant
  involvement of lung, skin, CNS
• A severe and rapidly progressive form of MFS may
  present at birth

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Muskeloskeletal Manifestations
Pectus excavatum
Reduced upper to lower body segment ratio Arm
span/height ratiogt1.05 Arms and legs unusually
long in proportion to torso
(dolichostenomelia) Reduced extension of
elbowslt170
Pectus carinatum
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Muskeloskeletal Manifestations

Joint hypermobility
Steinberg (thumb) sign
Arachnodactyly
Highly arched palate
Walker (wrist) sign
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Muskeloskeletal Manifestations
Pes planus
Scoliosis
Kyphosis
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Ocular Manifestations
Ectopia Lentis the lens dislocation is usually
bilateral, symmetrical and upward

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Other Ocular Manifestations
Myopia due to increased axial length of the globe
Nuclear sclerotic cataract
Retinal detachment
Hypoplastic iris
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Dura
Dural Ectasia

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Pulmonary Manifestations
Apical pulmonary blebs
Spontaneous pneumothorax

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Skin Manifestations
Striae atrophicae
Incisional Hernia
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Cardiac Manifestations in Marfan SyndromeOutline

• Incidence
• Mitral valve involvement
• Aortic root involvement
• Aortic dissection
• Other cardiac manifestations

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Cardiac ManifestationIncidence

• The most common cardiovascular features are MVP
  and dilation of sinuses of Valsalva
• Associated clinical problems of mitral
  regurgitation, aortic regurgitation, and aortic
  dissection account if untreated for most of early
  mortality that results in an average age of death
  in the fourth decade of life
• Children tend to be more severely affected by
  mitral valve disease whereas aortic disease is
  progressive and more likely in adolescence and
  beyond

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Mitral Valve Involvement in MFS

• MVP is age dependent
• More common in females
• Incidence reaches 60-80 when patients are
  studied by 2D echo
• The valve leaflets have an elongated and
  redundant appearance

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Mitral Valve Involvement in MFS

• Progression in severity as judged by the
  appearance of or worsening of MR by clinical and
  echo criteria occurs in at least 25 of patients
  (a much higher rate in compared to MVP in the
  general population)
• The mitral annulus dilates and contributes to the
  regurgitation, as do stretching and occasional
  rupture of chordae
• 10 of patients with marked prolapse have
  calcification of mitral annulus

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Aortic Root Involvement in Marfan Syndrome

• The sinuses of Valsalva are often dilated at
  birth
• Dilation of the aorta is found in 50 of children
  with Marfan and will progress with time
• 60-80 of adults with Marfan have dilation of the
  aortic root, often with aortic regurgitation
• The rate of progression varies widely among
  patients in general, thus predicting long term
  risks of developing aortic regurgitation is
  fraught with uncertainty.

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Aortic Root Involvement in Marfan Syndrome

• AI often appear in adults at a diameter of 50 mm,
  but may be absent at diameter of more than 60 mm
• The aortic dilation is limited to the ascending
  aorta. Hence, TTE is sufficient for detecting and
  monitoring changes in aortic root diameter
• The rate of aortic diameter change is slow,
  measured in millimeters per year
• Patients with dilation less than 1.5 times the
  mean diameter predicted for their body size can
  be observed annually, but as the diameter
  increases, the wall tension increases, and more
  frequent evaluation is necessary

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Pascal's principle requires that the pressure is
everywhere the same inside the balloon at
equilibrium. But examination immediately reveals
that there are great differences in wall tension
on different parts of the balloon. The variation
is described by Laplace's Law.
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Aortic Dissection in Marfan Syndrome

• Marfan is the cause of 50 of aortic dissections
  occurring before the age of 40, compared to only
  2 of older patients
• The risk of dissection increase with the size of
  the aorta.
• Many patients with Marfan and aortic dissection
  have a family history of dissection
• Fortunately occurs infrequently below a diameter
  of 55 mm in adults
• Hence, many physicians have adopted the criteria
  of 50 to 55 mm maximal aortic root dimension for
  performing elective surgery in Marfan regardless
  of the severity of AI.
• Marfan patients with family history of aortic
  dissection should have the surgery with the
  Aortic root max diameter of 50 mm

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Aortic Dissection in Marfan Syndrome

• Usually begins just above the coronary ostia, and
  extends the entire length of the aorta
• About 10 of dissections begin distal to the left
  subclavian artery
• Rarely, the dissection is limited to the
  abdominal aorta
• Not all acute dissections in patients with Marfan
  involve severe tearing chest pain radiating to
  the back, as some extensive dissections have been
  occult, reinforcing the need for a high level of
  suspicion by physicians

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Other Cardiac Manifestations

• Arrhythmias
• Ventricular
• Supraventricular often associated
  with chronic MR
• LV dysfunction
• occasional patients with Marfan syndrome who
  have no clinically important valvular
  abnormalities develop moderate-severe LV
  dysfunction
• -Could represent the unlikely coincidence of
  Marfan
• syndrome and IDCM
• -there has been evidence that certain
  fibrillin mutations
• could have detrimental effect on the
  myocardial
• function
• Further studies are needed

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DiagnosisThe Berlin Criteria

• Was implemented in 1988
• MFS diagnosis was based on involvement of
  skeletal system and two other systems
• and at least 1 major manifestation
• Ectopia lentis
• Aortic dilation or dissection
• Dural ectasia
• Because some of the symptoms and signs of Marfan
  (such as joint hypermobility) are much more often
  seen in patients without the disease, this has
  led to a recognized tendency to overdiagnose
  Marfan syndrome in index cases or family members
  
• Furthermore, no Family history or molecular data
  were incorporated in the diagnosis

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DiagnosisGhent criteria

• Was implemented in 1996, and have incorporated
  molecular data and family history, to the
  clinical data
• More stringent about 19 of patients diagnosed
  under Berlin criteria did not meet the Ghent
  criteria
• Note that some of the criteria used to diagnosis
  Marfan syndrome arise with age. Therefore, a
  child may fail to meet the criteria at first, but
  may have manifestations that definitely meet the
  criteria at a later date. This phenomena of
  partial expression of Marfan syndrome in a child
  that one suspects will meet the full criteria at
  an older age has been termed "emerging Marfan
  syndrome".

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DiagnosisGhent criteria

• The diagnosis is made if
• - In family members presence of major
• involvement in 1 organ system as well
• as involvement in a second organ
• system
• - If the family and genetic histories are
• not contributory major criteria in 2
• different organ systems and
• involvement of a third organ system are
• required

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American Journal of Medical Genetics
62417-426, 1996
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Overlap Heritable Connective Tissue Disorder

• According to a study at Johns Hopkins, more than
  half of all patients evaluated in their clinic
  for the possible diagnosis of a heritable
  disorder of connective tissue could not be
  determined to have any specifically defined
  disorder.
• In spite of that, those patients had considerable
  clinical evidence of a systemic defect of the
  extracelular matrix (MVP, Aortic root dilatation,
  muskeloskeletal abnormalities)
• The authors described these patients as having an
  "overlap disorder".
• They suggest that there is a continuum of
  connective disorder symptoms with mitral valve
  prolapse at the mild end and Marfan syndrome at
  the more severe end.

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Prognosis

• The life span of untreated patients with the
  classic MFS was about 32 years in 1972
• Improved therapy has resulted in marked increase
  in life expectancy up to 61 years in 1996
• Cardiovascular disease, especially aortic
  dilation and dissection is the major cause of
  morbidity and mortality
• Progression from MVP to MR is the most common
  cause of infant morbidity
• Aortic dissection is uncommon in childhood and
  adolescence
• Death after infancy usually involves ascending
  aortic dissection and chronic AI
• For reasons that are not well understood, life
  expectancy is significantly lower in men than
  women
• A family history of premature death or aortic
  surgery may identify patients at increased risk
  

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Management

• Beta Blockers
• Restriction of strenuous physical activities
• Monitoring of the aortic root size
• Elective surgical repair of the aorta
• SBE prophylaxis
• Correctional ophthalmologic and orthopedic
  surgeries
• Management during pregnancy

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dp/dtmax

• It has been suggested that the shape of the pulse
  wave (rate of change in the central arterial
  pressure with respect to time designated as
  dp/dt) is the most important initiator of the
  force which acts on the aortic wall to cause
  extension and rupture of acute dissecting
  aneurysms
• To test this, a standard model of the aorta was
  constructed, using tygon tubing with rubber
  cement lining
• An intimal tear was produced and aortic model
  was subjected to nonpulsatile and pulsatile flow

Prokop EK, et al. Circ Res 197027121-127
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• The aortic models were first subjected to a
  steady flow of water at rates starting at 500
  ml/min, and increasing in increments to a max
  6000 ml/min
• Then the flow was held constant at 2500 ml/min,
  the initial pressure was 50 mm Hg. The pressure
  was then increased in increments by changing the
  resistance in the distal tube, until a final
  pressure of 250 mm Hg was reached
• Pressure waveforms were measured through catheter

Prokop EK, et al. Circ Res 197027121-127
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• The aortic models was then subjected to pulsatile
  flow. With pumping rate 70 strokes/min, with
  systole being 60 and diastole 40 of the entire
  cycle
• The rate of dissection was calculated by
  recording the time necessary to dissect the
  intimal lining from the Tygon tubing (cm/min)
• The aortic model was subjected to a step increase
  of dp/dtmax. This was accomplished by changing
  the systole-diastole time ratio of the pulsatile
  pump

Prokop EK, et al. Circ Res 197027121-127
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• The same experiment were performed on dog aorta
  models
• The descending aortas were removed from 15
  sacrificed dogs
• the aorta was subjected to nonpulsatile flow,
  with incremental increase in peak systolic
  pressure until a final pressure of 175 mm Hg was
  reached
• The aorta was then subjected to pulsatile flow at
  rate 60 strokes/min.
• Then the aortas were subjected to step increase
  in dp/dtmax
• The presence of dissection were noted every 3 min
  or until the vessel ruptured

Prokop EK, et al. Circ Res 197027121-127
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Results

• With nonpulsatile flow alone (97 experiments) no
  dissection occurred at pressures up to 400 mm Hg
• Pulsatile flow produced rapid and usually
  complete dissection with a maximum systolic
  pressure of 120 mm Hg
• The extent of dissection per pulse was related to
  dp/dtmax
• No dissection occurred until a critical value of
  dp/dtmax (790 mm Hg/sec) was reached
• Similar results were obtained with dog aortas
• The rationale for decreasing dp/dtmax as a
  worthwhile method of therapy in acute dissective
  aneurysms of the aorta is supported by this study
  

Prokop EK, et al. Circ Res 197027121-127
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Prokop EK, et al. Circ Res 197027121-127
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Beta Blockers

• Recommended in all patients with Marfan including
  children unless contraindicated
• Propranolol was the BB found to have a beneficial
  effect on slowing aortic dilation, but other BB
  may be used as well
• The dose should be adjusted to maintain the heart
  rate at 110 beats/minute after submaximal
  exercise
• In pregnancy, labetolol is the preferred BB, as
  atenolol may impair fetal growth
• If intolerance to BB, then CCB may be used

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Beta Blockers

• An NIH-funded, open-label, randomized trial of
  propranolol in 70 adolescent and adult patients
  with classic Marfans syndrome
• 32 treated
• 38 untreated (control)
• Done at the center for Medical Genetics,
  Johns Hopkins University,
• Baltimore
• The Aortic-root dimensions, and clinical end
  points were monitored
• Aortic regurgitation
• Aortic dissection
• Cardiovascular surgery
• CHF
• Death
• Average f/u
• 10.7 years in the treatment group
• 9.3 years in the control group
• The dose of propranolol was individualized the
  mean dose was 212-68 mg per day

Shores, J, et al. N Eng J Med 19943301335
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(The aortic ratio is obtained by dividing the
measured aortic diameter by the diameter
predicted from the patient height, weight,
and age)
Plt0.001
Empirical Distribution Functions of the
Rate of Change in the Aortic Ratio
The height of each curve at any point shows
the proportion of patients with values
at or below the value given
on the x axis
Changes in the Aortic Ratio in the Treatment
Group and the Control Group.
Shores, J, et al. N Eng J Med 19943301335
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Numbers of patients who reached clinical
end points and their initial aortic ratios.
Kaplan-Meier survival analysis based on the
clinical end points in the Study (death, CHF, AI,
aortic dissection, cardiovascular surgery)
Shores, J, et al. N Eng J Med 19943301335
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Monitoring of the Aortic root Size

• The recommended threshold for elective surgery
  for aortic root dilation in adults is 50 mm
• In adults yearly sonographic measurement of
  aortic root diameter is recommended if the aortic
  root size is lt45 mm. Twice yearly monitoring
  should be performed for those with diameters ?45
  mm
• In children, it has been suggested that the
  aortic root dimensions be plotted serially
  against BSA, and an operation be considered if
  the diameter begin to increase rapidly from a
  previously stable percentile even if the absolute
  measurement is less than 50 mm. Also, an increase
  of gt10 mm/year is regarded as rapid enlargement
  in children

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Elective replacement of aortic root

• In a series of 675 patients from Johns Hopkins,
  the 30 day mortality was studied for
• -elective repair
• -urgent repair
• (within 7 days of surgical consultation)
• -emergency repair (within 24 hour of surgical
  consultation)

Gott, VL, et al. N Engl J Med 19993401307
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Gott, VL, et al. N Engl J Med 19993401307
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KaplanMeier Survival Analysis of 675
Patients with Marfan's Syndrome, According to
the Urgency of the Procedure. I bars are 95
percent confidence intervals
Gott, VL, et al. N Engl J Med 19993401307
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Pregnancy

• Women with Marfan syndrome who are contemplating
  surgery should have a screening TTE to assess
  aortic root dimension
• Elective repair before conception is recommended
  if the diameter is ? 50 mm
• Pregnancy should be discouraged if the diameter
  is ? 40 mm
• If the diameter is lt40, then
• -Careful clinical and echocardiographic
  monitoring
• -BB should be given (labetolol is preferred)
  
• -Epidural anesthesia to minimize pain during
  vaginal
• delivery
• -Surgical aortic repair during pregnancy
  should be
• considered if there is progressive
  dilation of the aortic
• root during gestation. Discussion of
  possible surgical
• intervention is appropriate when the
  aortic root diameter
• is 55 mm or at an earlier time if the
  aortic root is
• dilating rapidly

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Summary

• The diagnosis of MFS is based on the presence of
  characteristic skeletal, cardiovascular, and
  ocular findings in familial and sporadic cases.
  Although it is possible to identify mutations
  involving the FBN1 and TGFBR2 genes in many MFS
  patients, these genetic tests are not necessary
  for routine clinical diagnostic purposes
• Monitoring the aortic root diameter using U/S is
  recommended as a means of identifying patients at
  risk for aortic dissection. In adults, yearly U/S
  is recommended as long as the aortic root
  diameter is lt45 mm. Twice yearly if ?45 mm
• Restriction of physical activity, and BB are
  essential treatment modalities
• Because elective aortic repair is associated with
  reduced mortality in comparison to urgent or
  emergent repair, it should be considered when the
  aortic root is ?50 mm
• Women with MFS who are contemplating pregnancy
  should have a TTE. If the aortic root diameter is
  ?40 mm then the pregnancy is strongly
  discouraged. If the diameter is lt40 then close
  monitoring is recommended

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Thank you