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Update from the AHA 2010. Jonathan Silberberg February 2011. Next week...part 2. Cardiac hypertrophy Decompensated heart failure Brown & Goldstein PHT in heart failure LDL cholesterol Thoracic aorta. Rethinking cardiac hypertrophy. Foetal genes can be good for you! - PowerPoint PPT Presentation
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Update from the AHA 2010
Jonathan SilberbergFebruary 2011
Next week...part 2
• Cardiac hypertrophy• Decompensated heart failure• Brown & Goldstein• PHT in heart failure• LDL cholesterol• Thoracic aorta
Rethinking cardiac hypertrophy
a. Foetal genes can be good for you!b. α1 Gq coupled to foetal gene programc. Not downregulated in HFd. Negative consequences: ALLHAT /
VeHeFTe. Α1 induces β myosin in some cells.
Around valves, coronaries• Paul Simpson. Thomas Smith memorial lecture
Decompensated HF
>10,000 registryDiuretics the mainstay8% need CPAP/BiPAP30% readmission at 30daysSurvival f admissions
PHT in heart failure
a. Redfield et al Mayo clinicb. >2000 community echoesc. ‘HFpEF’ normal systolic function d. PCW estimated from E/E’e. PA >35mmHg in 80%f. PA >48 40% 2-yr mortality (cf 20%)
Treating PHT in HF
a. Semigran Bostonb. 4 trials with endothelin antagonists
negative or adversec. PDE5 inhibitors improve exercise
capacity and adaptive changes in animal models
RELAX trial
Treating PHT in HF
a. Michelals Edmontonb. Work of Srivastata 2006c. Embryogenesis: fields of origind. Different transcription factors and
response to loade. ETRAs depress RV contractility
Treating PHT in HF
a. Lewis Bostonb. Work of Burlaug 2010c. 2 patterns of CP exercise testing:
a. Plateau due to abnormal RVSWb. Failure of pulmonary tree to dilate
Exercise Hemodynamics Enhance Diagnosis of Early Heart Failure With Preserved Ejection FractionBarry
A. Borlaug, MD, Rick A. Nishimura, MD, Paul Sorajja, MD, Carolyn S.P. Lam, MBBS and
Margaret M. Redfield, MD
a. exercise PCWP was used to classify patients as having HFpEF (PCWP ≥25 mm Hg) or noncardiac dyspnea
b. Exercise-induced elevation in PCWP in HFpEF was associated with blunted increases in heart rate, systemic vasodilation, and cardiac output.
• Circulation: Heart Failure.2010; 3: 588-595
Brown & Goldstein: 1977
a. Homozygous FHb. Cell culture: surface receptorc. microassay for HMG-CoA reductased. how do normal cells extract the cholesterol of
LDL? Second messenger?e. Purified LDL receptor 1982; cloned human
cDNA; isolated gene1985
Brown & Goldstein: mid-90’s
a. LDL receptor is regulatedb. sterol-regulated membrane-bound
transcription factors : SREBPsc. Unlike other transcription factorsd. Synthesized as membrane-bound proteins
attached to the ERe. transported to Golgi; processed by proteases;
soluble fragment enters the nucleus
Brown & Goldstein: latest
a. How is cholesterol transferred from one organelle to another?
b. How is the membrane cholesterol content kept constant?
c. ‘Hydrophobic handover’ involving Niemann-Pick C (NPC) 1 and 2
2010 thoracic aorta guide
a. Overall repair at 5.5 cmb. Familial or syndrome 4-5 cmc. If growth 0.5 cm / yeard. ‘David’ reimplantation 98% survival
• Svensson Cleveland Clinic
Dissection treatment
a. Type A 50% survival at 21 daysb. Ao diameter can be misleading. Half are
‘normal’c. Standardise imaging! JACC 2010d. Spurious diameter in C-shape
• Eagle Michigan
Type B: endovascular?
a. Fattori et al 2006b. Endovascular devices for aneurysmac. Nonrandomised Circ CV Imaging 2010d. Devices for type B; e. expect these for type A
• Eagle Michigan
Mr CS
• 58 year old man• Atypical chest pain working in kitchen• Raised CK, normal troponin• Abnormal exercise test, negative sestamibi• Normal coronaries• Cold feet, stopped beta blocker
Mr CS
• Grandson neonatal myopathy ?mitochondrial• CK persistently raised• Referred to Hunter Genetics, dna• 5 years later: umbilical hernia repair• ECG LVH, hypertension• neurologist: EMG, muscle biopsy, MRI• Type B aortic dissection
Familial Thoracic Aneurysm and Dissection
a. There are five genes that are known to cause FTAAD: ACTA2, responsible for 10-15% of FTAAD, MYH11 (1%), FBN1 (rare), TGFBR1 (1%), and TGFBR2 (2.5%). Mutations in any one of these genes cause a predisposition to develop TAAD to be inherited in a family.