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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 a. b. c. d. Foetal genes can be good for you! α1 Gq coupled to foetal gene program Not downregulated in HF Negative consequences: ALLHAT / VeHeFT e. Α1 induces β myosin in some cells. Around valves, coronaries • Paul Simpson. Thomas Smith memorial lecture Decompensated HF >10,000 registry Diuretics the mainstay 8% need CPAP/BiPAP 30% readmission at 30days Survival f admissions PHT in heart failure a. b. c. d. e. f. Redfield et al Mayo clinic >2000 community echoes ‘HFpEF’ normal systolic function PCW estimated from E/E’ PA >35mmHg in 80% PA >48 40% 2-yr mortality (cf 20%) Treating PHT in HF a. Semigran Boston b. 4 trials with endothelin antagonists negative or adverse c. PDE5 inhibitors improve exercise capacity and adaptive changes in animal models RELAX trial Treating PHT in HF a. b. c. d. Michelals Edmonton Work of Srivastata 2006 Embryogenesis: fields of origin Different transcription factors and response to load e. ETRAs depress RV contractility Treating PHT in HF a. Lewis Boston b. Work of Burlaug 2010 c. 2 patterns of CP exercise testing: a. Plateau due to abnormal RVSW b. 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. b. c. d. e. Homozygous FH Cell culture: surface receptor microassay for HMG-CoA reductase how do normal cells extract the cholesterol of LDL? Second messenger? Purified LDL receptor 1982; cloned human cDNA; isolated gene1985 Brown & Goldstein: mid-90’s a. b. c. d. e. LDL receptor is regulated sterol-regulated membrane-bound transcription factors : SREBPs Unlike other transcription factors Synthesized as membrane-bound proteins attached to the ER transported to Golgi; processed by proteases; soluble fragment enters the nucleus Brown & Goldstein: latest a. b. c. How is cholesterol transferred from one organelle to another? How is the membrane cholesterol content kept constant? ‘Hydrophobic handover’ involving NiemannPick C (NPC) 1 and 2 2010 thoracic aorta guide a. b. c. d. Overall repair at 5.5 cm Familial or syndrome 4-5 cm If growth 0.5 cm / year ‘David’ reimplantation 98% survival • Svensson Cleveland Clinic Dissection treatment a. Type A 50% survival at 21 days b. Ao diameter can be misleading. Half are ‘normal’ c. Standardise imaging! JACC 2010 d. Spurious diameter in C-shape • Eagle Michigan Type B: endovascular? a. b. c. d. e. Fattori et al 2006 Endovascular devices for aneurysma Nonrandomised Circ CV Imaging 2010 Devices for type B; 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.