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Dharmesh Patel, MD, FACC - Case Studies

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Cleveland HeartLab 2013 Symposium

Cleveland HeartLab 2013 Symposium

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  • Model of the cross-reactivity hypothesis, in which the periodontal bacteria induce a local
    immune response and cross-react with self-antigens expressed on the vascular epithelium. This leads to vascular inflammation and atherosclerosis (based on the hypothesis of Wick et al11).
  • Prevalence of infarct in men: 19% MWO; 21% non-MWO
    Cerebellum infarcts were most common: 21% men; 14.7% women; therefore, lots of other areas too !!!!!!!!!! However the assoc. was not significant for cortical or subcortical infarcts.
    The significant assoc. was also just for visual aura
    Risk was independent of CV risk factors; no difference in age either (women younger than 50 still at risk!)
    Men still a bit of a question mark as only a small number of men had MWO; 85 men out of the 361.
    Possible explanations for the assoc. : ASVD causes; endothel. Dysfunction; shared genetic risk factors for migraines and strokes; medications taken to treat migraines; foramen ovale; dx’ed artifacts
  • CHD – RR 2.16(1.86-2.52) after 11.7 years; stroke 1.81(1.45-2.27) after 10.4 yrs.; VTE 1.79(1.37-2.33) after 4.7 yrs.
    Over all mortality RR 1.49(1.05-2.14) after 14.5 yrs.
    3,488,160 without and 198,252 with preeclampsia; 29,495 CV events
    Preeclampsia affects 3 -5% of preganancies; BP responsible for 12% maternal mortality
    Preeclampsia involves insulin resistance; DM & PCOS increased risk of preeclampsia
  • leading a healthy lifestyle has broader implications for the prevention and management of other noncommunicable diseases including cancer, diabetes mellitus, and chronic respiratory diseases.
  • measuring 18F-flourodeoxyglucose uptake ; (using baseline positron-emission tomography). The uptake of FDG within atherosclerotic plaques within predetermined locations of the thoracic aortic wall correlates with macrophage concentration in animals and humans and derives from the well-described phenomena of enhanced glycolysis in activated macrophages, especially macrophages activated by the classical/innate pathways.
  • measuring 18F-flourodeoxyglucose uptake ; (using baseline positron-emission tomography)
    within predetermined locations of the thoracic aortic wall
  • measuring 18F-flourodeoxyglucose uptake ; (using baseline positron-emission tomography). The uptake of FDG within atherosclerotic plaques within predetermined locations of the thoracic aortic wall correlates with macrophage concentration in animals and humans and derives from the well-described phenomena of enhanced glycolysis in activated macrophages, especially macrophages activated by the classical/innate pathways.
  • Baseline positron-emission tomography (PET) and sequential computed tomography (CT) images of incident calcium deposition. A, Axial and coronal PET/CT images demonstrate high focal 18F-flourodeoxyglucose (FDG) uptake within the wall of the aorta (yellow arrow). B and C, Baseline and subsequent CT images coregistered to the same locations depicted in the PET/CT images. Although in the baseline CT images (B) no calcium is seen in the location corresponding to the high FDG uptake (dashed white arrow), on the follow-up CT images (C) newly deposited arterial calcium is seen at that same location (solid white arrow).
  • consecutive patients with acute myocardial infarction (MI) treated with primary percutaneous coronary intervention (PCI) and successful thrombus aspirations; Aspiration of thrombi from the culprit artery
    total bacterial DNA, candidate bacterial DNA for endodontic bacteria (Streptococcus sp. mainly Str. mitisgroup, Str. mitis, Str. oralis, Str. sanguinis & Str. gordonii, Streptococcus anginosus -group, Staphylococcus aureus, Staphylococcus epidermidis, Parvimonas micra and Prevotella intermedia) and periodontal bacteria (Porphyromonas gingivalis, Aggregatibacter (néé
    Actinobacillus) actinomycetemcomitans, Fusobacterium nucleatum, Dialister pneumosintes, and Treponema denticola) as well as Chlamydia pneumoniae were determined in thrombus
    All patients received aspirin and clopidogrel or prasugrel prior to the intervention. Bivalirudin was used in 55.4 % and glycoprotein IIb/IIIa inhibitors in 18.8%.
    None of the samples contained DNA from Chlamydia pneumonia
    Viridans streptococcus is a pseudotaxonomic non-Linnean term for a group of human commensals, most commonly found in the oral cavity. Traditionally, six groups have been classified as viridans streptococci: the Str. mitis group, Str. sanguinis group, Str. Mutans group, Str. salivarius group, Str. anginosus group, and Str. bovis group; 98% of oral streptococci belonged to two viridans streptococci groups: Str. mitis and Str. salivarius
  • Panoramic x-rays were assessed by a board certified dentist without knowledge of the clinical patient data. For every x-ray picture, 9 parameters of dental findings were scored.
    The panoramic tomographies of the 30 MI patients showed that the most common dental findings were signs of dental treatment; fillings (one or more) in 86.7 %, and previous root canal treatments in 66.7 %; further pathological findings; furcating lesions in 63.3 %, vertical bone defects in 50.0 %, and periapical abscesses in 46.6 %; Of the periapical abscesses 33.3% coincided with previous root canal treatment.
    There was also a link between periodontal bacteria and periapical abscess (OR 7.00, 1.14 - 43.0; p=0.046, Fisher’s exact test) but this did not remain
    Significant after adjustment (p=0.115, logistic regression).
  • Not only bacterial DNA but also whole bacteria cells – even living pathogens - have been detected in atherosclerotic samples42-45. In our randomly selected thrombus samples, three out of nine cases were found to contain whole (dividing and / or non-dividing) bacteria whereas various
    bacteria components and DNA were found in all nine cases studied
    To evaluate the pathological significance of our bacterial findings, monocyte/macrophage markers for bacteria recognition (CD14) and inflammation (CD68) were immunohistochemically stained in available thrombus aspirates; The presence of bacterial DNA was detected in all those thrombi.
    Randomly selected frozen thrombus aspirates (n=9) for EM
    CD14 functions as a comolecule for toll-like receptors which detect conserved microbial patterns and endogenous ligands and play a key role in initiating inflammatory responses; Porphyromonas gingivalis and oral streptococci induce proinflammatory cytokine release and accumulation of macrophages through activation of CD14 / TLR2 complex
    CD68 correlates with the extent of inflammation in atherosclerotic lesion
    These findings suggest that these pathogens disseminate into systemic
    circulation, migrate to coronary plaques and cause and / or maintain inflammation
  • Transcript

    • 1. Case Study Speakers Carlos Jorge, MD Dharmesh Patel, MD, Atul Sachdev, MD Amy Doneen, RN, FACC BSN, MSN, ARNP
    • 2. NBC’s Tim Russert dies at 58 • Russert was recording voiceovers when he collapsed. • Previously diagnosed with asymptomatic coronary artery disease. Dr. Michael Newman (Russert’s physician) said his disease was “well-controlled with medication and exercise, and he had performed well on a stress test.”
    • 3. When asked if he thought he could have done more, Dr. Newman replied… “You know, as physicians, we always hope that we can change people's lives, that we can make them feel better, live longer, that we can intervene, and that's what our role is. Unfortunately, in many instances, our hopes are not fulfilled. Absolutely, I wish Tim was alive and with us today. ... And ... patients die of heart disease or cancer; we all struggle with the fact there are limits to what we can do.” Dr. Newman on The Larry King Show
    • 4. Carlos Jorge, MD Ballantyne Medical Associates Medical School Universidad Nacional Pedro Henriquez Urena School of Medicine (UNPHU), Santo Domingo, Dominican Republic , Doctorate of Medicine, 1999 Board Certifications Family Practice Clinical Lipidology Memberships National Lipid Association American Medical Association North Carolina Academy of Family Physicians North Carolina Medical Society
    • 5. Patient Compliance • What percentage patients are not compliant in taking their medications? a) 35% b) 40% c) 75% d) 55% Source: PhRMA 2011
    • 6. Patient Compliance • What percentage patients are not compliant in taking their medications? a) 35% b) 40% c) 75% d) 55% 75% Source: PhRMA 2011
    • 7. “Drugs don’t work in patients who don’t take them.” - - C. Everett Koop, MD
    • 8. America’s other drug problem Each year $290 billion is spent on avoidable medical costs due to medication non-adherence Hospitalizations (33-69%) Preventable adverse drug events (21%) Deaths (125,000/year) Gurwitz J et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA. 2003; 280 (9): 1107-1116. McCarthy R. The price you pay for the drug not taken. Bus Health. 1998; 16(10): 27-33. Adapted from a presentation by Crowe, M. “I never miss a dose”: Medication adherence for the practice of pharmacy. 2012
    • 9. Key Learning Points  LDL/Apo B are important but may not tell the whole story  MPO elevations – over other biomarkers – elucidate further risk and allow for adjustment of evaluation and compliance
    • 10. Initial Presentation A 55 y/o Hispanic female initially presented to my office in October of 2011 for a wellness visit Medical History • Non-smoker and non-drinker • History of hyperlipidemia, hypothyroidism, HTN, and pituitary adenoma (2008) • Mother – Breast cancer and CAD (deceased) • Father – Type II Diabetes (living)
    • 11. Current Medications Biometrics Taking inconsistently • Simvastatin 20 mg Height 5’0 Taking consistently • Aspirin 81 mg/daily • Toprol XL 50 mg • Lisinopril/HCTZ 20/12.5 mg • Synthroid 50 mcg • Vitamin D3 1000 IU BMI 36.3 HR 68 BP 122/70 Weight 186
    • 12. Initial Results--10/21/2011 Lipids Inflammation Metabolic TC 171 HbA1c LDL-C 89 HDL-C 40 Fasting 99 Glucose TG 212 VLDL-C 42 ApoB 84 Lp(a) 19 6.0 hsCRP 4.5 Lp-PLA2 <100
    • 13. Treatment Options  Counseled on diet/metabolic syndrome, exercise, weight loss and to continue taking all her medications.  Instructed to return to the office for a CIMT and 2hr. GTT
    • 14. Follow-Up Results • She did not schedule or follow-up for her 2hr. GTT • She returned for her CIMT 3 months later (1/10/2012) CIMT Vascular age – no discernible plaque Max IMT (Right CCA) 61 0.9
    • 15. Follow-Up Results • Unfortunately, patient did not return to the office until 10 months later--11/26/12 – She mentioned she had been trying to improve her diet and started walking – She stopped taking her Simvastatin 3 months prior to the visit b/c she ‘felt her diet had improved so much’ Ok – Well let’s find out if how she’s doing with ‘her regimen’…
    • 16. Follow-Up Results--11/26/2012 Biometrics Initial Results Follow-Up Results Height 5’0 -- Weight 186 189 BMI 36.3 36.9 HR 68 74 BP 122/70 116/82 • No significant change in her biometrics
    • 17. Follow-Up Results--11/26/2012 Lipids Initial Results Follow-Up Results TC 171 232 LDL-C 89 160 HDL-C 40 48 TG 212 120 VLDL-C 42 ApoB 84 Lp(a) 132 19 • Marked improvement in TGs and HDL-C, but worsening of TC, LDL-C, and Apo B
    • 18. Follow-Up Results--11/26/2012 Metabolic Initial Results Follow-Up Results HbA1c 6.0 5.9 Fasting Glucose 99 101 Inflammation Initial Results Follow-Up Results hsCRP 4.5 -- Lp-PLA2 <100 144 MPO 285 • Worsening of fasting glucose, HbA1C stable
    • 19. Treatment Options  We reviewed metabolic syndrome/lipid concerns and counseled her on TLC  Re-instituted her Simvastatin (20 mg/daily) along with her other meds  Re-scheduled her for a 2hr GTT What do you think happened?
    • 20. Follow-Up Results--7/02/2013 • She once again doesn’t schedule an appointment or follow-up for her 2hr. GTT • She returned 8 months later – States the medicines were not helping her and she could work on her diet, exercise and weight loss – Stopped taking Simvastatin 3-4 months prior – Only came back in to get her thyroid checked – And…she was having sternal chest pain with twisting and movement
    • 21. Follow-Up Results--7/02/2013 • No diaphoresis, no dyspnea, no SOB, no n/v, no jaw or arm pain, no dizziness, no increased thirst, no HA, no weakness, no polydipsia or polyphagia • Reproducible chest wall tenderness over the L- sternal border • ECG NSR no ST-T segment changes
    • 22. Follow-Up Results--7/02/2013 Biometrics Initial Results Follow-Up Results Height 5’0 -- -- Weight 186 189 192 BMI 36.3 36.9 37.5 HR 68 74 80 BP 122/70 116/82 122/78 • Weight is not improving - - Her ability to control her diet is not working
    • 23. Follow-Up Results--7/02/2013 Lipids Initial Results 11/26/12 7/02/13 TC 171 232 208 LDL-C 89 160 140 HDL-C 40 48 42 TG 212 120 131 VLDL-C 42 -- ApoB 84 132 Lp(a) 19 -- 120 • TC, LDL-C, and Apo B all improved OFF simvastatin- Maybe her diet has helped?!
    • 24. Follow-Up Results--7/02/2013 Inflammation Initial Results 11/26/12 hsCRP 4.5 -- Lp-PLA2 <100 7/02/13 144 MPO 285 1913 • Gene expression test for CAD done--score 3; likelihood of CAD 10% • Sent her immediately to cardiology colleague where she underwent a Lexiscan Nuclear Stress Test – No evidence of myocardial ischemia – Normal regional wall motion (EF 79%)
    • 25. Treatment Options  Re-instituted her Simvastatin (20 mg/daily) - again - - and stressed the importance of taking her aspirin  Medical management in coordination with cardiology What are the next steps?
    • 26. Follow-Up Results--7/11/2013 • Called her for follow-up approximately 1 week later – Feels good – No CP, SOB, diaphoresis, N/V or other sx’s • Of course, I reminded her about her 2 hr. GTT and she finally schedules it for 1 month later!
    • 27. Follow-Up Results--7/11/2013 Inflammation Initial Results 11/26/12 hsCRP 4.5 <100 7/11/13 -- Lp-PLA2 7/02/13 144 MPO 285 1913 • Rechecked her MPO and it’s still elevated • She returned 1 month later for the 2hr GTT 1553
    • 28. Follow-Up Results--8/27/13 Metabolic Initial Results Follow-Up Results HbA1c 6.0 5.9 Fasting Glucose 99 101 2 hr. GTT 133/183/159 • Abnormal 2hr. GGT warrants diagnoses of insulin resistance and diabetes
    • 29. Follow-Up Results--8/27/13 Inflammation Initial Results Follow-Up Results hsCRP 4.5 -- Lp-PLA2 <100 144 MPO 285 1913 1553 • Again, rechecked her MPO and it’s still elevated 846
    • 30. Treatment Options  We again stressed and reviewed all her risk factors, diet, exercise, weight and importance of ALL medications being taken  Started on Metformin 1000mg  Sent back to cardiology for further evaluation of CAD How did we do?
    • 31. Follow-Up Results • She of course did not go to the cardiology follow-up. • She has a follow up scheduled with me on 10/29/13
    • 32. Conclusions  Patient compliance with medications or for office visits is difficult to control  Biomarker elevations - especially in light of “improving” Apo B and LDL should guide further investigation and “encourage” patients to comply  Admittedly given her MPO elevations she still is at high risk--ideally would have loved to get a CT angio or cath--cost prohibitive??
    • 33. Key Learning Points  Aggressively exploring and managing her insulin resistance/diabetes needed to decrease inflammatory pathway  High risk for CV event in spite of “normal” gene expression test for CAD—possible because of her insulin resistance?
    • 34. Dharmesh Patel, MD, MBBS, FACC Chief Medical Officer | HASPA Stern Cardiovascular Foundation Medical School Guy’s & Kings College Hospital Medical School (London), Medicine MBBS 1996 Board Certifications Diplomate, American Board of Clinical Lipidology Certification, Specialist Clinical Hypertension Adult Cardiac Echocardiography Nuclear Cardiology Cardiac CT Angiography Cardiovascular Medicine Internal Medicine Memberships American College of Cardiology American Heart Association (Speaker for Women and Heart Disease) National Lipid Association American Society of Hypertension
    • 35. Initial Presentation A 75 y/o male referred due to an abnormal lipid profile Medical History • • • • Former smoker (quit ~50 years ago) History of HTN, hyperlipidemia, diabetes Normal carotid ultrasound (12/2012) Echocardiogram (12/2012) – EF ~60%, type 1 relaxation abnormality pattern, aortic valve sclerosis, mild aortic insufficiency • Family history of CAD (Mother, 70s)
    • 36. Current Medications Biometrics • • • • • • • Height 6’1” Livalo 2mg qhs Niaspan 1000 mg qhs Amlodipine Besylate 5 mg qd Benazepril 10mg qd Aspirin 325 mg Vitamin D Fish Oil 1200 mg Weight 288 BMI 38 HR 86 BP 142/66
    • 37. Initial Results Lipids Inflammation Initial Results Initial Results TC 128 hsCRP 47.5 LDL-C 60 MPO 856* HDL-C 50 TG 84 Lp(a) 42 ApoB 53 *Up from 350
    • 38. The plot thickens ……… • History of Malignant Melanoma • Surgical Removal 10 years ago
    • 39. Treatment Options • Do nothing? • CIMT score • PET/Chest CT scan • Stress Thallium • Cardiac catheterization
    • 40. CIMT score CIMT in association with a calcified plaque in a 75 year old male with CAD. The presence of plaque increases the diagnostic significance of CIMT. Arterial age 82 years old.
    • 41. Stress thallium
    • 42. Stress thallium Stress • • • • • Thallium 6 minutes Bruce protocol 6.9 Mets achieved No chest pain 2mm horizontal STD in the inferior leads Thallium images show no reversible ischemia but moderate sized fixed defect in the inferior wall
    • 43. Catheterization – Frame 3
    • 44. Catheterization – Frame 6
    • 45. Catheterization – Frame 9
    • 46. Catheterization – Frame 10
    • 47. Cardiac Catheterization Results • EF 60% • EDP 10mmHg • 30% stenosis proximal L anterior descending artery, 80% first diagonal artery • R coronary artery completely occluded with left-to-right collateral flow
    • 48. Complete Blood Count 15.9 7.8 212 43.8 Lymph 23.4% Mono 8.5% Eos 1.8% Baso 0.7%
    • 49. CT Chest and Abdomen
    • 50. Treatment Options • Hyperlipidemia status acceptable and inflammation biomarkers extremely elevated – F/U with dentist – CT of chest with contrast to rule out recurrence of malignancy – PSA and CBC with diff. to rule out malignancy • Obtain exercise thallium study to rule out cardiac ischemia – At risk of events/recurrence of events • Obtain 2hr. OGTT to rule out insulin resistance
    • 51. Treatment Plan • Patient has documented CAD and complete occlusion of right coronary artery – Will prescribe beta blockers for cardiac prevention • Hyperlipidemia under NCEP III guidelines – Recommend optimal LDL of <70 mg/dL • ASA 81mg-162mg ( already on it ) • ACE Inhibitors/ ARB ( already on it) • Diet and exercise
    • 52. Key Learning Points  Additive information gained above and beyond standard lipid guidelines  Increased hsCRP and MPO increases risk of cardiovascular event  Rule out insulin resistance/diabetes  Evaluate for dental disease  Caution regarding history of malignancy
    • 53. Atul Sachdev, MD Primary Care Physician Medical School University of Texas Health Science Center, Doctorate of Medicine, 1995 Board Certifications Family Practice Memberships Association of American Physicians and Surgeons American Academy of Family Practice American Medical Association Texas Medical Association
    • 54. Initial Presentation A 62 y/o Asian male presented to my office for an Annual Wellness Exam Medical History • • • • History of hypercholesterolemia and diabetes Carotid disease confirmed by CIMT Family history of HTN, stroke and diabetes Never-smoker
    • 55. Current Medications • • • • • Simvastatin 20 mg QD; 2 years Ramipril 5 mg QD; 10 years Lovaza 2g BID; 1 year Actos 30 mg QD; 5 years Declined ASA previously Biometrics Height 5’5” Weight 130 BMI 21.6 BP 106/70 Waist 35.5
    • 56. Initial Results Lipids Inflammation Metabolic F2-IsoPs 0.29 TC 196 HbA1c LDL-C 108 HDL-C 65 Fasting 114 Glucose Non-HDL-C 131 Lp-PLA2 146 TG 140 MPO ApoB 85 ApoA1 176 Lp(a) 7.0 HDL2b 15 7.1 MACR 23.0 hsCRP 0.9 259 • Some lipid abnormalities • Suboptimal control of diabetes • Endothelial dysfunction as evidenced by an abnormal MACR
    • 57. Treatment Options  Counseled patient on lifestyle adjustments including diet and exercise  Recommended ASA, but he declined
    • 58. Follow-Up Results Biometrics Initial Results Follow-Up Results Height 5’5” 5’5” Weight 130 126 BMI 21.6 21.0 BP 106/70 106/70 Waist 35.5 35 • Some weight loss, but no other significant changes
    • 59. Follow-Up Results Lipids Initial Results Follow-Up Results TC 196 193 LDL-C 108 122 HDL-C 65 51 Non-HDL-C 131 142 TG 140 87 ApoB 85 92 ApoA1 176 150 Lp(a) 7.0 11.0 HDL2b 15 11
    • 60. Follow-Up Results Metabolic Initial Results Follow-Up Results HbA1c 7.1 6.6 • Improvement in glycemic status – patient appeared to be motivated by truly watching his diet as recommended.
    • 61. Follow-Up Results Inflammation Initial Results Follow-Up Results F2-IsoPs 0.29 0.18 MACR 23.0 11.2 hsCRP 0.9 1.1 Lp-PLA2 146 135 MPO 259 495
    • 62. Treatment Options  Recommended ASA again, and he agreed to consider  A paradoxical increase in MPO levels – Sample handling – Vasculitis – Bone marrow dyscrasias – RA/SLE – Periodontal disease
    • 63. PD should be assessed and treated in programs designed to maintain CV wellness Level A evidence that Periodontal Disease is associated with arterial disease Available evidence shows a trend toward reducing CV risk with the therapy of PD Peter B. Lockhart, et. al. Circulation published online April 18, 2012 DOI: 10.1161/CIR.0b013e31825719f3 Copyright Bale/Doneen Paradigm
    • 64. Periodontal Disease Calculus & plaque accumulation Space between teeth due to loss of bone support & gum recession Red swollen gums Root exposure due to plaque & receding gums Humphrey LL et al. Periodontal disease and coronary heart disease incidence: A systematic review and meta-analysis. J Gen Intern Med. 2008; 23 (12): 2079-2086.
    • 65. Periodontal Disease • What percentage of the American population is affected by periodontal disease? a) 15% b) 25% c) 30% d) 50% Eke PI et al. Prevalence of Periodontitis in Adults in the United States: 2009 and 2010. J Dent Res. 2012; 91: 907-908
    • 66. Periodontal Disease • What percentage of the American population is affected by periodontal disease? a) 15% b) 25% c) 30% d) 50% 50% Eke PI et al. Prevalence of Periodontitis in Adults in the United States: 2009 and 2010. J Dent Res. 2012; 91: 907-908
    • 67. Eke PI et al. Prevalence of Periodontitis in Adults in the United States: 2009 and 2010. J Dent Res. 2012; 91: 907-908
    • 68. The Cross-Reactivity Hypothesis Periodontal Bacteria Local Immune Response Cross-Reactivity with Vascular Endothelium Vascular Inflammation Adapted from Seymour GJ et al. Infection or inflammation: The link between periodontal disease and systemic disease. Inside Dentistry. Volume 2 (Special Issue 1). Wick G, Perschinka H, Xu Q. Autoimmunity and atherosclerosis. Am Heart J. 1999; 138:S444-S449. Atherosclerosis
    • 69. Treatment Options  Patient was referred to a dental specialist who performed testing and confirmed the presence of periodontal disease  Patient was treated with Clindamycin (Cleocin) and given hygiene instructions by dentist.  Patient asked to return in 3 months, but took extended trip to India and didn’t return until 7 months later.
    • 70. Follow-Up Results Inflammation Initial Results Follow-Up Results F2-IsoPs 0.29 0.18 0.43 MACR 23.0 11.2 54.2 hsCRP 0.9 1.1 0.9 Lp-PLA2 146 135 152 MPO 259 495 226 • Treatment of periodontal disease reduced MPO levels and subsequent vascular risk
    • 71. Follow-Up Results Lipids/Metabolic Initial Results Follow-Up Results TC 196 193 200 LDL-C 108 122 114 HDL-C 65 51 71 Non-HDL-C 131 142 129 TG 140 87 62 ApoB 85 92 79 ApoA1 176 150 195 Lp(a) 7.0 11.0 9.0 HDL2b 15 11 12 HbA1c 7.1 6.6 7.6
    • 72. Treatment Options • States he WILL start ASA QD (we’ll see). • Increase Ramipril to 10mg (HOPE trial)? • Switch to Rosuvastatin (JUPITER trial)? • LDL goal <70 • Stay on top of dental hygiene. • Recheck CIMT, ABI, AAA screen, etc. • Continue monitoring vascular inflammation!
    • 73. Key Learning Points  Vascular inflammation testing can help identify unexplained inflammation  Periodontal disease is a documented cause of vascular inflammation  Appropriate periodontal measures can lead to CV risk reduction
    • 74. Amy Doneen, RN, BSN, MSN, ARNP Medical Director, Heart Attack and Stroke Prevention Center, Spokane, WA Graduate School/NP/ARNP Bachelors of Science, Masters of Nursing Practice & Advanced Registered Nurse Practitioner Family Practice (Suma Cum Laude) Gonzaga University, Spokane, WA, 2002 Doctorate of Nursing Practice, Gonzaga University, Spokane, WA, Current Memberships National Lipid Association American Heart Association American Stroke Association American Diabetic Association American Medical Association Preventative Cardiology Nursing Association
    • 75. “Pneumonia? Really?” Juli Copyright Bale/Doneen Paradigm
    • 76. “I went to the emergency room and I was surprised to find out that I had pneumonia with no fever, no cough, no respiratory symptoms” October 6, 2011 October 7, 2011 October 13, 2011 Shortness of breath w/ fatigue Shortness of breath & fatigue worse, anxiety Went in again – FINALLY Echo, EKG, CXR, Abd CT Diagnosed with MI 10/7 and 10/13 GP: Pneumonia, no CXR, no blood work, no EKG Copyright Bale/Doneen Paradigm ER: Given different antibiotic – sent home with cough med, “but I wasn’t coughing” CT Angiogram : Angioplasty, medical management
    • 77. Symptoms: Women are unique Prior to a heart attack At time of a heart attack •Unusual fatigue •Sleep disturbance •Unexplained anxiety •Shortness of breath •Abdominal pain •Sweating Copyright Bale/Doneen Paradigm
    • 78. Initial Presentation A 37 y/o Caucasian female and mother of a 3 y/o daughter Initially presented to the Heart Attack and Stroke Prevention Center on 11/25/2011 - nearly a month after experiencing multiple heart attacks.
    • 79. Current Medications • Metoprolol 25 mg BID • Simvastatin 40 mg daily • Aspirin 81 mg daily • CoQ10 100 mg • Omega-3 2 gm daily Biometrics Height 5’6” Weight 153 BMI 24.7 Waist 37 Why does Juli have heart disease?
    • 80. There is a better way! Bale/Doneen Method: EDFROG • • • • • • E – Education D – Disease F – ‘Fire’ Arterial Inflammation R – Root Causes O – Optimal Goals G – Genetics
    • 81. “How come I was fine one day and not the next day?” Lumen Thrombus Plaque
    • 82. Juli and Red Flags Migraine PCOS Pre-eclampsia
    • 83. Middle-age females who have migraine with Aura (MWO) are at increased risk for late-life brain infarcts • 4689 subjects; 57% female; mean age 51 when surveyed for HA; approx. 26 yrs. later MRIs of brain MWO > 1/mo. in 361 subjects • Prevalence of infarct in women: 23% MWO; 14.5% non-MWO • OR for women to have late life brain infarct if they have midlife MWO: 1.9 (95% CI 1.4-2.6) • Mid-life MWO women reported more CAD or TIA/Strokes than non-MWO women Scher, A. I., JAMA. June 24th, 2009, Vol. 301, No. 24:2563-2570.
    • 84. Women with polycystic ovaries are at higher CV risk • Women with the hallmark symptoms of polycystic ovary syndrome (PCOS) hirsutism and oligomenorrhea may also be at higher risk of cardiovascular disease • Women with PCOS may be at risk for early-onset cardiovascular disease. Based on these findings, women who suffer from PCOS should be closely monitored for CVD risk factors.” Taponen S et al. J Clin Endocrinol Metab 2004 May; 89:2114-2118. Boulman N et al. J Clin Endocrinol Metab 2004 May; 89:2160-2165.
    • 85. PCOS may place women at higher CV risk • Women with PCOS may be at increased risk for CAD and stroke • Polycystic ovary syndrome is probably the most common hormone disorder in human beings. One of my concerns is that many women will be frightened to hear that they have abnormal arteries. • PCOS appears to be an important risk factor for cardiovascular disease in women. 2002; 106:DOI:10.116101.CIR.0000020681.19400.8A
    • 86. Pre-eclampsia an indicator of increased CV risk • Meta-analysis: 200,000 pre-eclampsia versus 3.3 million without • Pre-eclamptics had doubling of risk of CHD & stroke in 10 to 12 years and venous thromboembolism in 4 to 5 years • Pre-eclamptics need CV risk assessment 3 to 6 mos. after delivery BMJ, doi:10.1136/bmj.39335.385301.BE 11/1/2007
    • 87. Vit D I.R Genetics Oral Health Lipids Psycho social Lipo(a)
    • 88. Initial Results What caused Juli’s disease? Metabolic Lipids Lp(a) 34 Met Synd 0/5 TC/HDL 2.6 TG/HDL 0.8 FBS 94 HbA1c 4.8 Insulin 5 OGTT 1 hr. 130 2 hr. 97 Inflammation MPO 344
    • 89. Initial Results (cont’d) Misc. tests Vitamin D, 25 OH 16 KIF6 Negative ApoE 3/4 9p21 Positive Anxiety: Yes; with hx eating disorder Sleep, dental, nicotine: No
    • 90. Initial Results (cont’d) Inflammation Oxidation F2-Isoprostanes 0.2 Endothelial hsCRP 1.3 Microalb/creat 11.0 Intima Lp-PLA2 204 MPO 344
    • 91. MACR cut points for marking increased CV risk Risk when MACR >7.5 in women and >4.0 in men End point Hazard ratio CV event 2.92 p <0.001 Fram. Offspring healthy pts. ; mean age 55; 58% women Followed 6 yrs. Ärnlöv J et al. Circulation 8/16/2005; 112:969-975.
    • 92. Fire makes the cat jump! hsCRP >1.0 MACR >7.5 Lp-PLA2 >180
    • 93. Cardiovascular disease and recidivism 50% of annual major coronary events are recidivistic 50% of these recurrent events are fatal Briffa, T. G., & Tonkin, A. (2013). Put Disease Prevention First. Circulation, 128(6), 573-575.
    • 94. Copyright Bale/Doneen Paradigm
    • 95. How can we follow Juli’s disease?
    • 96. Initial cIMT Report: Carotid Intima-Media Thickness Testing Mean CCA IMT 0.508 mm = age match Plaque Right internal 1.26 mm (soft/het) Left internal 1.05 mm (het)
    • 97. Echolucent (Soft) carotid plaque predicts coronary event risk • • • • • 215 stable CAD patients; followed monthly X 30 months or until an event 112 had echolucent (soft) plaques 29 coronary events 103 without soft plaques 4 coronary events Presence of soft carotid plaques associated with higher risk of coronary events – p<0.001 11 strokes – 10 in group with soft plaque Honda O, et.al. Journal of ACC. 2004:43(7):1177-1184.
    • 98. Arterial inflammation precedes calcification • 137 pts; age-61±13 yrs; 48.1% men; serial PET/CT scans 1–5 yrs apart; thoracic aorta focal arterial inflammation was prospectively (baseline) determined by PET/FDG • A blinded investigator evaluated calcium deposition on the baseline and follow-up computed tomographic scans along the same standardized sections of the aorta. • A vascular segment was classified as either with or without subsequent calcification. Abdelbaky, A., et. al. (2013). Focal Arterial Inflammation Precedes Subsequent Calcification in the Same Location: A Longitudinal FDG-PET/CT Study. Circulation: Cardiovascular Imaging, 6(5), 747-754.
    • 99. Arterial inflammation precedes calcification • Across all patients, subsequent Ca deposition was associated with the underlying inflammatory signal • Measured as standardized uptake value with OR of 2.94 (95%CI-1.27-6.89) 0.01– adjusted for CV risk factors. • First-in-human evidence that arterial inflammation precedes subsequent Ca deposition. Abdelbaky, A., et. al. (2013). Focal Arterial Inflammation Precedes Subsequent Calcification in the Same Location: A Longitudinal FDG-PET/CT Study. Circulation: Cardiovascular Imaging, 6(5), 747-754.
    • 100. Arterial inflammation precedes calcification Inflammation is an important driver of plaque progression. •Human studies have shown that high aortic and carotid FDG uptake is related to subsequent risk of plaque rupture and clinical events. Abdelbaky, A., et. al. (2013). Focal Arterial Inflammation Precedes Subsequent Calcification in the Same Location: A Longitudinal FDG-PET/CT Study. Circulation: Cardiovascular Imaging, 6(5), 747-754.
    • 101. Arterial inflammation precedes calcification Baseline (PET) and sequential (CT) images of incident calcium deposition. Abdelbaky, A., et. al. (2013). Focal Arterial Inflammation Precedes Subsequent Calcification in the Same Location: A Longitudinal FDG-PET/CT Study. Circulation: Cardiovascular Imaging, 6(5), 747-754.
    • 102. Juli’s missing diagnoses could have led to a recidivistic event • The mortality rate among women aged 35 to 44 has been increasing on average by 1.3% per year since 1997. Julie’s missing diagnoses 1. Insulin resistance 2. lipo(a) 3. Vitamin D deficiency 4. Apo E 4 5. KIF 6 negative 6. Anxiety 7. 9p21 positive Roger, V. L., et al. Heart disease and stroke statistics— 2011 update. Circulation 12/15/2010; DOI:10.1161/CIR.0b013e3182009701 .
    • 103. Treatment options  Disease treatment paradigm • Statin – Is her simvastatin an ok option?
    • 104. Clinical significance of KIF6 testing KIF6 carriers- may have higher life time CV risk 1. Maintain a disease treatment platform. (EDFROG) 2. Any statin is beneficial KIF6 noncarriers 1. Still can be at risk: monitor for disease 2. May want to favor statin therapy with simva or rosuva
    • 105. Treatment options  Disease treatment paradigm • Juli is of childbearing age • Currently using IUD • Would like to have another child – council  Statin: Continue with simvastatin 40mg  Aspirin 81 mg: f/u testing shows effective  ACE-I: Prevent recidivism! (concern: preg)  Omega-3: Fish daily or supplement 1 gm/d
    • 106. Treatment options  Root causes • Insulin resistance • Goal: Try to treat with lifestyle – exercise and nutrition counseling. LIFESTYLE to TREATMENT • If treatment necessary, consider metformin (preg), *Pioglitazone • Fine tune: Consider metoprolol to carvedilol for IR • Vitamin D deficiency • Goal: Supplement to levels 40-60 ng/dL • Lp(a) • Add: Niacin therapy at 1000-1500mg/day • Anxiety with history of eating disorder • Counseling for nutrition and anxiety
    • 107. What to follow to know if treatment is working? • • • • • • Risk Factor improvement - lipid, IR, Lp(a), Vit D Inflammation improvement/stability Heart Muscle – NT-ProBNP (baseline 266) Fitness – emotional, sleep, diet recall, fear Disease – monitor cIMT Safety – liver, kidney, electrolytes, etc. Honda O, et.al. Journal of ACC. 2004:43(7):1177-1184.
    • 108. Follow-Up Results Lipids Baseline Year One 2/4/2013 TC/HDL 2.6 2.2 2.1 ApoB 60 59 50 Lp(a) 34 33 21 266 194 159 Cardiac NTproBNP
    • 109. Follow-Up Results Metabolic Baseline FBS 94/4.8 OGTT Year One 89/5.2 130/97 2/4/2013 85/5.1 Due for repeat Inflammation hsCRP 1.3 0.5 37.6** MACR 11.0 10.0 10.0 Lp-PLA2 204 154 287**
    • 110. Periodontal disease associated with elevated levels of Lp-PLA2 • 421 healthy adult family members of pts hospitalized with CVD • Screened for traditional CV risk factors including hsCRP and Lp-PLA2 • Those with periodontal disease were 1.8 times more likely to have Lp-PLA2 levels >215 ng/mL • 37% of individuals with no CV risk factors except periodontal disease had elevated Lp-PLA2 Am J Cardiol 12/1/2008; 102:1509-1513
    • 111. Oral pathogens and acute heart attack • 101 acute heart attack pts; 76% male; ~63 yo • Oral viridans streptococci found in 78% of thrombi; PD pathogens found in 35% of thrombi Pessi, T., PhD, et. al. Circulation. published online February 15, 2013 http://circ.ahajournals.org/content/early/2013/02/14/CIRCULATIONAHA.112.001254
    • 112. Oral pathogens and acute heart attack • 30 pts had panoramic CT imaging • ~50% showed periapical abscess • If patients thrombus was positive for strep viridans DNA, they were 13 times more likely to have a periapical abscess OR 13.2 (95% CI 2.11 – 82.5) p=0.004 Pessi, T., PhD, et. al. Circulation. published online February 15, 2013 http://circ.ahajournals.org/content/early/2013/02/14/CIRCULATIONAHA.112.001254
    • 113. Oral pathogens and acute heart attack • Electron microscopy performed on 9 thrombi • Bacteria-like structures detected in all 9 thrombi • Whole bacteria in 3/9 (1/3) • Dental infection and oral bacteria are associated with the development of acute coronary thrombosis Pessi, T., PhD, et. al. Circulation. published online February 15, 2013 http://circ.ahajournals.org/content/early/2013/02/14/CIRCULATIONAHA.112.001254
    • 114. Treatment options/changes  Appointment 2/4/2013  Changes: • Sent to dentist – Painful tooth (root canal & Antibiotics 2/12/2013) • Change to Rosuvastatin 10mg and increase Niaspan to 1500 mg • Next appointment: 3/5/2013 to recheck inflammatory markers, liver and CK.
    • 115. Follow-Up Results Endodonic Tx – Root canal and ABO Inflammation 2/4/2013 3/5/2013 5/7/2013 8/8/2013 hsCRP 37.6 3.2 1.8 0.7 Lp-PLA2 287 236 218 202 Improvement of hsCRP and Lp-PLA2 results following root canal, increase in Niaspan and change to Rosuvastatin
    • 116. Follow-Up Results Carotid Intima-Media Thickness Testing 12/7/2011 Mean CCA IMT 0.508 mm 12/3/2012 0.530 mm Plaque Right internal 1.26 mm (soft/het) Left internal 1.05 mm (het) <0.6 mm
    • 117. Juli’s next journey: Living with heart disease • Planning to have another baby • So – the journey continues….. – Working with Perionatologist, Cardiologist, myself and her OBGYN – Juli remains on the following medications: baby aspirin, Omega 3, Niacin, Vitamin D, Metoprolol, Prenatal Vitamin – She is OFF HER STATIN and ACE-I – She is HIGH RISK – Inflammatory labs frequently • On September 17, 2013: + Pregnancy Test Honda O, et.al. Journal of ACC. 2004:43(7):1177-1184.
    • 118. Initial Presentation A 62 y/o male district superintendant referred for abnormal labs Medical History • History of HTN, obesity, hyperlipidemia • BP difficult to treat • Fatigue
    • 119. Initial Results Current Medications Biometrics • • • • Height 5’10” Valsartan-HCTZ 320/25 Amlodipine Toprol XL 25 mg ASA 81 mg Weight 267 BMI 38.3 HR 75 BP 150/75
    • 120. Initial Results Lipids Inflammation Initial Results Initial Results TC 211 OxLDL 52 LDL-C 142 MPO 457 HDL-C 35 TG 180 Lp(a) 85 ApoB 97 Other Initial Results NT-proBNP 426 TSH 3.724 Testosterone 225
    • 121. Initial Results2 Metabolic 2 hr. GTT hour OGTT 110/189/201 INSULIN RESISTANCE
    • 122. Atrial Fibrillation
    • 123. Echo showing mild LVH and mild left atrial enlargement Two-dimensional echocardiogram (parasternal long axis view) from a 62-year-old woman showing concentric left ventricular hypertrophy and left atrial enlargement.
    • 124. Tricuspid Regurgitation
    • 125. Echo Results • • • • • • Normal LV size. Ejection Fraction 60%. Mild concentric left ventricular hypertrophy Type I Relaxation Abnormality Pattern Mild left atrial dilation Mild tricuspid regurgitation Moderate pulmonary hypertension.
    • 126. Sleep Results • Severe Sleep Apnea • Severe: AHI ≥ 30 per hypopneic spells • Oxygen desaturation 82%
    • 127. Clinical Features of Sleep Apnea • • • • • • • • • • • • Daytime sleepiness Nonrestorative sleep Witnessed apneas by bed partner Awakening with choking Nocturnal restlessness Insomnia with frequent awakenings Lack of concentration Cognitive deficits Changes in mood Morning headaches Vivid, strange, or threatening dreams Gastroesophageal reflux • • • • • • • • • • • • Obesity Large neck circumference Systemic hypertension Hypercapnia Cardiovascular disease Cerebrovascular disease Cardiac dysrhythmias Narrow or "crowded" airway Pulmonary hypertension Cor pulmonale Polycythemia Floppy eyelid syndrome
    • 128. Treatment Options • • • • • • • Diet and Exercise Start metformin 500 mg po bid Add Lasix 40mg Kdur 20meq Wear CPAP mask Start statin + nicotinic acid Start coumadin vs novel anticoagulant Enquire about family History
    • 129. Key Learning Points  Resistant HTN  High NT-proBNP suggestive of OSA  OSA link with atrial fibrillation  Ox LDL increased risk of metabolic syndrome/ diabetes  Lipoprotein (a) is independent risk factor for CAD
    • 130. In Memory of Dr. Nirav Patel 1968-2012