Heart Failure

Heart Failure
By:S. Soliman MD

Definition:
* A state in which the heart cannot provide sufficient cardiac output to satisfy the metabolic needs of the body
* It is commonly termed congestive heart failure (CHF) since symptoms of increase venous pressure are often prominent
Etiology
-Inappropriate work load (volume or pressure overload)
-Restricted filling
-Myocyte loss

Causes of left ventricular failure

• Volume over load: Regurgitate valve
• Pressure overload: Systemic hypertension

Outflow obstruction
• Loss of muscles: Post MI, Chronic ischemia
Connective tissue diseases Infection, Poisons
(alcohol,cobalt,Doxorubicin)
• Restricted Filling: Pericardial diseases, Restrictive
cardiomyopathy, tachyarrhythmia

Pathophysiology
* Hemodynamic changes
* Neurohormonal changes
* Cellular changes

Hemodynamic changes
Neurohormonal changes
Cellular changes
Symptoms
Physical Signs
Framingham Criteria for Dx of Heart Failure
* Major Criteria:
o PND
o JVD
o Rales
o Cardiomegaly
o Acute Pulmonary Edema
o S3 Gallop
o Positive hepatic Jugular reflex
o ↑ venous pressure > 16 cm H2O
* Minor Criteria
LL edema,
Night cough
Dyspnea on exertion
Hepatomegaly
Pleural effusion
↓ vital capacity by 1/3 of normal
Tachycardia 120 bpm
Weight loss 4.5 kg over 5 days management

Forms of Heart Failure
* Systolic & Diastolic
* High Output Failure
o Pregnancy, anemia, thyrotoxisis, A/V fistula, Beriberi, Pagets disease
* Low Output Failure
* Acute
* Chronic
* Right vs Left sided heart failure:

Right sided heart failure :
Most common cause is left sided failure
Other causes included : Pulmonary embolisms
Other causes of pulmonary htn.
RV infarction
MS
Usually presents with: LL edema, ascites
hepatic congestion
cardiac cirrhosis (on the long
Differential diagnosis
* Pericardial diseases
* Liver diseases
* Nephrotic syndrome
* Protein losing enteropathy

Laboratory Findings
* Anemia
* Hyperthyroid
* Chronic renal insuffiency, electrolytes abnormality
* Pre-renal azotemia
* Hemochromatosis

Electrocardiogram
* Old MI or recent MI
* Arrhythmia
* Some forms of Cardiomyopathy are tachycardia related
* LBBB→may help in management

Chest X-ray
* Size and shape of heart
* Evidence of pulmonary venous congestion (dilated or upper lobe veins → perivascular edema)
* Pleural effusion

Echocardiogram
* Function of both ventricles
* Wall motion abnormality that may signify CAD
* Valvular abnormality
* Intra-cardiac shunts

Cardiac Catheterization
* When CAD or valvular is suspected
* If heart transplant is indicated

TREATMENT
* Correction of reversible causes
Diet and Activity
* Salt restriction
* Fluid restriction
* Daily weight (tailor therapy)
* Gradual exertion programs

Diuretic Therapy
* The most effective symptomatic relief
* Mild symptoms
* Side Effects
* More severe heart failure → loop diuretics
o Lasix (20 – 320 mg QD), Furosemide
o Bumex (Bumetanide 1-8mg)
o Torsemide (20-200mg)

Mechanism of action: Inhibit chloride reabsortion in ascending limb of loop of Henle results in natriuresis, kaliuresis

and metabolic alkalosis

Adverse reaction:
pre-renal azotemia
Hypokalemia
Skin rash
ototoxicity

K+ Sparing Agents
* Triamterene & amiloride – acts on distal tubules to ↓ K secretion
* Spironolactone (Aldosterone inhibitor)
recent evidence suggests that it may improve survival in CHF patients due to the effect on renin-angiotensin-aldosterone

system with subsequent effect on myocardial remodeling and fibrosis

Inhibitors of renin-angiotensin- aldosterone system

o Renin-angiotensin-aldosterone system is activation early in the course of heart failure and plays an important

role in the progression of the syndrome
o Angiotensin converting enzyme inhibitors
o Angiotensin receptors blockers
o Spironolactone

Angiotensin Converting Enzyme Inhibitors
Side effects of ACE inhibitors
* Angioedema
* Hypotension
* Renal insuffiency
* Rash
* cough
Angiotensin II receptor blockers
* Has comparable effect to ACE I
* Can be used in certain conditions when ACE I are contraindicated (angioneurotic edema, cough)
Digitalis Glycosides (Digoxin, Digitoxin)
* The role of digitalis has declined somewhat because of safety concern
* Recent studies have shown that digitals does not affect mortality in CHF patients but causes significant

Mechanism of Action
* +ve inotropic effect by ↑ intracellular Ca & enhancing actin-myosin cross bride formation (binds to the Na-K ATPase →

inhibits Na pump → ↑ intracellular Na → ↑ Na-Ca exchange
* Vagotonic effect
* Arrhythmogenic effect

Digitalis Toxicity
* Narrow therapeutic to toxic ratio
* Non cardiac manifestations
Anorexia,
Nausea, vomiting,
Headache,
Xanthopsia sotoma,
Disorientation
* Cardiac manifestations

Digitalis Toxicity Treatment
* Hold the medications
* Observation
* In case of A/V block or severe bradycardia → atropine followed by temporary PM if needed
* In life threatening arrhythmia → digoxin-specific fab antibodies
* Lidocaine and phenytoin could be used – try to avoid D/C cardioversion in non life threatening arrhythmia

β Blockers
* Has been traditionally contraindicated in pts with CHF
* Now they are the main stay in treatment on CHF & may be the only medication that shows substantial improvement in LV

function
* In addition to improved LV function multiple studies show improved survival
* The only contraindication is severe decompensated CHF

Vasodilators
Positive inotropic agents
Anticoagulation (coumadine)
* Atrial fibrillation
* H/o embolic episodes
* Left ventricular apical thrombus

Antiarrhythmics
* Most common cause of SCD in these patients is ventricular tachyarrhythmia
* Patients with h/o sustained VT or SCD → ICD implant
* Patients with non sustained ventricular tachycardia

New Methods
* Implantable ventricular assist devices
* Biventricular pacing (only in patient with LBBB & CHF)
* Artificial Heart

Cardiac Transplant
* It has become more widely used since the advances in immunosuppressive treatment
* Survival rate
Prognosis
Heart Failure

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Anaphylaxis Urticaria Angioedema

Anaphylaxis Urticaria Angioedema
By:Niraj Patel, MD, MS
Section of Allergy and Immunology
Texas Children’s Hospital & Baylor College of Medicine

Objectives
* Know the clinical presentation, diagnosis and treatment of anaphylaxis.
* Understand the pathophysiology of urticaria and angioedema
* Outline an approach for evaluation and treatment of patients with urticaria and/or angioedema

What is anaphylaxis?
* Affects > 1 organ system: skin, respiratory, cardiovascular, GI symptoms
* 100,000 episodes per year in U.S.
* 1% fatality rate: shock, larnygeal edema
* IgE vs nonIgE mechanisms

Histamine
IgE-Mediated
IgE-receptor
* Protein digestion
* Antigen processing
* Some Ag enters blood

Mast cell
APC
B cell
T cell
Non-IgE Mediated
Pathophysiology: Immune Mechanisms
Causes of Anaphylaxis
* Foods – peanuts, egg, milk, shellfish, wheat, fish, soy
* Insect stings
* Drugs – PCN, NSAIDs
* Contrast media
* Opiods

Clinical Features and Diagnosis
* Skin: Erythema, pruritis, hives, angioedema
* Respiratory: laryngeal edema, wheezing, rhinitis, itching of palate, conjunctivitis
* Cardiovascular: LOC, fainting, palpitations, sense of impending doom
* GI: N/V/D, abdominal pain
* Diagnosis

Management of Systemic Reactions
Stabilize Epinephrine, IV, airway, O2 antihistamine, steroids
Observe 3 hours (mild reaction) 6 hours (severe reaction)
Prevent Epinephrine self administration Referral to an allergist

EpiPen
* EpiPen
o Injection carried with the patient at all times.
o Self-injection to lateral thigh.
o Use EpiPen, Jr. for children < 20kgs.
Urticaria
* Urticaria = Hives
* Common condition, 15-25% at some time in their lives
* Type I hypersensitivity reaction
* Causes: foods, drugs (no identifiable cause in 50%)
Urticaria vs. Angioedema
* Urticaria – superficial dermis
o Characterized by intense pruritis due to histamine effect
* Angioedema – deeper dermal and subcutaneous layers
o May be pruritic but often is a deeper and dull discomfort – burning quality

Chronic Urticaria/Angioedema (Mast cell driven)
Acute vs. Chronic Urticaria
* Acute Urticaria – lasts 6-8 weeks or less
o Viral syndromes (especially in young children)
o Insect bites or stings (fire ants, scabies)
o Food induced reactions (eat this - get that)
o Medication related (antibiotics, NSAIDs, narcotics, angioedema due to ACE inhibitors)
* Chronic Urticaria – lasting longer than 8 weeks
o Physical urticarias (dermographism, cholinergic, cold)
o Urticarial vasculitis
o Urticaria/angioedema associated with autoimmunity
o Autoimmune urticaria
o Idiopathic urticaria

Urticaria - Mechanisms
* Immunologic
* Non-Immunologic
Underlying Mechanisms of Urticaria
Physical Urticarias
Symptomatic Dermatographism
Cholinergic Urticaria
Cold-Induced Urticaria
Delayed Pressure Urticaria
Solar and Aquagenic Urticaria
Schnitzler’s Syndrome
Hypocomplementemic Urticarial Vasculitis Syndrome (HUVS)
Therapeutic Options
* Antihistamines for most with acute short-lasting urticaria
o Start with non-sedating, long-acting second generation H1 antagonists (Allegra, Zyrtec, Claritin) and supplement

with short-acting, sedating H1 antagonists prn.
* Combination therapy if H1 antagonists do not suffice (30% of cases)
* Steroids and other immunosuppressants reserved for severe urticaria associated with angioedema of oropharnyx or other

systemic signs, moderate to severe drug reactions, urticarial vasculitis, and refractory cases of CIU
H1 Antagonists
* Previously felt to be only histamine receptor blockers
* Recent research now reveals that most of the second generation antihistamines have some mild anti-inflammatory

properties
* Although less expensive, first generation antihistamines have potential for sedation and impaired performance

Why Add an H2 Antagonist?
Immunomodulation Cyclosporine / Tacrolismus
Cyclosporine
ANGIOEDEMA

* Inhibits C1r and C1s of the complement system
* Inhibits activated factor XIIa and kallikrein
* An inhibitor of factor XIa and plasmin
* Inhibits activation of C1
C1 Inhibitor Functions
Hereditary Angioedema
* Autosomal dominant with incomplete penetrance.
o Spontaneous mutations in 50%
o Diminished C4 between attacks
o Very low C4 during attacks
* HAE I
o Low levels of C1 esterase inhibitor
* HAE II
o Dysfunctional C1 INH
* HAE III (estrogen-dependent angioedema)
o Normal C1 INH amount and function
o Normal complement levels
Acquired Angioedema (AAE)
Drug Induced Angioedema
ACE Inhibitor Angioedema
Treatment of Hereditary Angioedema
* Patient education very important; test family
* No regular medication needed in many cases
* Prophylactic stanozolol or danozol
* Epsilon aminocaproic acid (EACA) an option
* Fresh frozen plasma before emergency surgery
* C1 inhibitor
* Symptomatic treatment during attacks
* Steroids and antihistamines are NOT effective!!!
Summary
* Through several mechanisms a variety of mediators may lead to urticaria or angioedema
* Clinically, a causative agent is much more often identified in acute than in chronic urticaria/angioedema
* A number of medications are available to control chronic urticaria while awaiting a spontaneous remission
* Patients with angioedema without urticaria should be tested for C1 inhibitor deficiency

Questions
Anaphylaxis Urticaria Angioedema

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Mechanism of Bone Metastases

Mechanism of Bone Metastases
by: Dr.Priya Gopalan

Outline
* Background
* Predictors of metastasis to bone
* Tumor cell homing to bone
* Tumor cell interaction with bone
* Therapeutic interventions

Bone Metastases
Types of bone metastases
Diagnosis
* Bone scan - best for osteoblastic lesions
* MRI
* CT scan with bone windows
* PET-CT
* Plain films
* Markers of bone turnover

Prognosis
Relative risk ratios during zoledronic acid therapy
(skeletal-related events)
NSCLC and solid tumors
High vs. low NTX levels
Reasons for preferential metastasis to bone
* Highly vascular organ (sluggish blood flow)
* Paget’s “seed-and-soil” hypothesis
o Bone marrow niche provides:
+ Chemotactic signal to home (e.g. SDF-1)
+ Adhesion receptors to extravasate
+ Growth factors to proliferate (e.g. TGF-b, IGF-1)
Predictors of metastasis to bone (Breast Cancer)
Tumor cell homing
* Organs that are primary sites of breast cancer metastasis produce high levels of SDF-1
* Blocking CXCR4 in vitro inhibited prostate cancer migration through bone marrow endothelial cells
* Blocking CXCR4 in vivo reduces bone metastases in breast and prostate cancers
* CXCR4/ SDF-1 axis also important in
o NSCLC:
o RCC:
* Integrins may also direct organ-specific mets
o When avb3 is overexpressed on breast cancer cells, bone metastases are enhanced
o CXCR4 binding to SDF-1 activates avb3 and mediates its binding to endothelial cells
o avb3 antagonist inhibits bone colonization by avb3-expressing tumor cells
o a2b1 on prostate cancer cells supports bone colonization
* Other chemokines produced by OBs
o Osteopontin
o Bone sialoprotein

Normal bone remodeling
Osteoprotegerin
Osteoblasts/osteoclasts interaction with tumor cells
Osteomimicry by tumor cells
Therapeutic targets
* Osteoblastic lesions
o Endothelin-1 (anti-receptor antibody)
* Osteolytic lesions
o Bisphosphonates
o RANKL (anti-RANKL antibody)
o PTHrP
o Osteoprotegerin (Fc-OPG)
* Endothelin A receptor inhibitor, Atrasentan
o M00-211 trial - Double-blinded, randomized, multi-institutional placebo-controlled Phase III trial with 809 patients with hormone-resistant metastatic prostate cancer

+ Endpoint - TTP
+ Results
# TTP HR 0.89 (CI 0.76,1.04, p=0.136)
# Median time to bone alk phos progression 505 vs 254 days (p<0.01)

Bisphosphonates
* Long-term treatment of osteolytic metastases
* Preferentially bind areas of high bone turnover
* Aminobisphosphonates
o e.g. zoledronate, aledronate, risedronate
o Block prenylation of osteoclast proteins (small GTP-binding proteins, e.g. ras and rho), leading to apoptosis
* Non-aminobisphosphonates
o e.g. clodronate, etidronate
o Inhibit ATP-dependent enzymes, leading to apoptosis
* Also may inhibit tumor adherence to bone, inhibit angiogenesis, reduce IL-6 production

Bisphosphonates-clodronate
* Clodronate approved in Europe but not US
* Double-blind, placebo-controlled, multicenter trial with 1,069 patients with operable breast cancer randomized to clodronate or placebo
o 1° endpoint - relapse in bone
o 2° endpoints - relapse in other sites, mortality, toxicity
o Significant reduction in bone metastases during medication period (HR 0.44, CI 0.22-0.86, p=0.016), but not in total follow-up period
o Reduced mortality (98 in clodronate arm, 129 in placebo arm, p=0.047)

Bisphosphonates-pamidronate
* 754 pts with metastatic breast cancer (with osteolytic bone metastases) randomized to pamidronate or placebo
o 1° objective - skeletal events per year and time to 1st skeletal-related event (SRE)
o Only 115 of 367 (31.3%) on pamindronate arm and 100 of 384 (26.0%) on placebo arm completed the study
o Pamidronate arm - 2.4 skeletal events/yr; placebo arm - 3.7 events/yr (p<0.001); also observed longer time to 1st SRE in pamidronate arm (12.7 vs 7 months, p<0.001)
o Limited by significant number of pts who did not complete study
Bisphosphonate - zoledronate

* 1803 premenopausal women with Stage I and II breast cancer randomized to tamoxifen/anastrozole ± zoledronic acid
* 1° endpoint DFS; 2° RFS, OS; explor: bone met-free survival
* DFS (HR 0.643 [CI 0.46-0.91], p=0.011)
* RFS (HR 0.653 [CI 0.46-0.92], p=0.014)
* No change in OS
* See effects outside bone

Bisphosphonates - zoledronate (prostate cancer)
* Zometa 039 trial: 643 men with hormone-refractory metastatic prostate cancer received zoledronate 4 mg, 8mg then 4mg, or placebo for 18 months
o Zometa decreased SREs and pain, but no difference in disease progression or performance status
* Trials with pamidronate and clodronate in metastatic prostate cancer showed no significant benefits
* Randomized, placebo-controlled Phase III trial, with 773 pts with lung, RCC, etc. metastatic to bone randomized to zoledronate vs placebo q3 months for 21 months
* 1° endpoint - % patients with ≥1 SRE
* Zolendronate delayed the onset and reduced risk of skeletal-related events compared to placebo in pts with bone metastases due to lung cancer or other solid tumors.
o Reduced time to 1st SRE with treatment (236 vx 155 days, p=0.009), decreased number of events/year (1.74 vs. 2.71, p=0.012), HR developing skeletal event reduced in zoledronate arm (HR 0.693, p=0.003)

Bisphosphonates
* Osteonecrosis of the jaw

Other therapies

Mechanism of Bone Metastases.ppt

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