cardiology4 Flashcards
Major ASCVD Risk Factors
Cigarette smoking. Hypertension. Low HDL-C:
Emerging Risk Factors
Hypertriglyceridemia. Apolipoprotein B 100 (Apo B). LDL particle number. LDL particle size/density (small dense LDL). Lipoprotein (a) [Lp(a)]. Markers of Inflammation (hsCRP). Homocysteine. Prothrombotic Factors. Subclinical Atherosclerosis
4 Major Statin Benefit Groups
- Individuals with known clinical ASCVD. 2. Individuals with LDL ≥ 190 mg/dl. 3. Individuals with diabetes (>40 yo and LDL>70). 4. Individuals (>40 yo, LDL>70) without ASCVD or diabetes who have an estimated 10-year ASCVD risk ≥ 7.5%
Major Recommendations for Statin Therapy for ASCVD Prevention
In those whose 10-year risk is 5-7.5% or when the decision is unclear, other factors may be used to enhance the treatment decision making: Family History of Premature ASCVD, LDL-C > 160 mg/dl, hsCRP ≥ 2 mg/dl, Coronary Calcium Score ≥ 300 Agatston units or ≥ 75th percentile for age, sex, ethnicity, Ankle-Brachial Index
Hypertriglyceridemia
Severe hypertriglyceridemia is associated with acute pancreatitis. Moderate hypertriglyceridemia is associated with ASCVD. Biologically plausible associated risk factor. But unclear whether triglyceride lowering is beneficia. Associated with insulin resistance, metabolic syndrome, type 2 diabetes. “Risk factor” for ASCVD
HDL-C
Biologic Plausibility: HDL “removes” cholesterol from periphery and HDL has antioxidant and anti-inflammatory effects. Epidemiology: Low HDL levels are associated with increased risk for ASCVD. High HDL levels are associated with a protective effect against ASCVD. Randomized Trials: No evidence to date that HDL raising reduces ASCVD related events/death
Atherosclerosis HLD and LDL
Atherosclerosis is a slow, complex process. Elevated atherogenic lipoproteins (primarily LDL-C) are a critical component in the development of atherosclerosis and the progression to acute events. Cholesterol lowering therapy especially with statin therapy is effective in preventing acute atherosclerotic events, both acutely and chronically. What specific lipid goals should be is still not entirely clear. The “jury is still out” on whether HDL raising or TG lowering are clinically beneficial over and beyond LDL lowering
LDL particles
pose a risk for cardiovascular disease when they invade the endothelium and become oxidized, since the oxidized forms are more easily retained by the proteoglycans. A complex set of biochemical reactions regulates the oxidation of LDL particles, chiefly stimulated by presence of necrotic cell debris and free radicals in the endothelium. Increasing concentrations of LDL particles are strongly associated with increasing amounts of atherosclerosis within the walls of arteries over time, eventually resulting in sudden plaque ruptures and triggering clots within the artery opening, or a narrowing or closing of the opening, i.e. cardiovascular disease, stroke, and other vascular disease complications. LDL particles (though far different from cholesterol per se) are sometimes referred to as bad cholesterol because they can transport their content of fat molecules into artery walls, attract macrophages, and thus drive atherosclerosis. In contrast, HDL particles (though far different from cholesterol per se) are often called good cholesterol or healthy cholesterol because they can remove fat molecules from macrophages in the wall of arteries.
How Do Inflammation and Atherogenesis Overlap?
Subintimal LDL activates the endothelium. Activated leukocytes localize to sites of endothelial injury and initiate local inflammation. Intensified inflammation promotes plaque growth and eventual instability. LDL penetrates endothelium and is retained in the intima, where it undergoes oxidative modification. Proinflammatory lipids released from LDL stimulate endothelial cells to express adhesion molecules. Circulating monocytes adhere to endothelial cells expressing VCAM-1 and other adhesion molecules respond to chemokines (eg MCP-1) and migrate into the intima. Microphages begin taking up oxLDL and cholesterol accumulates in the cell, which develops into a lipid-laden foam cells and release proinflammatory mediators.
Why is Inflammation Implicated in Atherogenesis?
Evolution of host response to bacterial infection increases risk of sterile inflammation. Pathogen-associated molecular patterns (PAMPs). Danger-associated molecular patterns (DAMPs), such as Oxidized LDL and Cholesterol crystals
Monocytes
innate immune system leukocytes (2-10% of all leukocytes). Differentiate into tissue macrophages. Monocyte accumulation in atherogenesis is progressive and proportional to extent of disease. Monocyte adhesion to activated endothelium is an obligate step in atherogenesis. Inhibiting monocyte adhesion limits atherosclerosis initiation, such as VLA-4 and beta 2 integrins.
VLA-4
responsible for monocyte tight adhesion to VCAM-1. Knockout limits atherogenesis
ß2 integrins
include CD11a/CD18, CD11b/CD18, CD11c/CD18, CD11d/CD18. Knockout of all 4 CD18 integrins. Specific knockout of CD11c
Adaptive Immunity in Atherogenesis
Dendritic cell antigen presentation with subsequent T cell activation promotes clonal T cell expansion. Th1 response promotes IFN-gamma elaboration and atherosclerosis. TH17 cells may promote plaque instability and neoangiogenesis. Elaborate IL-17A, IL-22, and IL-21. Blockade of IL-17A may reduce atherosclerosis.
Inflammation and Atherogenesis: Summary
Immune response to injury initiates atherogenesis. Innate immune cell interaction with endothelium drives initial plaque formation. T cells promote further lesion expansion and plaque vulnerability.
T lymphocytes in Atherosclerosis
The major class of T lymphocytes present in atherosclerotic lesions is CD4+. In response to the local milieu of cytokines, CD4+ cells differentiate into the Th1 or Th2 lineage. Among the principal inducers of the Th1 and Th2 cells are interleukin (IL)-12 and IL-10, respectively. Activated T lymphocytes are functionally defined by the cytokines produced with interferon (IFN)-γ secreted from the Th1 cells and IL-4 from the Th2 cells. Much of the emphasis in atherosclerosis research in relation to T lymphocytes has focused on the role of Th1-type responses. The evidence for the role of Th1 cells includes the detection of IFN-γ mRNA and protein in lesions. A direct role in the disease process has been defined in atherosclerotic-susceptible mice that are deficient in either IFN-γ receptors7 or the cytokine itself. Conversely, injection of IFN-γ or the IFN-γ–releasing factors IL-12 and IL-18 enhances the extent of disease in apolipoprotein E −/− mice.
Progression of Atherosclerosis
After establishment of fatty streak, inflammatory mediators drive additional plaque expansion. Th1 mediated process in conjunction with macrophage apoptosis. Plaque growth transitions from stable plaque to unstable/ruptured plaque. Interplay of atherosclerosis and thrombosis.
What are the Major Drivers of Plaque Instability?
Macrophage apoptosis and necrosis promotes a “necrotic core”. Matrix metalloproteinases degrade the fibrous cap. Intra-plaque hemorrhage further weakens core.
Plaque Progression and Vulnerability
Progression from atherosclerotic plaque to myocardial infarction involves: Lesion expansion, Macrophage apoptosis and necrosis, Weakening of fibrotic cap, and Eventual plaque rupture
Can a Biomarker of Inflammation Predict Cardiovascular Risk?
Inflammatory underpinning of atherogenesis suggests inflammatory markers may predict residual risk. Add additional prognostic information on top of standard risk factors.
C Reactive Protein
Pentraxin acute phase reactant is produced by hepatocytes. It is possibly also expressed by macrophages and smooth muscle cells. Binds to modified membranes, apoptotic cells, and lipoproteins. Activates classical complement pathway
Mechanisms of Accelerated Atherogenesis in Autoimmune Diseases
Increased monocyte/macrophage activation, which is a potential common mechanism underlying all IMIDs. Impaired endothelial vasodilator function. This is observed in rheumatoid arthritis. Proatherogenic Lipoproteins include pro-inflammatory HDL, which increases LDL oxidation, and observed in RA, psoriasis. Plaque instability. RA associated with similar extent of CAD, but increased plaque vulnerability
HDL
and its protein and lipid constituents help to inhibit oxidation, inflammation, activation of the endothelium, coagulation, and platelet aggregation. All these properties may contribute to the ability of HDL to protect from atherosclerosis, and it is not yet known which are the most important. In the stress response, serum amyloid A, which is one of the acute-phase proteins and an apolipoprotein, is under the stimulation of cytokines (IL-1, IL-6), and cortisol produced in the adrenal cortex and carried to the damaged tissue incorporated into HDL particles. At the inflammation site, it attracts and activates leukocytes. In chronic inflammations, its deposition in the tissues manifests itself as amyloidosis.
Inflammation and HDL Function
Endotoxemia alters HDL size and decreases reverse cholesterol transport capacity. In chronic inflammation, HDL may lose its anti-atherogenic functions or become pro-atherogenic. HDL cholesterol efflux capacity is inversely associated with carotid intima-media thickness and risk of coronary artery disease. Relationship remains significant even after adjusting for HDL level or levels of apolipoprotein A-I. Impaired HDL efflux associated with more severe psoriasis. Those with rheumatoid arthritis have a similar overall prevalence of vessel DAC and had significantly more vulnerable plaque in LAD.
Association of Psoriasis With CV Events
Multiple studies have shown an association between psoriasis and myocardial infarction. Highest HR in younger patients with severe disease. Potential confounding by higher prevalence of cardiovascular risk factors. Obesity, hypertension, smoking, diabetes, metabolic syndrome. Each risk factor associated with an increased prevalence OR of 1.5-2.0
Is TNF-alpha Inhibition Associated with Decreased CV Risk?
Observational studies in rheumatoid arthritis have suggested a potential benefit of TNF alpha inhibition in reducing cardiovascular mortality and incident myocardial infarction. Initial studies in psoriasis have also suggested a possible reduction in CV events among patients prescribed TNF alpha inhibitors. Potential residual confounding remains in all of these observational studies.
Epidemiology and risk factors of peripheral artery disease
Adult prevalence 10%-12%. 20% over the age 70 or younger patients with diabetes or smoking. Risk Factors: Diabetes (4-fold increased risk), Smoking (2-3 X), Lipids (2 X), and Hypertension (2X). PAD has 6-fold increased risk of CV death
Symptoms of peripheral artery disease
Intermittent Claudication: Cramp, calf fatigue with exercise, resolves with rest, Blood flow normal at rest, limited with exercise, and No symptoms at rest, onset only with exercise. Ischemic rest pain/ischemic ulcers: Pain in the distal foot or heel, worsened by leg elevation and improved by dependency, Distal, painful ulcers on toes or heel, Blood flow limited at rest and exercise, and Symptoms at rest and with exercise
Signs of peripheral artery disease
Decreased or absent pulses. Bruits (abdominal, femoral). Muscle atrophy. In severe PAD (critical leg ischemia): Pallor of feet with elevation and Dependent rubor
Claudication Pathophysiology and Implications for Therapy
Prevent CV events (MI, stroke, vascular death). Improve limb symptoms, exercise performance and QOL. Heal ulcers and prevent limb loss. Treatments: Surgery or angioplasty improves hemodynamics, Exercise training improves muscle metabolism, and Drugs (cilostazol) have multiple mechanisms
Mechanisms of Aneurysm Formation
aneurysm formation is characterized by destruction of elastin and collagen in the media and adventia, loss of medial smooth muscle cells with thinning of the vessel wall, and transmural infiltration of lymphocytes and macrophages. Atherosclerosis is a common underlying feature of aneurysms. However, atherosclerosis is not the primary driving factor in the development of AAAs. Atherosclerosis is a disease that is widespread throughout the vasculature, however aneurysms only form in specific locations and only in certain individuals. Additionally, atherosclerosis is primarily a disease of the intima, while aneurysm formation primarily affects the media and adventitia. Currently there are thought to be four mechanisms relevant to AAA formation including: 1) proteolytic degradation of aortic wall connective tissue, 2) inflammation and immune responses, 3) biochemical wall stress, and 4) molecular genetics. Inflammation is driven by b and t lymphocytes, macrophages, cytokines, and autoantigens. Proteolytic enzymes such as MMP-2 and MMP-9 are upregulated while tissue inhibitor MMPs (TIMPs) are downregulated. uPa and tPa is also upregulated. Biomechanical stress causes elastin distribution, turbulent blood flow, and mural thrombus.
Epidemiology of AAA
Annual incidence estimated 40 to 50 per 100,000 men and 7 to 12 per 100,000 women. Accounts for approximately 16,000 deaths annually in U.S. Ruptured aneurysms are the 13th leading cause of death in US
Four major risk factors of aortic aneurysm
male gender, age, smoking, and family history
Abdominal Aortic Aneurysm Clinical Presentation
70% of patients are asymptomatic, then present with sudden death. 30% present with abdominal discomfort or severe pain radiating to the back, then die. Physician physical examination (rarely). Incidental discovery from imaging for another indication
Diagnosis of Abdominal Aortic Aneurysm
Plain X-ray, Ultrasound, Computerized tomography, Magnetic resonance imaging, and Arteriography (May miss it because angiography views the lumen not the arterial wall)
Computed Tomographic Imaging in diagnosing AAA
High resolution imaging of the aorta. Determines proximal and distal extent of AAA. Defines relationship of AAA to branch vessels. Planning for intervention
Aortic Dissection
Epidemiology ~ 30 cases / million / yr and account for 3-5 % sudden deaths. Untreated natural history: 1 % / hour mortality x 24 hours, 75 % mortality at 2 weeks, and 90 % mortality at 3 months
Aortic dissection mechanisms
1) primary intimal tear 2) rupture of vasa vasorum.
Aortic dissection risk factors
Hypertension (drugs e.g. cocaine), Inherited disorders of connective tissue (Marfan syndrome and Ehlers-Danlos syndrome), Bicuspid aortic valve, Coarctation, Pregnancy, Aortitis, Iatrogenic (surgery, arterial catheterization), and Trauma
Clinical manifestations of aortic dissection
Majority present with severe, tearing pain. Disruption of major arterial circulation leads to: Stroke (carotid), Syncope (vertebral), Myocardial infarction (coronaries), Intestinal ischemia (mesenteric vessels), and Renal failure (renal arteries)
Treatment of aortic dissection
Medical Rx includes Control of ΔPressure/ΔTime (Beta Blockade), Control of Blood Pressure (Nitroprusside, ACE inhibitors, and Calcium Channel Blockers) Control of Pain (Narcotic analgesia). Surgical Rx for Acute type A, Chronic type A with Aortic regurgitation, and Acute type B with: Rupture, Organ ischemia, and Marfans
Venous thromboembolic disease
3rd most common peripheral vascular disease. Nearly 2/3 of VTE are asymptomatic or undiagnosed. VTE account for 5%-10% of all hospital deaths. If no prophylaxis 24% of MI patients develop VTE, 60% of paralytic stroke patients develop VTE, and 75% of hip surgery patients develop VTE. 58% of PE deaths had not received any prophylaxis. Post-phlebitic syndrome in 40-80% of patients with VTE
Stages of chronic VTE
1) swelling, 2) visible collaterals, 3) stasis dermatitis, 4) ulceration.
Mechanisms of Thrombophilia
Thrombophilia caused by any alteration in coagulation balance that: increases thrombin production, enhances platelet activation/aggregation, mediates endothelial activation/damage, and/or mediates fibrinolytic inhibition
Thrombophilia Risk Factors
Severe inherited thrombophilia (homozygous protein C deficiency) is rare. Mild inherited thrombophilia (heterozygous Factor V Leiden) is common. Acquired thrombophilia is especially common in infection, inflammatory and certain drugs (estrogens).
Direct vs. Indirect Factor Xa Inhibitors
indirect Xa inhibitors (fondaparinux and idraparinux) are parenteral, require cofactor (AT), bind PF4, and inhibit free factor Xa only. Direct factor Xa inhibitor (rivaroxaban, apixaban, edoxaban) is taken orally, no cofactor need and is reversible, do not bind PF4 (no risk of HIT), inhibit free factor Xa and factor Xa in prothrombinase complex (better attenuation of thrombin generation).
Venous Thromboembolism
Risk factors include hypercoagulable states, venous trauma and stasis. Morbidity of acute venous and pulmonary thrombosis. Chronic risk for post phlebitic syndrome. Primary management is acute and chronic anticoagulation. Development of new anticoagulants
Apolipoprotein C2 or Apolipoprotein C-II
is a protein that in humans is encoded by the APOC2 gene. The protein encoded by this gene is secreted in plasma where it is a component of very low density lipoproteins and chylomicrons. This protein activates the enzyme lipoprotein lipase in capillaries, which hydrolyzes triglycerides and thus provides free fatty acids for cells.
Lipoprotein lipase (LPL)
is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very low-density lipoproteins (VLDL), into two free fatty acids and one monoacylglycerol molecule. It is also involved in promoting the cellular uptake of chylomicron remnants, cholesterol-rich lipoproteins, and free fatty acids. LPL requires ApoC-II as a cofactor. LPL is attached to the luminal surface of endothelial cells in capillaries by heparen sulfated proteoglycans. It is most widely distributed in adipose, heart, and skeletal muscle tissue, as well as in lactating mammary glands.
Stages of prevention
Primordial – prevention of the emergence or development of risk factors for disease. Primary – prevention actions taken before the development of disease. Secondary – prevention actions taken after the development of disease to halt its progress and subsequent complications. Tertiary – prevention actions taken to reduce disability from disease and minimize suffering from its effects
Therapeutic Rationale of Antiplatelet
Anti-platelets prevent platelet adhesion to the site of a ruptured plaque, reduce platelet activation, and prevent platelet aggregation
Aspirin
Reduces platelet activation by blocking cyclooxygenase and thromboxane A2 (a vasoconstrictor) production. Aspirin blocks cyclooxygenase (prostaglandin H synthase), the enzyme that mediates the first step in the biosynthesis of prostaglandins and thromboxanes (including TxA2) from arachidonic acid.
Thienopyridines
(clopidogrel, ticlodipine, prasugrel, and ticagrelor). Inhibits adenosine diphosphate (ADP) production and platelet aggregation. The P2Y12 receptor blockers, thienopyridines clopidogrel, ticlopidine, prasugreland cyclopentyltriazolopyrimidine ticagrelorblock the binding of ADP to a platelet receptor P2Y12, thereby inhibiting activation of the GP IIb/IIIa complex and platelet aggregation.
Anti-GP IIb/IIIa antibodies and receptor antagonists
inhibit the final common pathway of platelet aggregation (the cross-bridging of platelets by fibrinogen binding to the GP IIb/IIIa receptor) and may also prevent adhesion to the vessel wall.
Class I antiplatelet guidelines
Aspirin 75-162mg daily for all CAD patients. Thienopyridines in all patients with ACS or PCI for one year following the event, in addition to aspirin 81-325mg. For post-bypass surgery patients, aspirin 100-325mg for at least one year. For post-stroke patients, aspirin alone (75-235mg), clopidogrel alone (75mg), or combined aspirin/dipyridamole (25mg/200mg) daily chronically. For symptomatic (not asymptomatic) peripheral arterial disease patients, aspirin alone (75-235mg) or clopidogrel alone (75mg). If the patient requires warfarin for another indication (e.g. AF), then continue low-dose aspirin 75-81mg and monitor closely for bleeding
Beta-blockers
reduce myocardial oxygen demand. Reduces heart rate. Reduces contractility. Reduces conduction velocity. Reduces systemic blood pressure
Class I beta-blocker guidelines
Beta-blockers in all with LVSD (ejection fraction
Class IIa beta-blocker guidelines
Beta-blockers in all with LVSD (ejection fraction
RAAS blockade
has multiple effects on the CV system. Vasodilation, Natriuresis, Decreased sympathetic activity, and Reduces cardiac remodeling. RAAS inhibition reduces mortality among post-MI patients, especially diabetics and LVSD
Class I RAAS inhibition guidelines
ACEIs: All with LVSD (ejection fraction 5.0 mEq/L)
2014 Class I blood pressure control guidelines
Age
Non-statin lipid treatments
are also available, but most have no evidence of efficacy. Bile-acid binding agents. Niacin. Fibrates
Smoking
promotes atherosclerosis and cardiac outcomes. Oxidizes LDL, Inflammatory, Decreases HDL, Causes endothelial dysfunction and reductions in NO. Smoking hurts, and cessation helps
Early Cardiogenesis
Male and female gametes fuse -> Fertilization. The unicellular zygote goes through a series of cleavages resulting in an increased number of cells -> morula. Morula -> transforms into a blastocyst
Blastocyst
Blastocyst has 3 components: Outer cell mass = trophoblast. Inner cell mass = embryoblast. Central cavity = blastocyst cavity
Embryoblast
the inner cell mass (abbreviated ICM and also known as the embryoblast or pluriblast, the latter term being applicable to all mammals) is the mass of cells inside the primordial embryo that will eventually give rise to the definitive structures of the fetus. The embryoblast has 2 layers: External layer = epiblast and Internal layer = hypoblast. These layers form a flat disc = Embryonic disc
Precardiac Cells
At the blastocyst stage, the precardiac cells are located within the epiblast on either side of the primitive streak. Epiblast cells migrate through the primitive streak -> giving rise to the intraembryonic mesoderm.
Gastrula
the single-layered blastula is reorganized into a trilaminar (“three-layered”) structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and endoderm. The precardiac cells are located within the mesoderm. The precardiac cells then migrate cephalically.
Development of the cardiogenic region
In the splanchnopleuric mesenchyme on either side of the neural plate, a horseshoe-shaped area develops as the cardiogenic region. This has formed from cardiac myoblasts and blood islands as forerunners of blood cells and vessels.
Development of endocardial tube
The cardiogenic cells migrate so that they are now ventral to the forebrain and foregut. The cardiogenic cells begin to form 2 endocardial tubes. By day 19, an endocardial tube begins to develop in each side of this region. These two tubes grow and by the third week have converged towards each other to merge together, using programmed cell death to form a single tube, the tubular heart. From splanchnopleuric mesenchyme, the cardiogenic region develops cranially and laterally to the neural plate. In this area, two separate angiogenic cell clusters form on either side and coalesce to form the endocardial tubes. As embryonic folding continues, the two endocardial tubes are pushed into the thoracic cavity, where they begin to fuse together, and this is completed at about 22 days
Morphologic Stages of heart development
DAY 21-22: Primitive heart tube is formed. The heart begins to beat on approximately DAY 22. The heart then goes through a looping process: Pre-loop, Loop, Post-loop (early and late) Septation begins at this stage
Pre-loop Stage
DAY 22. Straight heart tube. Atrioventricular Sulcus will become the intraventricular septum. The Primitive Ventricle is the primordium of the trabeculated portion of the LV. The proximal portion of the Bulbus Cordis is the primordium of the trabeculated portion of the RV. Blood flow begins.
Derivation of Cardiac Components
The inner layer of the heart tube is composed of an endothelial lining which will develop into the endocardium. The outer layer of the tube is derived from mesoderm (epimyocardium) and will go on to develop into myocardium and epicardium. Between the inner and outer layer is a substance called “cardiac jelly” which plays a role in the looping of the heart as well as septation.
Looping Stage
DAY 23-25. If the heart loops to the embryo’s Left it would be an L-loop and result in a malformed heart. The primitive atria rotate posteriorly. The long axis of the atrioventricular canal is initially cephalic to caudal, but with looping becomes posterior to anterior.
Early Post-Loop Stage
DAY 26-28. Note that the ventricles and atria are now in alignment. Septation begins. The ventricular septum is visible. The ventricles actually develop as outpouchings of the 2 areas visualized. At this stage the atria and ventricles are not entirely septated.
Truncus
Aortic and pulmonary valves. Ascending aorta. Pulmonary trunk
Conus
Infundibula of both ventricles
Bulbis Cordis
Trabeculated portion of the RV
Primitive Ventricle
Trabeculated portion of the LV
Blood Flow
DAY 25. Blood flow enters the heart tube through the sinus venosus via 3 sets of veins. 1) Umbilical vein- from the placenta (Disappears after birth). 2) The Vitelline vein- from the yolk sac. 3) The Cardinal vein-drains the embryo
The umbilical vein
is a vein present during fetal development that carries oxygenated blood from the placenta to the growing fetus. The unpaired umbilical vein carries oxygen and nutrient rich blood derived from fetal-maternal blood exchange at the chorionic villi. More than two-thirds of the blood enters the liver from its inferior border, while the remainder is shunted to the inferior vena cava through the ductus venosus, whence it returns to the fetal right atrium. Within a week of birth, the infant’s umbilical vein is completely obliterated and is replaced by a fibrous cord called the round ligament of the liver (also called ligamentum teres hepatis).
Vitelline Vein
are veins which drain blood from the yolk sac. The vitelline veins give rise to Hepatic veins, Inferior portion of Inferior vena cava, Portal vein, Superior mesenteric vein and contribute to the hepatic sinusoids.
Cardinal Vein
empty in the sinus venosus. Right becomes SVC, brachiocephalic vein, innominate veins. Left becomes Ligament of Marshall
Development of the Pulmonary Veins
Part of the splanchnic plexus forms the pulmonary venous plexus -> develops into the pulmonary veins. An endothelial projection from the LA connects to the pulmonary venous plexus and forms a common pulmonary vein. A lumen forms and the common vein branches forming the right and left pulmonary veins.
Atrial and Ventricular Septation
Approximately DAYS 28-42 (Post-loop Stage). Abnormalities will result in septal defects: Atrial septal defects and ventricular septal defects respectively.
Great Artery Formation
Approximately DAYS 35-56. Starting closest to the heart: Septation of the Conus, Septation of the Truncus
Septation of the Conus.
In the early post-loop stage, masses appear on the inside wall of the conus. Dextrodorsal and sinistroventral conal crests. The conal crests fuse with the ventricular septum caudally
Septation of the Truncus
Masses appear in the truncus: Dextrosuperior and sinistroinferior truncal swellings. Right intercalated swelling -> noncoronary aortic cusp. Left intercalated swelling -> anterior pulmonary cusp
Spiral shape of septation
The aorticopulmonary septum originates as an extracardiac septum in the aortic sac. SVCC becomes continous with SITS and DDCC becomes continuous with DSTS. The septum of the aortic sac, truncus and conus is therefore spiral shaped. At the great artery level, the pulmoanry artery is posterior and to the left. At the semilunar valve level, the pulmonary valve is anterior and to the left. At the infundibular level, the pulmonary infundibulum is anterior and to the right of the aortic infundibulum.
Development of the Aortic Arches
Related to the development of the head and neck. During the 4th week of development the pharyngeal arches appear. As each arch appears, the aortic sac contributes a right and left branch. These connect with the right and left dorsal aortas to form 6 pairs of arteries called the aortic arches.
Development of the aortic arches
Ascending aorta comes from the aortic sac and the descending aorta comes from the left dorsal aorta
1st Aortic Arch
earliest to disappear. Contributes to the maxillary and external carotid arteries.
2nd Aortic Arch
also disappears. Dorsal portion becomes stapedial artery.
3rd Aortic Arch
carotid arteries
4th Aortic Arch
right side becomes right brachiocephalic artery, right subclavian artery. Left side becomes the transverse aortic arch.
5th Aortic Arch
disappears
6th Aortic Arch
proximal portion of right becomes the proximal right pulmonary artery. Proximal portion of left becomes the proximal left pulmonary artery. Distal portion of left becomes ductus arterious.
Embryology Summary
Straight heart tube composed of the truncus, bulbus cordis, primitive ventricle, primitive atria. Looping normally occurs to the right with the primitive atria rotating posteriorly. Conus, truncus and aorticopulmonary septation is spiral in nature. Although many of the embryonic aortic arches disappear the 6th arch in particular is important as it contributes to the development of the proximal branch pulmonary arteries and the ductus arteriosus. Ventricular and atrial septation to be covered in conjunction with discussion regarding atrial and ventricular septal defects. The RV ejects 2/3 of combined ventricular output. 1/3 of the output travels right to left across the atrial septum. Lung blood flow is only 6-8%, so the ductus arteriosus carries 55-60% of combined ventricular output.
Patent Ductus Arteriosus
Embryologically the ductus arteriosus is persistence of the distal portion of the left 6th aortic arch. Incidence of a PDA is 5-12% of all congenital heart defects. Increased incidence of persistence in premature infants and babies born at elevations >9,000 feet and maternal rubella infection. Incidence of 70% in infants that weigh
Patent Ductus Arteriosus
Functional closure of the ductus usually occurs 10-15 hours after birth (delayed at higher elevation). Anatomic closure occurs in the 2nd-3rd week of life. By age of 1 year- the ductus has closed in >98% of children.
How does the ductus arteriosus close?
The ductus is thought to have fewer elastic fibers and more muscular tissue than the aorta and pulmonary artery. The increased PaO2 after birth results in contraction of the spiral muscular fibers in the wall of the PDA. This response is weaker in premature infants. The aorta and PA have circumferentially arranged fibers compared to the spiral fibers of the ductus. Functional closure (first 12 hours after birth). Contraction and cellular migration of the medial smooth muscle in the wall of the ductus results in intimal thickening with protrusion into the lumen. Anatomic closure (by 2-3 weeks) is a morphologic process that occurs via vascular remodeling: The internal elastic membrane of the ductus fragments, the intima and media proliferate, mucoid lakes form in the intima and media -> hyaline mass forms that totally occludes the lumen.
Why does the ductus arrteriosus stay open?
Prostaglandins: product of the metabolism of arachidonic acid; potent vasoactive agent. PGE2 is the most potent agent for maintaining ductal patency. Site of production is not entirely understood- locally from the ductal wall and/or from the placenta. Administration of PGE2 in intravenous form will maintain ductal patency postnatally.
Clinical Presentation of a PDA
Depends on the amount and direction of flow moving across the ductus: the size of the “shunt”.
Pernio
is a condition characterized by the development of cold-induced erythrocyanotic skin lesions. Pernio manifests as erythematous to violaceous macules, papules, plaques, or nodules in sites of cold exposure. The most common sites for involvement are the fingers and toes. Symptoms of pruritus, pain, or burning often accompany the skin lesions, and complications of blistering, ulceration, or secondary infection can occur.
Erythromelalgia
Is a rare neurovascular peripheral pain disorder in which blood vessels, usually in the lower extremities or hands, are episodically blocked (frequently on and off daily), then become hyperemic and inflamed.
Acrocyanosis
persistent blue or cyanotic discoloration of the extremities, most commonly occurring in the hands, although it also occurs in the feet and distal parts of face.
The common congenital heart diseases leading to right-to-left shunts
Truncus arteriosus (1 vessel), Transposition of great vessels (2vesselsswitched), Tricuspid atresia (Tri = 3), Tetralogy of Fallot (Tetra = 4), Total anomalous pulmonary venous return (TAPVR = 5 letters). Note that the right-to-left shunt conditions all begin with the letter T, and thus can be remembered as the 5 T’s. The right-to-left shunts cause early hypoxia, so the patients manifest cyanosis in early childhood, or even at birth. Generally, right-to-left shunts result from a high pulmonary venous resistance and low systemic vascular resistance. Increased pulmonary vascular resistance (PVR)(e.g., crying, hypoventilation, and acidosis) or decreased systemic peripheral resistance(SVR) (e.g., hypotension, histamine release, sepsis) will increase the shunting and worsen the hypoxia.
The common congenital heart diseases leading to left-to-right shunts
Ventricular septal defect (VSD), Atrial septal defect (ASD), and Patent ductus arteriosus (PDA)
Ventricular septal defect
is characterized by a harsh holosystolic murmur that occurs at the left lower sternal border. The murmur heard in ventricular septal defect is a systolic murmur that occurs due to the large pressure difference generated during systole. Blood from the high pressure left ventricle to the low pressure right ventricle causes the holosystolic murmur.
Atrial septal defect
is characterized by a loud S1 with a wide, fixed split S2 that is best heard at the upper left sternal border. The wide, fixed split S2 is due to the right ventricular stroke volume being equal during both inspiration and expiration. This occurs due to the left to right shunt in the atrium. There is an ejection, systolic murmur due to increased blood flow across the pulmonary valve because of the left to right shunt.
endocardial cushion defect
Down syndrome children often have an endocardial cushion defect with VSD, ASD, or AV septal defects. Unlike other children, these kids usually have a low baseline heart rate.
Tetralogy of Fallot
Another rare congenital heart defect associated with Down syndrome is Tetralogy of Fallot. Tetralogy of Fallot is characterized by four congenital abnormalities that include: Pulmonic stenosis, Right ventricular hypertrophy, Overriding aorta, Ventricular septal defect. Mnemonic: PROVe. The severity of tetralogy of Fallot is dependent upon the degree of pulmonic stenosis. Tetralogy of Fallot typically presents as early cyanosis. An associated feature is thepresence of “tet spells”. When crying increases pulmonary resistance, the increase in RV pressure leads toincreased blood flow from right to left ventricle via VSD resulting increasedcyanosis. A compensatory mechanism children with tetralogy of Fallot during a “tet spell” often use involves crouching down, which increases systemic vascular resistance. This leads to increased left ventricular pressure and lessens the effect of the right-to-left shunt, decreasing cyanosis.
The definite treatment of tetralogy of Fallot
involves surgical repair, which consists of VSD patch closure and right ventricular outflow tract reconstruction.
Eisenmenger’s syndrome
describes a condition in which a left-to-right shunt reverses to become a right-to-left shunt in the presence of progressive pulmonary hypertension secondary to increased pulmonary circulation. Late cyanosis with clubbing and polycythemia often accompany Eisenmenger’s syndrome.
Persistent truncus arteriosus
is caused by abnormal neural crest cell migration, leading to incomplete fusion of the AP septum and failure of the truncus arteriosus to divide. In persistent truncus arteriosus, only one large vessel leaves the heart. This vessel receives blood from both ventricles, effectively causing a right to left heart shunt. Patients with persistent truncus arteriosus typically present with cyanosis.
Transposition of the great vessels
is a condition in which the aorta originates from the right ventricle and the pulmonary artery originates from the left ventricle. A transposition of the great vessels is characterized by early cyanosis in the newborn since deoxygenated blood from systemic circulation is immediately pumped back out into the periphery by going directly from the right ventricle into the aorta. Initial management of a transposition of the great vessels includes intravenous prostaglandins to maintain patency ofPDA, which allows for some mixing of arterial and venous blood. Definitive treatment of a transposition of the great vessels involves surgical correction of the transposition. In this surgery the great vessels are removed distal to the arterial valves and switched. The blood supply of the coronary arteries must be transferred to the new location of the aorta as well. Transposition of the great arteries is commonly associated with maternal diabetes.
Patent ductus arteriosus (PDA)
is characterized by persistence of the ductus arteriosus, which serves as a connection between the pulmonary artery and aorta. The ductus arteriosus functions to divert blood away from the pulmonary circuit before birth. Upon birth, the systemic pressure increases, and causes blood to leak from the aorta, through the PDA and into the pulmonary circulation. Patent ductus arteriosus is characterized by a continuous machine-like murmur. Patent ductus arteriosus is often associated with congenital rubella. Patent ductus arteriosus can be treated pharmacologically withCOXinhibitors, such as NSAIDs (e.g., indomethacin),or may require invasive procedures in refractory cases. The murmur associated with patent ductus arteriosus can best be heard over the upper, left sternal border.
Coarctation of the aorta
is aortic narrowing near the insertion of the ductus arteriosus that is classically divided into infantile and adult forms. Adult coarctation of the aorta is commonly asscociated with a bicuspid aortic valve. Adult coarctation of the aorta presents as hypertension in the upper extremities and hypotension with weak pulses in the lower extremities. Adult coarctation of the aorta leads to increased collateral circulation over the intercostal arteries, these enlarged arteries cause progressive “notching of ribs” on x-ray. Infantile form of coarctation of the aorta is associated with a PDA, and the coarctation lies distal to the aortic arch but before the PDA. Infantile coarctation of the aorta commonly presents as lower extremity cyanosis in infants, generally found at birth. Infantile coarctation of the aorta is often associated with Turner syndrome.
Fetal circulation
Fetal blood is oxygenated in the placenta, and reaches the fetal heart through the left umbilical vein. Following birth, the left umbilical vein fibroses to form theligamentum teres. Deoxygenated blood is circulated to the placenta via the right and left umbilical arteries. The medial umbilical ligaments is the post-natal remnant of the right and left umbilical arteries. The right umbilical vein obliterates during fetal development.
The fetal circulation involves three shunts
Ductus venosus, Foramen ovale, Ductus arteriosus
The ductus venosus
directsblood entering the fetus through the left umbilical vein, bypassing the liver, and into the inferior vena cava. The ductus venosus closes approximately 1 week postnatally, obliterating to form the ligamentum venosum.
The foramen ovale
connects the atria, allowingoxygenated blood to bypass the lungs and right ventricle to circulate systemically. The foramen ovale closes as the result of: Decreased pulmonary vasculature resistance following neonatal breathing, leading to an increase in left atrial pressure and reduced blood flow and pressure in the right atrium following placental circulation occlusion. The adult remnant of the closed foramen ovale is called thefossa ovalis.
The ductus arteriosus
allows most of the blood pumped from the right ventricle to bypass the fetal lungs through a connection between the pulmonary artery and the aortic arch. The ductus arteriosus closure is mediated by elevated oxygen levels and decreased prostaglandins.The ductus arteriosus may remain patent as a result ofasphyxiating conditions or prostaglandin E administration. The ductus arteriosus may close with introduction of the following substances: Indomethacin(a prostaglandin inhibitor), Acetylcholine, Histamine, and Catecholamines. The remnant of the ductus arteriosus is the ligamentum arteriosum.
The primitive heart tube forms five dilations
Truncus arteriosus, Bulbus cordis, Primitive ventricle, Primitive atrium, Sinus venosus(right and left horns)
The truncus arteriosus
develops into the ascendingaorta and pulmonary trunk.
The bulbus cordis
develops into theconus arteriosus (smooth part of the right ventricle)and the aortic vestibule (smooth part of left ventricle).
The primitive ventricle
develops into trabeculated part of right and left ventricles.
The primitive atrium
develops into the muscular (trabeculated)part of right and left atrium and the septum primum.
The left horn of the sinus venosus
develops into the coronary sinus.
The right horn of the sinus venosus
develops into the smooth part of the right atrium.
crista terminalis
The junction of the trabeculated and smooth parts of the right atrium.
Class IV anti-arrhythmic agents
calcium channel blockers (e.g., Diltiazem, Verapamil), which exert their anti-arrhythmic effect mainly by slowing AV node conduction by inhibiting Ca2+ influx. Additional effects of Class IV agents include: 1. ↓ SA/AV node automaticity 2. ↑ effective refractory period 3. ↑ PR interval
Calcium channel blocker toxicity
Cardiovascular effects (CHF, AV block, sinus node depression). Facial flushing, headache, gingival hyperplasia. Constipation (especially seen with verapamil because calcium is needed for the smooth muscle contractions that facilitate gut motility). Edema. Class IV Antiarrythmics are used in the prevention of nodal arrhythmias, as well as rate control during atrial fibrillation.
Immediate angiographyandrevascularizationis recommended for patients with non-ST elevation ACS and at least one of the following
Hemodynamic compromise or cardiogenic shock. Systolic heart failure. Recurrent or persistent angina despite medical therapy. Evolving mitral insufficiency or ventricular septal defect. Sustained ventricular arrhythmias
Initial pharmacologic treatment of UA/NSTEMI
is the same as STEMI with the singular exception that fibrinolytics are never indicated. Otherwise, pharmacologic therapycan be remembered as the mnemonic BEMOANS: Beta-blocker (unless acute heart failure is present). Enoxaparin/Heparin (reduces probability ofrecurrent coronary events). Morphine(for control of unacceptably high pain levels). Oxygen(supplemental; indicated for patients with SpO2
Nitrates
(e.g., nitroglycerin, isosorbide dinitrate) increase nitric oxide in vascular smooth muscle. This increases cGMP, leading to smooth muscle relaxation and preferential vasodilation of veins over arteries (most nitrates have a much more potent vasodilatory effect on veins than arteries). The most important anti-anginal effect is a decrease in preload: There is decreased Preload (end-diastolic volume). There is decreased afterload (mean arterial pressure, which is proportional to total peripheral resistance). There is a reflex increase in heart rate in response to peripheral vasodilation (reflex tachycardia). Decreased MVO2 (oxygen consumption) leads to a decrease in myocardial stretch tension (preload) which will decrease EDP (end-diastolic pressure). Thereby there is a decreased myocardial demand and oxygen consumption. Nitrates dilate coronary arteries as the decrease in myocardial stretch (preload) allows for increased coronary blood flow through the uncongested myocytes
Statins
In order of descending potency: rosuvastatin > atorvastatin > simvastatin > lovastatin ~ pravastatin > fluvastatin . LDL ↓↓↓. HDL ↑ (minimal effect). Triglycerides ↓. 2 Main side effects: Myopathy/ rhabdomyolysis, which can manifest as elevated creatinine kinase and acute renal failure. hepatitis which can manifest with elevated LFTs. FDA consumer update in 2012: Routine measurement of LFTs is no longer necessary. Statins may cause cognitive impairment such as memory loss or confusion. Statins may increase the risk of hyperglycemia and DM2
Aspirin
is a non-selective, irreversible inhibitor of cyclooxygenase (both COX-1 and COX-2). Aspirin therapy increases bleeding time, but does not change PT/INR or PTT. Reye syndrome is a type of nonicteric hepatic encephalopathy characterized by cerebral edema and microvesicular fatty change of the liver.Reye syndrome occurs when children with a viral infection (especially varicella zoster virus or influenza) are treated with aspirin. Because of the risk of Reye syndrome, aspirin use in children is exclusively limited to treating the acute phase of Kawasaki disease. Aspirin-exacerbated respiratory disease refers to the triad of asthma, nasal polyps, and sensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) which occur in certain susceptible individuals. It is a type of pseudoallergic reaction, because it is not IgE-mediated.
Clopidogrel, ticlopidine
Irreversibly bind ADP receptors -> prevents GPIIb/IIIa activation -> ↓ platelet aggregation. Indications: coronary stents, thrombotic stroke, *antiplatelet therapy in post-stroke and post-TIA patients
A recent study found that adding clopidogrel to aspirin in patients who already suffered a stroke or transient ischemic attack reduces the chance of further cerebrovascular events compared to aspirin alone. Toxicity: ticlopidine – neutropenia
Abciximab (ReoPro®)
is an Fab fragment of a chimeric human-murine monoclonal antibody. It inhibits platelet aggregation by bindingthe GPIIb/IIIareceptor. Abciximab is used in combination with aspirin and heparin in patientsundergoing percutaneous coronary intervention (PCI).
Eptifibatide (Integrilin®)and tirofiban (AGGRASTAT®)
are other GPIIb/IIIa receptorinhibitors.
Indomethacin
is a nonselective inhibitor of cyclooxygenase (COX) 1 and 2, enzymes that participate in prostaglandin synthesis from arachidonic acid. Prostaglandins are hormone-like molecules normally found in the body, where they have a wide variety of effects, some of which lead to pain, fever, and inflammation. Prostaglandins also cause uterine contractions in pregnant women. Indomethacin is an effective tocolytic agent, able to delay premature labor by reducing uterine contractions through inhibition of PG synthesis in the uterus and possibly through calcium channel blockade. Indomethacin has two additional modes of actions with clinical importance: It inhibits motility of polymorphonuclear leukocytes, similar to colchicine. It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, like salicylates. These additional effects account as well for the analgesic and the anti-inflammatory properties. Indomethacin readily crosses the placenta and can reduce fetal urine production to treat polyhydramnios. It does so by reducing renal blood flow and increasing renal vascular resistance, possibly by enhancing the effects of vasopressin on the fetal kidneys.
Congenital heart defect with mother with lupus
VSD, transposition of great arteries, CoA, heart block
Risk factors for congenital heart disease
maternal diabetes causes a threefold increased risk. Fetal echo is recommended in this subpopulation of patients. Family history of a cardiac defect in a first degree relative (parent or sibling) is a major risk factor.
Congenital Heart Lesions
Persistent (patent) ductus arteriosus (PDA), Atrial septal defect (ASD), Ventricular septal defect (VSD), Tetralogy of Fallot (TOF), and Coarctation of the Aorta
What is a “shunt”?
A shunt is defined as a connection between 2 chambers/vessels. Shunt direction is primarily determined by the pressure or resistance difference between the 2 chambers. Standard nomenclature: Left-to-right shunt implies blood flow from a systemic chamber into a pulmonary chamber. Systemic chambers -> Pulmonary veins, left atrium, left ventricle, aorta. Pulmonary chambers ->Systemic veins, right atrium, right ventricle and pulmonary arteries. The magnitude of the shunt across a PDA is based on: The size of the PDA, The relative resistances of the aorta and pulmonary artery, and Pressure differences between the aorta and pulmonary artery. Usually because aortic resistance and pressure are greater than pulmonary resistance and pressure blood shunts through the PDA from the aorta -> pulmonary artery. A “left-to-right” shunt
Clinical Presentation of a PDA
Can be asymptomatic if a small PDA. Moderate or large PDA in a neonate (especially in preterm infants) usually results in clinical signs/symptoms: Respiratory effects (Difficulty weaning off the ventilator, Pulmonary edema/hemorrhage), Congestive heart failure, Feeding intolerance (can lead to bowel ischemia- necrotizing enterocolitis), Renal insufficiency, Intraventricular hemorrhage or stroke, and Death (rarely). Older infant or young child with a large ductus may present with a hoarse cry, history of pneumonias, failure to thrive, increased work of breathing and diaphoresis with activity/feeding. Even a large ductus can be “asymptomatic” in an older child. Subtle exercise intolerance or frequent “infections”/asthma
Physical Exam of PDA
A large PDA with left-to-right flow in a neonate: Wide pulse pressure, Bounding pulses (palpable palmar pulses), Increased work of breathing, Hyperactive precordium, and Murmur- variable.
Murmur of a PDA
Classic: Continuous or machinery sounding murmur along the left upper sternal border. Can be associated with a diastolic rumble if the shunt is large. No murmur if there is a low velocity or tiny shunt. Accentuated P2 component of the heart sounds if there is associated pulmonary hypertension
Diagnosis of PDA
Often can diagnose based on history and physical exam. Chest radiograph: Normal if the PDA is small and Increased pulmonary vascular markings, enlarged left atrium and left ventricle if large. Confirm with echocardiogram
Management of PDA
Depends on the age of the patient and symptoms. Asymptomatic neonate -> Conservative management. Symptomatic neonate: Trial of cyclooxygenase inhibitors (non-steroidal anti-inflammatory agents -> IV indomethacin or IV ibuprofen lysate) and If medication fails -> surgical ligation via lateral thoracotomy. Symptomatic older child or large ductus in an older child: Percutaneous occlusion. Asymptomatic older child -> Controversial: Murmur -> percutaneous closure, Silent -> no need to intervene, Controversy is whether or not a silent ductus has an increased risk of SBE.
Why COX inhibitors (NSAIDs) and which one for PDA management?
Block conversion of arachidonic acid to prostaglandin. Indomethacin and ibuprofen have equal efficacy. 70% effective in closing PDA in preterm neonates. Indocin is protective against intraventricular hemorrhage, but results in decreased blood flow to kidneys and brain. Ibuprofen Lysine is preferred in the setting of renal disease/insufficiency. Most effective in the first week of life and in preterm infants. Usually try to wait until 48 hours of life to allow spontaeous closure
Natural History of a PDA
If large and untreated, could result in pulmonary veno-occlusive disease (pulmonary hypertension) and/or Eisenmenger’s Disease. Increased risk of subacute bacterial endocarditis (SBE)
ASD
7-8% of all congenital heart defects. Different types based on location of defect: Secundum ASD most common. Embryological basis of secundum ASD: Too large a central hole (ostium secundum) in the septum primum OR Inadequate development of the septum secundum. The magnitude of the shunt across an ASD is based on: The size of the defect and The relative inflow resistances of the left and right ventricles. A “large defect” is usually defined as those with a diameter equal to or greater than that of the mitral valve. Embryologic basis is an excessive ostium secundum or inadequate septum secundum. Magnitude and direction of shunt depends on size of defect and inflow resistance to RV vs LV. RV is more compliant than the LV (L -> R shunt). Murmur is NOT caused by flow across the defect- pressure differential is too small. Murmur is caused by excessive flow across the pulmonary valve (systolic) and tricuspid valve (diastolic)
Why is the shunt left-to-right?
LA pressure is usually slightly higher than RA pressure. LA and RA pressure equalize if the ASD is large. ASD shunts are left-to-right if. The right ventricle is thinner and it’s compliance higher than the left ventricle (usual!). Systemic vascular resistance is higher than pulmonary vascular resistance -> dependent shunt!
ASD Clinical Presentation
Rarely presents in infancy. LV and RV myocardium are similar immediately after birth -> similar inflow resistance -> minimal atrial level shunt ->minimal symptoms. As pulmonary vascular resistance falls and RV wall thins and becomes more compliant left-to-right shunting increases
Physical exam of ASD
Dependent on degree of shunting. Small defect with no/minimal shunt or neonate: Normal exam. Large defect: May present in infancy with increased respiratory rate, sweating with feeds, but may be asymptomatic, Liver 2-3 cm below right costal margin, 2-3/6 systolic ejection murmur at upper left sternal border ± diastolic rumble at lower left sternal border, and Second heart sound is widely split
ASD murmur
NOT related directly to blood flowing across the defect. Systolic ejection murmur: Secondary to excessive blood flow across the pulmonary valve. Diastolic rumble: Excessive blood flow in diastole across the tricuspid valve
Widely split S2
Second heart sound (S2) is comprised of an A2 and P2 component: A2 represents aortic valve closure and P2 represents pulmonic valve closure. During inspiration, the A2- P2 split is more prominent: negative intrathoracic pressure increases right heart filling- delaying RV emptying. RV volume overload secondary to an ASD results in delayed RV emptying and therefore wide splitting of S2 in all phases of respiration
ASD diagnosis
Chest radiograph. Heart is of variable size depending on degree of shunting. Main pulmonary artery is enlarged. Pulmonary vascular markings are prominent. Echocardiography is diagnostic. Size and location of defect. Magnitude of shunt. Associated lesions
ASD Natural History
Often undetected in childhood: Lack of loud murmur and Lack of symptoms. Long term risks of a hemodynamically significant ASD: Development of pulmonary vascular disease, Occurrence of atrial arrhythmias, and Onset of cardiac failure
Pulmonary Vascular Disease
High pulmonary blood flow results in increased pulmonary vascular resistance (PVR). High PVR occurs in only 5-10% of patients. Unusual in childhood. At elevated altitudes (>4000’), pulmonary vascular disease is more common and occurs at an earlier age
ASD Management
Medical therapy can be instituted for symptoms in infants: Diuretic therapy can relieve breathlessness in most. In older children, adolescents or adults with a significant ASD (or infants who are symptomatic despite medications) treatment is close the hole with either surgery of percutaneous device closure: Depends on size of patient, Depends on size and anatomy of the defect, and Patient/cardiologist preference
VSD
Comprises 20% of all congenital heart defects. May be present in 5% of fetuses: High incidence of spontaneous closure. Seen in combination with other complex congenital heart lesions. Many different types based on location in septum
Embryology of Ventricular Septation
Post-loop stage: ~DAY 28-42. The intraventricular septum grows towards the base of the heart as the ventricular outpouchings develop. As this is occurring, 4 endocardial cushions appear. Ventricular septation occurs DAYS 28-42. Ventricular septation is complex. 4 endocardial cushions: Inferior, Superior, Left and Right endocardial cushions. Deficiency or lack of the Membranous portion of the interventricular septum results in a Perimembranous VSD, the most common type of VSD. Septum Primum, Endocardial cushions and the primitive interventricular septum become continuous. After fusion of the superior and inferior endocardial cushions, have a right and a left atrioventricular canal.
Superior Endocardial Cushion
becomes Left surface of the Outlet portion of the interventricular septum. Part of the mitral valve
Inferior Endocardial Cushion
Becomes: Inlet portion of the interventricular septum. Membranous portion of the interventricular septum. Parts of the tricuspid and mitral valves
Right Endocardial Cushion
becomes parts of the tricuspid valve.
Left endocardial cushion
becomes posterior leaflet of the mitral valve.
VSD Physiology
Large defects are defined as those measuring the same diameter as the aortic orifice. Large defects are often “unrestrictive”. There is equalization of right and left ventricular pressure. Magnitude of a VSD shunt depends on: Size of the defect, Systemic and pulmonary vascular resistances, and Right or left heart obstructive lesions will also influence shunt magnitude and direction if present (eg pulmonary or aortic valve stenosis). PVR is lower than SVR which leads to: preferential flow to lungs (L to R shunt), pulmonary blood flow returning to the left atrium is increased, increased end-diastolic volume of the LV, muscle fiber length is increased, Frank-Starling mechanism results in increased LV contractility, and increased LV output.
VSD Clinical Presentation
Asymptomatic until PVR falls after birth, even if defect is large. Fall in PVR is delayed at elevated altitudes. Large VSD: Respiratory distress and diaphoresis- especially noted with feeds and Failure to thrive. Small VSD: Tachypnea, diaphoresis usually mild or absent. Large VSD Exam: Active precordium, Accentuated second heart sound, 2-3/6 harsh, holosystolic murmur loudest at LLSB, but can usually be heard throughout the chest, Diastolic murmur- secondary to increased flow across the mitral valve. Small VSD Exam: Precordial activity usually normal, Normal second heart sound, 2-4/6 early systolic murmur, No diastolic murmur. A murmur that gets louder is not always a bad thing. It could mean a closing/Restrictive VSD or low PVR. A murmur that goes away is not always a good thing. Large VSD with equalization of RV and LV pressure. Elevation in PVR
Diagnosis of VSD
Characteristic exam. Gold-standard is echocardiography: Defines location and number of defects, Can estimate magnitude of shunt, and Can identify associated lesions or complicating factors such as aortic insufficiency. ECG: Normal in small defects. Large defects ->Right axis deviation and increase in RV and LV voltages (combined hypertrophy)
Chest Radiograph of Large VSD
increased lung vascularity, enlarged right pulmonary artery, enlarged main pulmonary artery, and cardiomegaly.
VSD Management
Symptom-based management in infancy. “Heart Failure” symptoms (tachypnea, diaphoresis). Pulmonary edema is a consequence of excessive pulmonary blood flow. Diuretics are the mainstay. Historically digoxin and afterload reduction (ACE-inhibitor). Small defects are usually asymptomatic: No treatment necessary
VSD Management
Indications for surgical closure of a VSD: Development of pulmonary vascular changes in the setting of a large defect, Persistent symptoms or poor growth despite medical therapy, and Development of secondary complications (aortic insufficiency, double-chambered RV etc). Device closure possible for some muscular VSDs. Most small defects close spontaneously. Many large defects decrease in size. Large defects left untreated can be devastating.
Eisenmenger’s Syndrome
starts with large left to right shunt leading to increased pulmonary blood flow. This leads to muscularization of pulmonary arterioles and pulmonary hypertension, leading to increased right ventricular pressure. When pressure gets high enough there is shunt reversal (R->L) causing cyanosis and clubbing eventually leading to heart/lung transplant or death.
VSD summary
Magnitude and direction of shunt depend on size of defect and difference in pulmonary and systemic vascular resistance. PVR is lower than SVR (L -> R shunt!). Murmur IS caused by flow across the defect- pressure differential between LV and RV is significant. Small defects can have louder murmurs than large defects.
Tetralogy of Fallot
Cyanotic heart disease complex: Right ventricular outflow tract obstruction, Right ventricular hypertrophy (RVH), Dextraposition of the aorta (aorta overrides the VSD), and VSD. 15% of all congenital heart defects. Most common of the cyanotic defects
Embryological Basis for TOF
Abnormal development of the conal crests resulting in an infundibular (outlet) septum that is displaced anteriorly, rightward and superiorly. This results in obstruction of the subpulmonary outflow tract
Physiology of TOF
VSD is large in vast majority of cases: RV and LV pressures are equal. Magnitude of Pulmonary Blood Flow is determined by: Source of pulmonary blood flow (PBF), Severity of right ventricular outflow obstruction, Balance of RV and LV pressure, and Ductus arteriosus. Source of PBF: Antegrade RV output to the pulmonary arteries. Ductus arteriosus (DA) flow. If outflow obstruction is severe, most PBF is derived from the DA: Size of the ductus is the primary determinant of magnitude of PBF
RV outflow obstruction
Narrowing of the infundibular region. Stenosis of the pulmonary valve. Shunt direction in TOF depends on relative resistance to flow: R -> L shunt if RV outflow resistance is higher than systemic vascular resistance -> Cyanosis (“Blue tetralogy”) and L ->R shunt if RV outflow resistance is less than systemic vascular resistance ->No cyanosis (“Pink tetralogy”)
Role of Circulatory System during exercise
The main responsibility of the circulatory system during exercise is to delivery oxygen to skeletal muscle and vital organs. It is also responsible for the removal of waste products from the body, the transport of vital nutrients to skeletal muscle, and the regulation of temperature. The circulatory and respiratory systems are linked in regards to the delivery of oxygen. The Fick equation is the unifying concept between the respiratory and circulatory systems.
Fick Equation
Cardiac output = VO2 / a-v O2 [CaO2 – CmvO2 ]. Cardiac output is the product of heart rate and stroke volume.
The major circulatory adjustments to exercise
increase in blood flow (cardiac output, muscle blood flow), redistribution of blood flow (inactive organs to working skeletal muscle), and maintaining blood pressure (driving force of blood flow; importance of maintaining blood flow to vital organs (brain)
Aspects of the Cardiac Cycle during Ventricular Filling and Contraction
Systole - contraction phase Diastole – filling and relaxation of the ventricle. At rest 2/3 of the ventricular volume is ejected in systole with 1/3 remaining. With exercise there is an increased in the amount of blood ejected from the left ventricle. LV ejection fraction (LVEF) = (LVEDV – LVESV)/ LVEDV. LVEDV – LVESV is stroke volume. At rest a normal LVEF is 60%. With exercise the LVEF can increase by 10-20%, depending on the type and intensity of exercise. At rest diastole lasts longer than systole. During exercise the increase in heart rate results in a decrease in diastolic filling time. Duration of systole is also affected but not as much as diastole.
Heart Rate Response to Exercise
At rest, a typical heart rate in an untrained person is 60-80 bpm. In an endurance athlete the resting heart rate can be as low as 28-40 bpm. Just prior to beginning exercise the heart rate is often increased compared to a true resting heart rate. This is the anticipatory response and is caused by sympathetic stimulation as a result of central command in the brain preparing the circulatory system for exercise. The heart rate during exercise has several features: 1. The increase in heart rate is directly related to exercise intensity. 2. There is a linear response of heart rate to workload up to near maximal exercise. 3. Maximal exercise heart rate is highly reproducible and consistent. It can be
estimated by the formula: 220 – age. 4. After age 15, maximal heart rate decreases by 1 bpm annually. 5. During lower levels of exercise the increase in heart rate up to 100 bpm is related
to parasympathetic withdrawal. Above this level, during moderate to heavy exercise, the heart rate is controlled by sympathetic activity. Increases in heart rate alone will not result an improvement in stroke volume and cardiac output. An increase in heart rate (pacemaker) at rest will result in a decrease in ventricular filling time and lead to a decrease in stroke volume. However, when heart rate increases with exercise, there is an increase in stroke volume caused by a combination of peripheral vasodilation, increase in venous return, and venoconstriction. All these factors lead to preservation of ventricular filling.
Stroke Volume Response to Exercise
Stroke volume is EDV – ESV. Factors which influence stroke volume during exercise include: 1. End-diastolic volume (EDV) which is cardiac preload. Both venous return and ventricular distensibility are important in maintaining cardiac preload. 2. Strength of contraction (Contractile State).3. Aortic or pulmonary pressure, depending on the ventricle of interest. This is
cardiac afterload.
Factors which influence venous return
- Venoconstriction - This is the result of reflex sympathetic control of vascular smooth muscle. The majority of blood at rest is in the venous return channels (veins venules, venous sinuses). 2. Muscle Pump – Major component of venous return in dynamic exercise. 3. Respiratory Pump – Major factor for venous return in upright exercise.
Negative thoracic pressure aids venous return to the heart.
Effect of preload on stroke volume
Starling’s Law of the Heart – The force of contraction is proportional to the initial resting length.
Starling Curves: EDV on x-axis and stroke volume on Y-axis. Determination of either LV end-diastolic pressure or pulmonary capillary wedge pressure (surrogate for left atrial pressure) occasionally substituted for EDV. With an increase in EDV (preload) there is an increase in stroke volume on the steeper portion of the curve. If the curve is shifted to the left, then there will be a greater increase in stroke volume for any EDV value. The Starling Curve has been found to be shifted to the left in athletes. (see Power Point presentation). In patients with chronic LV systolic dysfunction, the curve is shifted to the right and is flatter; therefore, there is less of a preload effect on stroke volume in these patients.
Effect of Enhanced Ventricular Contractility on stroke volume
Mechanisms of enhanced ventricular contractility enhances the stroke volume response to exercise. There are two main factors responsible for the enhanced contractility: increase in sympathetic nervous system activity and the Frank Starling Effect. Increases in sympathetic activity are caused by both direct innervation and elevation in circulating catecholamines (norepinephrine and epinephrine). According to the Frank Starling effect there is increased stretch of ventricular muscle fibers that leads to enhanced contractility.
Stroke Volume Response to Exercise
Stroke volume increases during exercise up to workloads 40-60% of maximal exercise and then stroke volume reaches a plateau with no further increases. In upright exercise in sedentary subjects the resting stroke volume (50-60 ml) doubles to values of 100-120 ml. In endurance athletes there is greater resting stroke volume (80-110 ml) with a doubling to values of 160-200 cc. In more elite athletes who either are genetically endowed or have trained for many years, stroke volume continues to increase throughout exercise. (see Power Point presentation). This change in stroke volume is responsible for the greater cardiac output responses in these subjects. The mechanism for this enhanced stroke volume response has been explained as an increase in EDV with enhanced Starling forces at lower levels of exercise and increased ventricular contractility at higher levels of exercise. During supine exercise, the resting stroke volume is greater than in the upright position. The stroke volume only increases 20-40% with supine exercise. Because of the increase in EDV with supine posture, there is less augmentation during exercise to reach similar values of stroke volume at maximal exercise.
Cardiac Output Response to Exercise
The increase in cardiac output during incremental exercise is proportional to the metabolic rate and VO2 required to perform the exercise. There is a linear relationship between cardiac output and % VO2 max. CARDINAL ROLE: It requires a 6 L/min in cardiac output for each 1 L/min increase in oxygen uptake beyond resting conditions. With upright exercise at workloads 50% maximum only increases in heart rate are responsible for the increase in cardiac output. The exception is elite athletes who increase their stroke volume throughout exercise. After age 30, maximal exercise cardiac output decreases in a linear fashion in both men and women, primarily due to the age related reduction in maximal HR (220-age). There is a large increase in cardiac output between rest and maximal exercise. The resting cardiac output is approximately 5 l/min in sedentary males and 4.5 l/min in sedentary females. The resting cardiac output is similar in trained athletes. However, in athletes there is a greater resting stroke volume with a lower resting heart rate (training- induced bradycardia). At maximal exercise there is a 4-5 fold increase in cardiac output. In sedentary persons the maximal cardiac output is approximately 22 l/min in males and 18 l/min in females. However the response is greater in trained persons and athletes. The maximal cardiac output is 34 l/min in trained males and 24 l/min in trained females. This represents a 6-7 fold increase compared to the 4-5 fold increase in sedentary persons. At maximal exercise trained persons have the same maximal heart rate as untrained persons but they have a greater stroke volume. Thus, maximal cardiac output depends on both body size, reflected in the gender differences, and the degree of exercise conditioning.
Relationship between blood flow, pressure, and resistance
Blood flow through the circulatory system depends on differences in pressure at two ends of the system. The rate of flow is proportional to the pressure difference. The aortic pressure is 100-120 mmHg while the pressure in the systemic veins and right atrium is
Major factors influencing blood flow during exercise
During exercise the increase in blood flow is accomplished by a decrease in vascular resistance and not an increase in blood pressure. Blood pressure is maintained by the increase in cardiac output. The vessel diameter is under dynamic control with the sympathetic nervous system controlling blood flow in both non-exercising and somewhat in exercising muscle beds. Single leg exercise requires > 50% of maximal blood flow. However, two-legged exercise does not result in a doubling of the blood flow seen with one-legged exercise; therefore, there is some increased resistance to control blood flow during exercise. The main determining factor of regulating blood flow in exercising muscle beds is autoregulation. This is a local blood flow regulation involving substances released locally at the time of exercise. Finally blood viscosity can theoretically affect blood flow and is related to RBC concentration. However, viscosity alone is not responsible for changes in blood flow. It’s the arterial oxygen content associated with either anemia (decreased viscosity) or polycythemia (increased viscosity) that is responsible for changes in muscle blood flow. In this fashion, oxygen delivery (blood flow x arterial oxygen content) is maintained at a homeostatic level.
Systemic Blood Pressure during Exercise
Mean arterial pressure (MAP) is the average blood pressure during a cardiac cycle. This is not an average of systolic and diastolic blood pressure as more time is spent in diastole. The formula for MAP is: MAP = diastolic BP + 0.33 (SBP-DBP) MAP determines the rate of blood flow through the systemic circuit. Systolic pressure is the pressure generated as blood is ejected from the left ventricle. This is the same as left ventricular systolic pressure in the absence of aortic valve obstruction.
Diastolic pressure is the pressure during ventricular relaxation and it reflects the compliance of the systemic vascular bed. The pulse pressure is the difference between systolic and diastolic pressure (SBP-DBP). During incremental exercise systolic blood pressure rises along with cardiac output and heart rate. There is little change in diastolic blood pressure. MAP increases due to the rise in systolic pressure.
Redistribution of Blood Flow During Exercise
At rest, skeletal muscle blood flow is 15-20% of total cardiac output, while during exercise muscle blood flow increases to 80-85%. This great increase in blood flow is accomplished by vasodilatation in the exercising muscle bed and vasoconstriction of non-exercising vascular beds with redirection of blood flow to exercising muscle. Splanchnic blood flow to the liver, kidneys, and intestines decreases in response to the increase in muscle blood flow as a function of % VO2 max. The blood flow to the brain is maintained during exercise. The absolute blood flow increases slightly during exercise as compared to rest. However, the % of total cardiac output decreases. At rest, the brain blood flow is 15% of the resting cardiac output (5l/min). During exercise brain blood flow is 3-4% of a cardiac output of 25 l/min.
Coronary Blood Flow during Exercise
Coronary blood flow increases during exercise in proportion to the increase in cardiac output. Myocardial oxygen consumption (MVO2) is also a reflection of increased cardiac work. The rate-pressure product (HR x SBP) is a good estimate of myocardial oxygen consumption. At rest the coronary venous O2 saturation is very low at 25%. This is much lower that the resting mixed venous O2 which is 65%. This indicates a high level of oxygen extraction by resting myocardium. During exercise the coronary O2 saturation decreases further and this along with the increased coronary blood flow provide adequate oxygen delivery to the heart during exercise. The coronary O2 saturation decreases from 25% to 10% with exercise. Only skeletal muscle and coronary blood flow increase during intense exercise. All other inactive vascular beds have decreased blood flow. In hot, humid conditions, skin blood flow also increases as a means to regulate temperature.
Regulation of Regional Blood Flow during Exercise in nonexercising muscle beds
Vasoconstriction occurs as a result of sympathetic nervous system activity. Vasoconstriction is regulated by muscle ergoreceptors and the cardiovascular control center in the medulla. The intensity of exercise and the # motor units recruited determine the need for muscle blood flow and the redirection of cardiac output from nonexercising vascular beds.
Regulation of Regional Blood Flow during Exercise in exercising muscle beds
Autoregulation occurs which results in vasodilatation: There is intrinsic metabolic control with various substances including
decreased PO2 , increased PCO2 , nitric oxide, [K+], acidosis, and adenosine; Regulation occurs at the arterioles and small artery level. Capillary Recruitment:
At rest, only 5-10% of capillaries in skeletal muscle are open; During exercise there is recruitment of nearly 100% of the capillaries in skeletal muscle. This increases the surface area for oxygen delivery and extraction.
Role of Sympathetic Activity on Exercising Skeletal Muscle Beds
Moderate to Heavy Exercise: 1. Sympatholysis – vasodilation and not constriction 2. MAP maintained by cardiac output and vasoconstriction in non-exercisingvascular beds.Very High Workloads: 1. Large amount of active muscle mass 2. Muscle vasodilation exceeds cardiac pump capacity 3. Sympathetic mediated vasoconstriction occurs in exercising vascular bedsto preserve MAP
Concept of Oxygen Delivery during Exercise
O2 delivery = blood flow x arterial O2 content.
Blood flow = cardiac output, muscle blood flow. Arterial O2 content = [Hgb] x 1.34 x O2 saturation (%). Aspects of blood oxygen: PaO2 (partial pressure, mmHg) – driving force of tissue oxygenation. Gradient of oxygen from arteriole – capillary – tissue – vein. CaO2 (content, ml/100ml) – bulk quantity of deliverable oxygen. SaO2 (content/capacity, %) – relative quantity of oxygen.
Approaches to Increase Oxygen Delivery during exercise
Exercise training – increases in blood flow (cardiac output and muscle blood flow) Blood Doping – increase in CaO2. Blood transfusion, erythropoietin injections, high altitude exposure
Peripheral Oxygen Extraction during Exercise
According to the Fick equation, changes in the arteriovenous oxygen content difference (a-v O2 difference) can also affect oxygen consumption. Fick Equation: VO2 = cardiac output x a-v O2. At rest the arterial oxygen content is 20 ml per 100 ml of blood while the venous oxygen content is 15-16 ml per 100 ml of blood. Then the a-v O2 difference at rest is around 5 ml O2 per 100 ml of blood. At high intensity exercise the arterial oxygen content is unchanged as it does not usually change with exercise. However, the venous oxygen content can drop as low as 5 ml O2 per 100 ml of blood. Thus, the a-v O2 difference is 15 ml O2 which represents a 3 fold increase over resting values.
Comparison of the two main components of the Fick equation during exercise
5 fold increase in cardiac output.
3 fold increase in a-v O2 . Thus, oxygen consumption during exercise is influenced more by cardiac output and blood flow than by oxygen extraction.
Factors leading to increased muscle oxygen extraction (Increase in a-v O2 difference)
Increase in skeletal muscle microcirculation with a high capillary/fiber ratio. This is the major factor in the decrease in venous O2 saturation with exercise. An increase in the aerobic activity of skeletal muscle. Increase in the size and number of mitochondria. Local vascular and metabolic improvements in skeletal muscle. An increase in arterial O2 content usually is not a factor.
Determinants of Myocardial Oxygen Supply
Oxygen content,
Coronary Blood Flow, which includes Coronary Perfusion Pressure and Coronary Vascular Resistance. Coronary vascular resistance depends on External compression
(Intramyocardial pressure: greatest in systole and Subendocardium more vulnerab) and Intrinsic regulation
(Local metabolites – adenosine vasodilates, Endothelial factors – NO, EDRF vs endothelin 1, and Neural innervation - alpha and Beta-2 receptors).
Determinants of myocardial oxygen demand
wall stress is determined La Place’s relationship. Wall stress= P*r/h. P=systolic ventricular pressure. R=radius of left ventricle. H=ventricular wall thickness. Heart rate: increased number of contractions= increased number of ATP. Contractility is caused by enhanced by sympathetic stimulation.
Increased in coronary blood flow
is the primary mechanism to meet increased myocardial oxygen demand.
Factors that decrease myocardial oxygen supply
hypotension (MAP
Factors that increase myocardial oxygen demand
exercise, fever, acute hypertension, emotional distress, cardiac disease (enlarged left ventricle), drugs.
Definition of myocardial ischemia
myocardial oxygen supply doesn’t equal myocardial oxygen demand.
Consequences of myocardial ischemia
angina (angina equivalents), electrical abnormalities (ST segment depression or arrhythmias), mechanical abnormalities (decrease in systolic function (stroke volume, SBP), decrease in diastolic function (PCWP), mitral regurgitation), hemodynamic abnormalities (increase in heart rate, BP (sympathetics)).
Severity of coronary stenosis determines when O2 supply decreases
at rest, need 905 stenosis to cause decrease in coronary blood flow. With exercise, coronary blood flow decreases with 70% stenosis. Exercise can be used to determine significant coronary stenosis. Clinical correlates include symptoms (chest pain), ECG changes (ST depression), abnormal wall motion (echo), and perfusion defect (nuclear scan).
Decrease in intracellular K in subendocardium
leads to negative deflection of ST segment (early repolarization).
Rate pressure product (RPP)
an index of myocardial O2 consumption. RPP is mostly influenced by chronotropic work (heart rate) but also by pressure and volume. RPP can determine deverity of coronary disease, effects of therapy that alter MVO2, and effects of therapy that alter myocardial oxygen supply.
Ischemic threshold
RPP where signs of myocardial ischemia occur. ST-segment marker of ischemia. Myocardial O2 supply is inadequate to meet O2 demand. Dependent on an inadequate to meet O2 demand. Ischemic threshold is dependent on an inadequate increase in coronary perfusion due to severity of coronary stenosis with fixed RPP (heart rate) or abnormal coronary vasomotion with variable RPP (heart rate).
Example of severe myocardial ischemic responses on exercise testing
decrease in stroke volume with systolic BP as surrogate, chronotropic incompetence= [peak exertional HR- rest HR]/[(220-age)-rest HR]. normal is equal or greater than 80%.
Benefits of exercise training in coronary disease
Improve aerobic capacity (peak VO2). Increase in peripheral O2 extraction. Possible increase in stroke volume. Decrease in sympathetic activity. Decrease in heart rate and BP at submaximal exercise. No change in total body VO2 at given workload. Decrease in myocardial VO2 at given workload
Effects of Exercise Training on Coronary Physiology in Coronary Disease
Exercise training delays time to ischemia. Same RPP but at a higher total body VO2 (workload). Submaximal exercise after training is at a lower percent of peak VO2 with a lower heart rate and blood pressure (RPP). No effect of training on coronary blood flow related to MVO2. Minimal increase in myocardial O2 extraction. Decrease in coronary blood flow at constant exercise load after training dueto lower % peak total body VO2.Exercise training can later ischemic threshold in coronary disease: Uncommon result of exercise training;
High RPP where signs of ischemic occur;
Increase in myocardial perfusion by nuclear methods; Less vasoconstriction with exercise
Potential Mechanisms of Improved Myocardial Perfusion with Exercise Training
Correction of endothelial dysfunction; Regression of coronary; atherosclerosis; Formation of collaterals; Promotion of vasculogenesis by bone-marrow derived stem cells
Application of cardiopulmonary exercise testing in cardiac patients
- Cardiopulmonary exercise test is the standard exercise evaluation (ECG, HR, BP). Expired gas analysis (metabolic cart) can give you VO2 and VCO2. Can also calculate ventilation (Ve) and other derived parameters such as aerobic threshold and respiratory exchange rate. Measuring this ratio can be used for estimating the respiratory quotient (RQ), an indicator of which fuel (carbohydrate or fat) is being metabolized to supply the body with energy. 2. VO2, oxygen consumption, is directly related to workload and energy requirement during aerobic exercise. There is a linear increase through mild through intense exercise. VO2 max is the plateau of VO2 despite continued work and is an indicator of aerobic capacity. It is a quantitative measure of person’s capacity for aerobic ATP resynthesis. VO2 increases with workload until a plateau is reached where further increases in workload do not result in an increase in VO2. This has been designated as VO2 max and is the ultimate descriptor of exercise capacity. Since many people, especially those with cardiovascular disease are unable to attain a plateau, the highest attainable VO2 has been called the “peak VO2”. Fick Equation is the link between the cardiovascular function and respiratory measurements (VO2)
Fick equation
VO2= cardiac output* (CaO2-CmvO2). Cardiac output is blood flow (L/min). CaO2= [Hgb * 1.36 * O2 saturation (%). CmO2= [Hgb] * 1.36 * venous O2 saturation (%).
Rearrangement of the Fick Equation (cardiac centric)
Cardiac Output = VO2 / CaO2- CMVO2. Cardiac Output * a-v O2 = VO2.
Cardiac Output = heart rate * stroke volume. Ca or VO2 = [Hgb] * 1.36 * O2 saturation (%)
Use of cardiopulmonary exercise testing in chronic systolic heart failure
accurate assessment of functional limitation. LVEF alone not a good indicator of severity of disease. It is a predictor of prognosis in severe heart failure, assessment of response to medical or device therapy, and pre-transplantation evaluation.
Hemodynamics of left ventricular systolic dysfunction (decrease in LVEF)
rest hemodynamics: increase in heart rate, decrease in stroke volume, normal or decreased cardiac output, and dilated ventricle. The dilated ventricle leads to increase end diastolic volume, increased end- systolic volume, decreased LV ejection fraction (LVEF), increased preload (high filling pressures), and increased afterload (increased systemic vascular resistance). Exercise hemodynamics: limited cardiac output increase leading to limited stroke colume response, limited heart rate response, and increased HR reserve (peak HR- rest HR). high cardiac filling pressures causing dyspnea. Limited vasodilation in exercise muscle beds leading to high sympathetic tone may override vasodilation in exercising muscle beds and deconditioning and low muscle blood flow reduces oxidative capacity of skeletal muscle
Peak VO2
Exercise capacity can be quantitated clinically by measurement of oxygen uptake (Vo2), carbon dioxide production (Vco2), and minute ventilation, Peak VO2 is more closely relate to the cardiac output response and not oxygen extraction in patients with LV systolic dysfunction. Patients classification by ranges of peak VO2 related to differences in the cardiac output response to exercise. Peak VO2 is used in patients with LV systolic function as an indicator of prognosis and serves as one criteria for cardiac transplantation candidacy. Exercise training in coronary disease patients improves total body exercise capacity (pk VO2) but usually does not improve myocardial blood flow.
