1. Define and classify severity of pulmonary arterial hypertension (PAH).

2. Explain the pathophysiology of PAH.

3. Identify patients with PAH who may benefit from advanced medical therapy.

4. List indications for implantable cardioverter defibrillators as prophylaxis for sudden cardiac death.

5. Describe benefits of cardiac resynchronization therapy in the treatment of CHF.

Pulmonary Hypertension and the Primary Care Physician
William E. Hopkins, MD, Associate Professor of Medicine, Division of Cardiology, University of Vermont College of Medicine, and Director, Pulmonary Hypertension Program, Fletcher Allen Health Care, Burlington, VT

Common misconceptions about pulmonary hypertension (PH): “I don’t see any patients with PH”; no treatment for PH available; all patients with PH can and should be treated with advanced therapy; calcium channel blockers main-line therapy for PH

Case presentation: woman, 52 yr of age, with exertional dyspnea and fatigue; diagnosed with severe PH after comprehensive evaluation; right ventricle (RV) slightly dilated and dysfunctional; invasive hemodynamic assessment—slightly elevated right atrial pressure consistent with RV failure; pulmonary artery (PA) pressure highly elevated (107/41 mm Hg; mean, 64 mm Hg); left-sided pressures normal; cardiac output reduced; pulmonary vascular resistance markedly elevated; woman developed systemic hypotension on “vasodilator challenge”; if untreated, “what you’ve done is given her a death sentence”

Normal pulmonary circulation: resistance low (one-fifteenth of normal systemic vascular resistance); accommodating; no autoregulation in pulmonary bed based on metabolism; autoregulates by matching between ventilation and perfusion (V/Q; as in, eg, pneumonia); receives 100% of cardiac output; as flow increases, little increase in PA pressure; normal PA pressure, 25/10 mm Hg (mean, ≈15 mm Hg); normal left atrial (LA) pressure, 4 to 12 mm Hg; transpulmonary gradient (difference between mean PA pressure and mean LA pressure) should be ≤10 mm Hg

Pulmonary hypertension: mean PA pressure >25 mm Hg at rest; PA systolic pressure >35 mm Hg at rest; pulmonary arterial hypertension (PAH)—mean PA pressure >25 mm Hg, with normal left-heart pressures (pulmonary capillary wedge pressure <15 mm Hg), and pulmonary vascular resistance >3 Wood units; can be explained to patients as “high blood pressure (BP) of blood vessels of lungs” (explain difference between BP in lungs and BP in body); patient complaints—shortness of breath (due to decreased cardiac output); fatigue; edema; syncope; chest pain

World Health Organization (WHO) classification: group I—disease of small arteries of lungs; idiopathic; group II—left-heart disease; group III—parenchymal lung disease; hypoxia; sleep apnea; group IV—thromboembolic disease; group V—miscellaneous; classification important (medications approved for patients in group I may be harmful to patients in groups II or III); ≈75% of patients in groups I or II

WHO group I PAH: idiopathic or familial disease (autosomal dominant); may be associated with collagen vascular disease (eg, scleroderma), congenital heart disease, liver disease, HIV infection, drugs and toxins (eg, dexfenfluramine [Redux; withdrawn]), sickle cell disease, splenectomy, and myeloproliferative disorders; “pathology all looks the same”; disease of small arteries; response rate to medications similar; in patients with symptomatic primary or idiopathic PH, 3- yr mortality ≈50% (higher if systemic illness associated with PH); no significant improvement in long-term survival with transplantation

Pathophysiology: death primarily due to RV failure or complications related to primary disease (eg, liver disease); as right atrial pressure increases (RV failure increases; cardiac output decreases), mortality increases; if right atrial pressure reaches 20 mm Hg, 3- to 6- mo mortality ≈100%; calcium channel blockers may be harmful to patients with PH (beneficial to small percentage of patients; perform invasive evaluation and follow-up invasive evaluation to prove benefit); PH not exclusively caused by vasoconstriction; PH problem of proliferation (treatment must affect remodeling); pathways—1) decreased nitric oxide (NO; most potent vasodilator in body) in lungs; 2) decreased prostacyclin (prostaglandin I2 [PGI2 ]; potent vasodilator); NO and prostacyclin also prevent proliferation; 3) increased endothelin (potent vasoconstrictor); promotes cell division; results in persistently constricted vessels and cell proliferation

Advanced medical therapy: prostanoids—epoprostenol (eg, Flolan; synthetic prostacyclin); treprostinil (Remodulin); iloprost (Ventavis); constant intravenous (IV) infusions of epoprostenol for >8 yr shown beneficial for seriously ill patients; endothelin receptor antagonists (ERAs)—oral medications; bosentan (Tracleer); ambrisentan (Letairis); NO enhancers or phosphodiesterase type 5 (PDE-5) inhibitors—sildenafil (Revatio [reformulated and repackaged version of Viagra for treatment of PH] ); drugs distributed by national pharmaceutical chains; high cost of treatment—Flolan and Remodulin, $100,000 to $200,000/yr; inhaled Ventavis (taken ≈9 times daily), ≥$100,000/yr; oral Tracleer (bid) and oral Letairis (taken once daily), $35,000/yr; sildenafil (tid), $1000/mo; appropriate paperwork required for reimbursement; sildenafil—increases intracellular response to NO, resulting in antiproliferative and vasodilatory action; due to presence of phosphodiesterase in retina, side effects may include loss of ability to visually discriminate blue and green colors; effects of drugs—improved functional status (shown by 6-min walk test); delayed clinical worsening; minimal data appear to indicate improved survival; improved hemodynamics; advanced medications approved by Food and Drug Administration (FDA) for patients in New York Heart Association (NYHA) functional class II, III, or IV with WHO group I PAH

WHO group II PAH: elevated LA pressure associated with, eg, left-heart disease, mitral valve disease (eg, mitral valve prolapse, mitral regurgitation, mitral stenosis), aortic stenosis, myocardial infarction (MI), or primary cardiomyopathy; as LA pressure increases, pulmonary venous pressure and capillary pressure increase (can lead to pulmonary edema due to increase in PA pressure (if PA pressure did not increase in proportion to LA pressure, blood would flow backwards); body compensates by enhancing lymphatics for faster fluid removal; inflow into pulmonary capillaries decreased by vasoconstriction of PAs (can lead to remodeling of vessels); use of prostanoid, ERA, or PDE-5 inhibitor in patient with elevated LA pressure and PH may lead to pulmonary edema; increase in pulmonary vascular resistance temporary protective mechanism in patients with left-heart problems, but not long-term

Obesity and PH: patients develop restrictive cardiomyopathy; left and right ventricles become stiff, leading to shortness of breath; sildenafil not “magic pill”; improves with exercise, weight loss, and treatment of sleep apnea

Group III PAH: lung disease; use of vasodilators may enhance V/Q mismatch; drugs may increase flow (in patients with, eg, parenchymal lung disease) to nonventilated segment and decrease O2 level; may be reasonable to treat patients, but be aware of potential harm; full evaluation required

Group IV PAH: pulmonary emboli should be considered in all patients with PH

Device-based Therapy in Prevention of Sudden Death and Treatment of CHF
Daniel L. Lustgarten, MD, PhD, Assistant Professor of Medicine, Division of Cardiology, University of Vermont College of Medicine, and Cardiologist, Fletcher Allen Health Care, Burlington

Sudden cardiac death: overall incidence <1%; risk—5% with previous coronary event; >20% with ejection fraction (EF) <30%; high incidence in patients with history of out-of-hospital cardiac arrest; during electrophysiology (EP) study, if ventricular tachycardia (VT) can be readily induced and cannot be suppressed with drug, annual risk >30%; ≈300,000 cases/yr in United States

Implantable cardioverter defibrillators (ICDs) for prevention: studies show ≥30% reduction in mortality associated with use of ICD therapy in patients who had survived sudden cardiac death; small trials looking at highest risk subgroup (ie, patients inducible for VT and nonsuppressible with antiarrhythmic drug therapy) demonstrated statistically significant increase in longevity and decrease in mortality associated with use of ICD therapy; ICD indicated for ≈50% of patients (patients usually have underlying coronary artery disease [CAD] and manifest first episode with thrombotic event in coronary artery); indications for primary prophylaxis—EF ≤35%; congestive heart failure (CHF) symptoms; ischemic basis for cardiomyopathy; no recent (≤40 days) MI or recent (3 mo) revascularization; if cardiomyopathy nonischemic, duration must be ≥3 mo; high-risk hereditary diseases (eg, prolonged QT syndrome, hypertrophic cardiomyopathy, short QT syndrome, Brugada syndrome); indications for secondary prophylaxis—sudden cardiac arrest survivor with no reversible cause and reasonable life expectancy after event; concerning patients who do not meet criteria—eg, patient 40 to 50 yr of age with acute MI after revascularization and drug therapy and EF ≈40%; patients at increased risk for sudden cardiac arrest, but risk not demonstrated to benefit from prophylactic ICD therapy; refer to cardiologist for further risk stratification

CHF and death: most patients with NYHA class II CHF die from sudden cardiac death; as CHF symptoms worsen, likelihood of death due to pump failure increases (likelihood of death due to sudden cardiac death decreases); ICD therapy particularly warranted in patients with less severe CHF

Counseling patients about ICD therapy: not all patients who meet criteria receive ICD; offer ICD as “insurance policy” against sudden cardiac death; determine whether ICD appropriate for patient; dissuade patient from notion of “this will make me feel better”; allow patient to make personal choice about ICD therapy

Devices in management of CHF: devices detect CHF episodes; devices can perform daily measurements of transthoracic fluid and track them over time; other devices can directly measure intracardiac pressure (measurements can be monitored and assessed to determine whether more or less medication needed); handheld personal digital assistant (PDA) device can provide patient with recommendations (eg, “avoid exertion”); impedance measurement device—decrease in impedance can be tracked and reported; device can trigger alarm, but use of alarm currently not approved in United States; many devices transmit information via Internet; benefits of devices individually variable

Devices in treatment of CHF: pathogenesis of CHF—myocardial insult leads to dysfunction of heart muscle, reduced system perfusion, activation of sympathetic nervous system and renin-angiotensin-aldosterone system, altered gene expression, apoptosis, and fibrotic remodeling of cardiac tissue (reflects further myocardial insult); devices attempt to intercede between myocardial insult and at level of myocardial dysfunction by improving filling dynamics through pacing of heart

Cardiac resynchronization therapy (CRT): use of electrical pacing to optimize ventricular filling and contraction in patients with CHF and dyssynchrony; dyssynchrony—alteration of normal sequential activation and coordinated pumping of heart chambers, leading to compromise in cardiac output; therapeutic targets—failing heart with dyscoordinate contraction (frequently associated with left bundle branch block [BBB; electrical impulse passes through atrioventricular node and His bundle system to right bundle system, but is blocked through left bundle system; results in eccentric activation of left ventricle {LV}, due to slow electrical spread through ventricular tissue]); biventricular pacing—placement of pacing leads in RV (and right atrium if warranted) and along vein in back of heart (with lateral extensions to LV); pacing leads can be timed to activate at similar times, leading to resynchronization of LV in respect to activation of RV

Consequences of dyssynchrony: when septum contracts earlier than lateral wall, septum pushes against lateral wall, resulting in early activation and increased pressure on septum; stroke volume decreases, resulting in decreased cardiac output; late activation of lateral wall to LV results in mitral regurgitation; increased wall stress results in myocardial ischemia

Lead placement: objective to insert lead in coronary sinus; wire passed through subselecting sheath into vein, allowing lead to be advanced over wire into vein; 2 leads can provide simultaneous activation of right and left ventricles; since venous anatomy highly variable, lead placement challenging; pacing of phrenic nerve along lateral wall of LV can be problematic; generally, lateral wall target for placement; lateral chest x-ray can be used to determine whether lead properly placed (lead should be directly behind heart); results in mixed right and left BBB morphology on ECG

Candidates for CRT: patients on optimized pharmacologic therapy with refractory CHF; patients with BBB (usually left) with fairly wide QRS complex most likely to respond; patients may respond if EF 30% to 40%

Effects of CRT: compensates abnormal electrical conduction that causes mechanical dysfunction; acute responses include increased LV pressure, aortic pressure, and contractility; statistically significant improvement in quality of life; at 6 mo, significant decrease in NYHA category from class III to class II; also at 6 mo, marked decrease in LV end-diastolic diameter (potential for reversal of remodeling) in patients with biventricular pacing, compared to control group; mortality—study saw statistically significant prolonged reduction in death or hospitalization for CHF if ICD present (at 3 yr, confluence between optimal medical management and CRT-alone groups seen); statistically significant benefit in secondary end point of all-cause mortality with ICD and CRT and with CRT alone; trial concluded biventricular pacing had significant benefits for patients, and addition of ICD further reduced mortality; in patients with CHF with interventricular conduction delay, CRT can have clinical benefit, especially with ICD; Cardiac Resynchronization Heart Failure Study (CARE-HF)—800 patients classified as NYHA class III or class IV, and with EF <35% and stringently defined dyssynchrony randomized to optimal medical therapy or biventricular pacing (without defibrillator); end points composite of hospitalization for cardiovascular event or all-cause mortality; found statistically significant decrease in mortality and hospitalization associated with CRT; all-cause mortality reduced by 36% with CRT alone, consistent with benefits demonstrated for β-blocker and angiotensin-converting enzyme inhibitor therapy in similar population; showed systolic BP, LV EF, LV end-systolic volume, mitral regurgitation, and B-type natriuretic peptide (BNP) levels improved at 3- and 18-mo follow-up; concluded CRT alone substantially reduced risk for complications and death in patients with moderate or severe heart failure owing to LV systolic dysfunction and cardiac dyssynchrony; significant evidence of progressive reverse remodeling in response to CRT; overall response rate—70%; ≈30% of patients with BBB do not have mechanical dyssynchrony (associated with extent and homogeneity of level of myopathy); response may be lower with suboptimal lead placement or suboptimal programming of ICD

Indications for biventricular pacing: moderate to severe CHF; dyssynchrony as evidenced by BBB; dependence on ventricular pacing—Dual Chamber and VVI Implantable Defibrillator (DAVID) trial saw no statistical difference between patients who received ICDs programmed to backup ventricular pacing (VVI) and those who received ICDs programmed to dual-chamber pacing; trend to increased mortality associated with dual-chamber devices, and this correlated to extent of ventricular pacing

Conclusion: ICDs should be considered and discussed with patients with persistent EF ≤35%; in patients with RV pacing, risk of developing or exacerbating CHF can be avoided