History
In 1985 this previously healthy patient had a syncopal episode while driving. Presumably she was found to have high-degree atrioventricular block that was treated with implantation of a permanent dual-chamber pacemaker. Except for the diagnosis of moderate chronic obstructive pulmonary disease, the patient’s clinical course was uneventful until 2006, when she was hospitalized for acutely decompensated heart failure. During this hospitalization she underwent coronary angiography, which demonstrated the absence of coronary artery disease, and right heart catheterization, which demonstrated the following intracardiac pressures: right atrial, 18 mm Hg; pulmonary arterial, 88/34/53 mm Hg; and pulmonary artery wedge pressure, 25 mm Hg. Cardiac output was not measured, and hemodynamic response to vasodilators was not evaluated. Sildenafil was initiated at a twice daily dose of 50 mg.
Early in 2008 the patient required admission to the hospital for progressive exertional dyspnea, with more than 5 kg weight gain, increased jugular venous pressure, and anasarca. Admission weight was 117 kg, and renal function was severely compromised (blood urea nitrogen, 78 mg/dL; serum creatinine, 2.7 mg/dL). Transthoracic echocardiogram revealed mild left ventricular systolic dysfunction, mild-to-moderate mitral regurgitation into an enlarged left atrium, a markedly enlarged and hypokinetic right ventricle, severe tricuspid regurgitation into an enlarged right atrium, and an estimated pulmonary artery systolic pressure of greater than 65 mm Hg. To determine the appropriate therapy, hemodynamics were measured at baseline and after administration of excalating doses of inhaled nitric oxide (Table 5-1).
Based on these findings indicative of severe fluid overload, isolated venovenous ultrafiltration was initiated at a rate of 100 mL/hr and continued for 5 days. Weight and renal function changes observed with extracorporeal fluid removal were as shown in Table 5-2.
Before discharge the patient was placed on oxygen by nasal cannula at 2 L/min and on nightly bilevel positive airways pressure (BiPAP). The sildenafil dose was 20 mg three times daily, the endothelin receptor antagonist bosentan was initiated at a dose of 125 mg orally twice daily. At the follow-up office visit the patient reported improvement in exertional dyspnea and physical examination revealed a decrease in jugular venous pressure to 8 cm H2O, absence of pulmonary crackles, and minimal lower extremity edema.
The patient continued to improve until July 2009, when she reported increasing fatigue and was found to have atrial fibrillation. With the initiation of amiodarone, sinus rhythm was spontaneously restored. In March 2010, because of malfunction and generator battery depletion of the existing pacemaker, the patient underwent implantation of a dual-chamber permanent pacemaker and placement of two new right atrial and ventricular leads. Three months after implantation of the device, atrial fibrillation recurred, but at controlled ventricular rates of approximately 75 bpm, and sinus rhythm was restored with electrical cardioversion. Atrial fibrillation recurred in October 2010, and sinus rhythm was once again restored with electrical cardioversion. Yet another recurrence of atrial fibrillation was refractory to electrical cardioversion; over the subsequent 3 months, ventricular rates increased from 110 to 120 bpm. Over the ensuing weeks the patient experienced worsening exertional dyspnea and peripheral edema, which became increasingly more difficult to control despite frequent intensification of diuretic therapy. Early in December 2010 the patient underwent ablation of the atrioventricular node, which was associated with improvement in the signs and symptoms of congestion lasting until the end of 2011. Early in 2012 the patient began to experience worsening exertional dyspnea, weight gain, fatigue, and peripheral edema despite frequent adjustments of diuretic therapy.
TABLE 5-1
Hemodynamic Values at Baseline and after Administration of Inhaled Nitric Oxide
| Hemodynamics | Baseline | NO to 80 ppm |
| BP (mm Hg) | 93/61 | 71/46 |
| RA (mm Hg) | 21 | 18 |
| PA (mm Hg) | 71/26/45 | 63/21/42 |
| PAWP (mm Hg) | 12 | 16 |
| TPG (mm Hg) | 33 | 26 |
| CO (L/min), Fick | 5.2 | 6.1 |
| CI (L/min/m2), Fick | 2.5 | 2.9 |
| PVR (Wood units) | 6.4 | 4.3 |
| PVRI (Wood units/m2) | 13.2 | 9.0 |
BP, Arterial blood pressure; CI, Cardiac index; CO, cardiac output; NO, nitric oxide; PA, pulmonary arterial pressure; PPM, parts per million; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; PVRI, pulmonary vascular resistance index; RA, right atrial pressure; TPG, transpulmonary gradient.
TABLE 5-2
Weight and Renal Function Changes Observed with Extracorporeal Fluid Removal
| Factors Measured | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 |
| Weight (kg) | 117 | 114.5 | 112 | 109 | 104 |
| Blood urea nitrogen (mg/dL) | 78 | 60 | 45 | 40 | 34 |
| Serum creatinine (mg/dL) | 2.7 | 2.4 | 2.0 | 1.4 | 1.1 |
Comments
The patient had true pulmonary arterial hypertension as demonstrated by the coexistence of the three hemodynamic variables that define this disease entity: a mean pulmonary arterial pressure greater than 25 mm Hg at rest, pulmonary artery wedge pressure less than 15 mm Hg, and pulmonary vascular resistance greater than 3 Wood units. The cause of pulmonary arterial hypertension in this patient is unknown, but factors such as obesity, obstructive sleep apnea, and thyroid disease have been shown to contribute to its severity.8
Notably, after the first right heart catheterization, the phosphodiesterase inhibitor sildenafil was initiated without knowledge of the patient’s pulmonary vascular resistance or hemodynamic response to vasodilator administration. Practice guidelines recommend that drugs specific for pulmonary arterial hypertension be initiated only after a complete hemodynamic evaluation to avoid potentially deleterious effects in patients with pulmonary arterial hypertension secondary to left heart disease.8
In this patient, severe pulmonary arterial hypertension is the principal cause of right ventricular dysfunction manifested by the physical findings of venous congestion and peripheral edema, the elevated right atrial pressure, and echocardiographic evidence of right ventricular enlargement and decreased systolic function.8 Recent studies demonstrated that increased central venous pressure is a key determinant of worsening renal function because transmission of the elevated venous pressure to the renal veins further impairs the glomerular filtration rate by reducing net filtration pressure. On hospital admission the patient had severe renal impairment, which improved with extracorporeal fluid removal.1 Loop diuretics, the most commonly used medications to reduce congestion, block sodium chloride uptake in the macula densa, independent of any effect on sodium and water balance, thereby stimulating the renin-angiotensin-aldosterone system. This pathophysiology and the growing literature documenting the adverse consequences of diuretic use on acute heart failure outcomes has led to exploration of other approaches.1 Fluid removal by ultrafiltration at a rate that does not exceed the interstitial fluid mobilization rate of 14 to 15 mL/min avoids further activation of the renin-angiotensin-aldosterone system. Moreover, for the same fluid volume, more sodium is removed by isotonic ultrafiltration than by diuretic-induced hypotonic diuresis. In this patient, venovenous ultrafiltration was associated with a progressive reduction in weight and improvement in renal function.2
After approximately 12 months of clinical stability, the patient’s disease progression accelerated, as suggested by the increasing burden of atrial fibrillation. In addition, because the patient has right ventricular dysfunction, she tolerates rapid ventricular rates especially poorly. As in this patient, atrial fibrillation occurs in the majority of individuals in the setting of structural heart disease. Changes in metabolic, mechanical, neurohormonal, and inflammatory factors associated with heart failure contribute to the development of atrial fibrillation. However the mechanisms linking these factors to the development of the substrate for atrial fibrillation and its progression from paroxysmal to permanent are not completely understood. A recent Euro Heart Survey analysis documented that paroxysmal atrial fibrillation progressed to persistent forms in 178 of 1219 (15%) patients. On multivariable analysis, hypertension, age older than 75 years, previous transient ischemic attack, chronic obstructive pulmonary disease, and heart failure independently predicted progression of atrial fibrillation from paroxismal to persistent. Using the regression coefficient as a benchmark, the investigators developed a score to predict the risk for atrial fibrillation progression. Based on the presence of heart failure (2 points), history of chronic obstructive pulmonary disease (1 point), and age older than 75 years, the patient had a score of 4, indicative of moderate-to-high risk for progression from paroxysmal to persistent atrial fibrillation.3
The patient tolerates rapid ventricular rates poorly. This is typical of patients with right ventricular failure. In normal individuals, 85% of the blood volume is stored in the venous circulation and 15% in the arterial circulation. Patients with right ventricular failure have a larger proportion of the blood volume stored in the venovenous circulation, which renders them especially susceptible to intraarterial volume depletion. This risk is further accentuated if conditions such as atrial fibrillation with rapid ventricular response further compromise filling of the left ventricle.3
Current Medications
The patient’s current medications are torsemide 60 mg twice daily, hydrochlorothiazide 25 mg once daily 30 to 60 minutes before taking the torsemide, spironolactone 50 mg in the morning and 25 mg in the evening 30 to 60 minutes before taking the torsemide, potassium chloride 30 mEq daily, sildenafil 20 mg three times daily, bosentan 125 mg twice daily, warfarin 7.5 mg daily, aspirin 81 mg daily, levothyroxine 75 mcg daily, omeprazole 20 mg daily, and fluticasone-salmeterol 250/50 mcg, one inhalation twice daily.
Comments
The loop diuretic used in this patient is torsemide. It is preferred over furosemide because it has better oral bioavailability (unpredictable for furosemide, 100% for torsemide) and longer half-life (2.5 vs. 6.5 hours), which reduces the length of time of postdiuretic renal sodium retention. With chronic loop diuretic therapy the distal tubular cells adapt to reabsorb sodium more efficiently, thus reducing the natriuresis produced by loop diuretics. Because thiazide diuretics and aldosterone antagonists have a longer half-life than loop diuretics, the patient was instructed to take these medications before the loop diuretic to mitigate the effects of distal tubular adaptation to loop diuretics and thus maintain the effectiveness of torsemide.4
The patient’s therapy for pulmonary arterial hypertension included the phosphodiesterase inhibitor sildenafil and the nonselective endothelin antagonist bosentan. The presence of severe right ventricular failure warrants consideration of the addition of a prostacyclin preparation. This was not used in this patient because of concerns that this type of medication may increase intrapulmonary shunting when left ventricular systolic function is below normal and left cardiac filling pressures rise in response to inhaled nitric oxide.8
Therapy also did not include antiarrhythmic agents. The authors of the Euro Heart Survey analysis found that use of antiarrhythmic agents did not prevent progression of atrial fibrillation in high-risk patients and suggested that in these patients therapy should be aimed at controlling heart rate rather than rhythm.2 In this patient a rate control agent, such as diltiazem, was not used because its negative inotropic action could worsen the systolic function of the already compromised right ventricle and increase fluid retention.8
Current Symptoms
The patient’s current symptoms are dyspnea with minimal exertion, 5.4 kg weight gain, fatigue, increased oxygen requirements.
