Cardiac Resynchronization Therapy in Patients with Right Heart Failure Resulting from Pulmonary Arterial Hypertension

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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.

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.

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. 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. 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. 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.

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.

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.

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.

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.

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. 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.

Comments

After ablation of the atrioventricular node the patient had a period of symptomatic improvement before experiencing the current clinical deterioration. This observation raises the question of which factor(s) produced the initial improvement and why such improvement was not sustained beyond 12 months. With right ventricular pressure overload, which in this patient’s case is due to pulmonary arterial hypertension, leftward bowing of the interventricular septum during diastole causes decreased left ventricular filling, chamber size, compliance, and contractility. Atrial fibrillation with rapid ventricular response further compromises left ventricular filling, thus increasing left cardiac filling pressure and decreasing forward cardiac output. This hemodynamic deterioration is the likely culprit of the worsening heart failure symptoms experienced by the patient. It is plausible that the clinical improvement occurring immediately after atrioventricular node ablation resulted from improvement in left ventricular filling permitted by slower heart rates.

It is more difficult to explain why the clinical improvement occurring after atrioventricular node ablation persisted for almost 12 months. A recent study demonstrated that right ventricular pressure overload results in both myocardial and electrical remodeling. The effects of the latter—conduction slowing and action potential prolongation—contribute to the lengthening of right ventricular contraction duration and marked delay in right ventricular peak myocardial shortening and, consequently, in the onset of diastolic relaxation in contrast to the septum and the left ventricle. This interventricular mechanical dyssynchrony decreases left ventricular filling and stroke volume. Therefore left ventricular dysfunction, initially caused by left ventricular compression by the diastolic bowing of the septum, is maintained and amplified by low left ventricular preload and underfilling. It has been suggested that in patients with right ventricular pressure overload the interventricular delay in systolic contraction and diastolic relaxation may be improved with preexcitation of the right ventricle with right ventricular pacing. Therefore it is possible that the clinical improvement occurring in the patient after atrioventricular node ablation can be explained by the fact that, for a time, right ventricular pacing may have decreased diastolic interventricular delay and improved left ventricular filling and stroke volume.

After an extended period of relative clinical stability, the patient experienced a decline in functional capacity and worsening signs and symptoms of congestion. This clinical deterioration may be due to the detrimental effects of prolonged right ventricular apical pacing on cardiac structure and left ventricular function. This may be related to the abnormal electrical and mechanical activation pattern of the ventricles caused by right ventricular apical pacing. Several large, randomized clinical trials of pacing mode selection have suggested an association between a high percentage of right ventricular apical pacing and worse clinical outcomes. Pertinent to this case is the fact that the negative effects of apical right ventricular pacing may be more pronounced in patients with underlying conduction disease and those who underwent atrioventricular node ablation.

Comments

The patient’s physical examination findings are consistent with a “wet and cold” hemodynamic profile, in which a low cardiac output, suggested by a low systolic blood pressure, is associated with signs of fluid overload, manifested by an elevated jugular venous pressure, enlarged liver, and marked peripheral edema.

The right ventricular lift and the increased pulmonary component of the second heart sounds (S ₂ ) are consistent with marked right ventricular enlargement and dysfunction and with severe pulmonary arterial hypertension.

Comments

The elevated blood urea nitrogen/creatinine ratio is a manifestation of the effects of an elevated central venous pressure on renal function. As explained earlier, an increase in central venous pressure produces a reduction in renal blood flow. The renal reabsorption of urea increases with decreasing renal blood flow. Therefore in this patient the elevation of blood urea nitrogen is due to increased renal reabsorption of urea resulting from the decrease in renal blood flow produced by the elevated central venous pressure.

The patient’s serum potassium level is in the upper limits of normal as a result of the use of the potassium-sparing diuretic spironolactone in a patient with significant renal dysfunction.

According to the Modified Diet in Renal Disease (MDRD) equation, the patient’s estimated glomerular filtration rate is 40 mL/min/1.73 m ² , consistent with moderate reduction in renal function. North American and European practice guidelines for the treatment of heart failure in adults include specific recommendations for the monitoring, prevention, and treatment of hyperkalemia in patients receiving aldosterone antagonists.