Outflow Tract Obstruction: Prevalence, Clinical Importance, and Target for Therapy

When categorizing patients with HCM, three distinct hemodynamic groups of patients should be distinguished: those with resting outflow tract obstruction (obstructive), those with provocable gradients but no obstruction at rest (latent obstruction), and those with no gradient either at rest or on provocation (nonobstructive).

Resting LVOTO (LVOT gradient ≥ 30 mm Hg) is present in about 25% to 30% of patients with HCM. However, a multicenter study using stress echocardiography identified that with exercise, provocable outflow tract gradients are present in up to 70% of patients with HCM. LVOTO is associated with a higher risk for progressive heart failure and cardiovascular death, likely because of chronic elevations in LV intracavitary pressure and wall stress. Available data on the prevalence and effect of LVOTO on clinical outcomes come mainly from a large consecutive series of 1,101 patients with HCM followed for an average of 6 years. In this study, 25% of patients had evidence of resting LVOTO (defined as a gradient ≥ 30 mm Hg). The presence of resting obstruction was associated not only with a higher probability of death due to HCM (the probability of sudden cardiac death was greater in obstructive than nonobstructive patients, although the overall annual sudden death rate in the cohort was low) but also with progression to severe New York Heart Association class III and IV symptoms or death secondary to heart failure or stroke. It is well documented that the prognosis for patients with obstructive HCM is poorer than for those without, especially in the presence of severe symptoms. Disease consequences related to the presence of chronic outflow tract gradients (increased wall stress, myocardial ischemia, and eventual cell death and replacement fibrosis) justify interventions to relieve obstruction in those patients with limiting symptoms despite maximally tolerated medical therapy.

Initial treatment of symptomatic patients with LVOTO is pharmacologic, with β-blockade and, if necessary, the addition of disopyramide or verapamil. The negative inotropic effects of this combination are usually effective at reducing the gradient and symptoms if adequate doses of medications can be maintained. The current American College of Cardiology and European Society of Cardiology expert consensus recommendations suggest invasive septal reduction strategies in those patients who remain symptomatic despite maximal medical therapy. Both septal myectomy and alcohol septal ablation are now established therapies to relieve obstruction, with a recent meta-analysis demonstrating comparable improvements in New York Heart Association class and similar in-hospital mortality. Surgical myectomy remains the primary treatment for patients with medically refractory obstructive HCM, and at experienced centers, perioperative mortality rates during the past decade have been <2% (approximately 1% at high-volume centers). Despite the positive predictive value of LVOTO as a risk factor for sudden cardiac death being only 7%, McLeod et al. demonstrated that in those patients undergoing septal myectomy, there was a significantly lower rate of appropriate implantable cardioverter-defibrillator interventions compared with a nonoperated group with obstructive HCM (0.24% per year vs 4.3% per year). Alcohol septal ablation is an effective alternative for the amelioration of outflow tract obstruction, but mortality is no lower than with surgery, the risk for procedure-related complete heart block is higher, time to benefit is longer, and there have been concerns raised about the long-term risk for ventricular tachyarrhythmia and ongoing postinfarct remodeling. Thus, alcohol septal ablation is performed on the basis of patient preference, advanced age, and the presence of significant comorbidities that would increase surgical risk.

Variability of Left Ventricular Outflow Tract Obstruction

Outflow tract obstruction in HCM is by nature dynamic and affected by numerous hemodynamic changes that occur during daily life. This variability is dependent not only on heart rate, inotropic state, and systemic vascular resistance but also on loading conditions. Postprandial exacerbation of symptoms occurs in about a third of patients. The hemodynamic changes that occur after a meal result in an increased heart rate and cardiac output and a decrease in systemic vascular resistance (due to splanchnic vasodilatation), are akin to those seen after the administration of amyl nitrite, and have been shown to be associated with an increase in the LVOT gradient compared with the fasting state. In addition, the ingestion of alcohol may have profound effects on the LVOT gradient. In small amounts, the vasodilatory effects of alcohol result in a decrease in systemic vascular resistance and an accompanying increase in heart rate and contractility, all of which may serve to increase the magnitude of LVOTO. This increase in LVOT gradients was demonstrated in a series of 36 patients. In larger amounts, the myocardial depressive effect of alcohol may actually serve to decrease LVOT gradients.

Variability of Left Ventricular Outflow Tract Obstruction

Outflow tract obstruction in HCM is by nature dynamic and affected by numerous hemodynamic changes that occur during daily life. This variability is dependent not only on heart rate, inotropic state, and systemic vascular resistance but also on loading conditions. Postprandial exacerbation of symptoms occurs in about a third of patients. The hemodynamic changes that occur after a meal result in an increased heart rate and cardiac output and a decrease in systemic vascular resistance (due to splanchnic vasodilatation), are akin to those seen after the administration of amyl nitrite, and have been shown to be associated with an increase in the LVOT gradient compared with the fasting state. In addition, the ingestion of alcohol may have profound effects on the LVOT gradient. In small amounts, the vasodilatory effects of alcohol result in a decrease in systemic vascular resistance and an accompanying increase in heart rate and contractility, all of which may serve to increase the magnitude of LVOTO. This increase in LVOT gradients was demonstrated in a series of 36 patients. In larger amounts, the myocardial depressive effect of alcohol may actually serve to decrease LVOT gradients.

Latent Outflow Tract Obstruction

In this issue of the Journal of the American Society of Echocardiography , Joshi et al. report the effects of varying provocation maneuvers on LVOT gradients in 98 consecutive patients with HCM. The effects of upright posture, the Valsalva maneuver, and upright exercise on the measured LVOT gradient were compared with measurements obtained supine at rest. The authors report the ability to acquire acceptable traces in the upright posture in 98% of cases in the hands of an experienced sonographer. Resting obstruction was demonstrated in 43% of patients, with an increase in the mean gradient from 25 to 44 mm Hg on standing, from 25 to 64 mm Hg with the Valsalva maneuver, and from 25 to 100 mm Hg with exercise. The Valsalva maneuver resulted in higher mean gradients than standing, with upright exercise provoking the highest mean gradient in the patient group. Gradients ≥ 50 mm Hg, a better measure of symptomatic status, were present in patients taking negatively inotropic medications in about 30% of patients when measured supine, 50% when measured standing, and 70% after the Valsalva maneuver and exercise (performed off β-blockers). The authors conclude that although the upright posture resulted in an increase in gradients of 76%, it was not as potent a maneuver as either Valsalva or exercise provocation. The authors suggest that upright posture and exercise as provocative tests do mimic the physiologically experienced gradients during normal daily activity.

Although standing is a physiologic maneuver, in daily life, most patients do not experience symptoms on assuming the upright posture. In addition, the mean gradient on standing was only 44 mm Hg, which may not be a significant gradient or relate to the underlying cause of a patient’s symptoms.

Although the authors report acceptable traces in 98% of patients, it is yet to be determined whether, at other centers and in the hands of less experienced sonographers, the acquisition of high-quality traces is feasible in the standing position without contamination from the jet of mitral regurgitation. Indeed, in the patient group, they report a range of gradients from 0 to 309 mm Hg in the upright posture. Extremely high gradients (>200 mm Hg) are uncommon, and it appears that their patient with a gradient of 309 mm Hg (Figure 2) likely had contamination of the LVOT continuous-wave signal with mitral regurgitation.