Left ventricular outflow tract velocity time integral outperforms ejection fraction and Doppler-derived cardiac output for predicting outcomes in a select advanced heart failure cohort

Congestive heart failure is persistently growing health care dilemma in the United States, resulting in more than 50,000 deaths annually and more than 2 million yearly hospitalizations [1, 2]. The clinical assessment of patients with heart failure has been shown to be a valuable tool in guiding therapy and predicting prognosis, with the presence or absence of congestion and hypoperfusion dividing heart failure patients into one of four hemodynamic profiles [3]. Patients with both congestion and low cardiac output have been shown to have more than twice the mortality and cardiac transplantation rates of those without hypoperfusion and congestion [3]. Thus, accurate and timely identification of high risk profiles is crucial. Due to the burden of disease, as more patients with heart failure are cared for by clinicians without expertise in advanced heart failure, an easily utilized screening tool for identifying such patients would be helpful to facilitate timely assessment for advanced therapies such as left ventricular assist device and cardiac transplantation [4].

Echocardiography has emerged as an invaluable tool in the diagnosis and management of congestive heart failure (CHF) and is routinely performed in patients with CHF [5]. Measurements of left and right ventricular dysfunction, presence of valvular disease, Doppler derived cardiac output, and estimates of intracardiac pressures are frequently obtained metrics [6]. Multiple studies have demonstrated a close correlation between cardiac output calculated by Doppler echocardiography and invasive thermodilution and Fick methods [7, 8]. Doppler derived cardiac output is typically obtained by measuring flow across the left ventricular outflow tract (LVOT) which is determined by the velocity time integral of the Doppler signal directed across the LVOT (LVOT velocity time integral or LVOT VTI), multiplied by the cross sectional area of the LVOT and heart rate. LVOT VTI has been shown to be a reproducible measurement even in the context of severe chronic heart failure [8, 9] and is superior to flow measured at other locations, including the right ventricle, pulmonary artery, mitral valve, and aortic arch [10] due to multiple factors: ability to obtain insonation parallel to blood flow and a relatively flat profile of blood velocity distribution [11].

Because estimation of the area of LVOT represents the major source of error in deriving cardiac output due to the elliptoid shape of the LVOT and squaring of the measured radius (πr ²) [12, 13], using LVOT VTI alone rather than Doppler derived cardiac output has been suggested as a reliable surrogate for cardiac output in the absence of left ventricular outflow tract abnormalities [9]. Prior studies have evaluated LVOT VTI in acute myocardial infarction, demonstrating 100% one-month survival for subjects with LVOT VTI greater than 100% predicted for age and greater than 80% survival at 5 years. In contrast, mortality rate at one month and five years were 18% and 43% respectively when LVOT VTI was less than 65% predicted [14]. More recently, a study of 990 patients with stable coronary artery disease demonstrated increased rates of heart failure hospitalization for subjects within the lowest VTI quartile [15]. Our study was designed to test the following concept: for those within the lowest VTI quartile, is extremely low VTI a marker for patients at highest risk of death and who will go on to need advanced therapies such as transplant or LVAD? We hypothesized that because extremely low LVOT VTI is an accurate marker of the low output state, LVOT VTI may be used to discriminate between early stage heart failure versus advanced heart failure with low cardiac output, thus providing clinicians with a readily obtainable noninvasive tool to identify patients who may benefit most from advanced heart failure interventions such as LVAD and heart transplantation.

LVOT VTI is used to estimate stroke volume since it reflects the column of blood which moves through the LV outflow tract during each systole, per the following equation [16]:

LVOT VTI is calculated by placing the pulsed Doppler sample volume in the outflow tract below the aortic valve and recording the velocity (cm/s). When the velocity signal is integrated with respect to time, the distance blood moves with each systole is calculated in cm/systole (Fig. 1). Assuming laminar flow through the LVOT, this has been shown to correlate well with cardiac output, which is equivalent to stroke volume x heart rate [16].

The study protocol was approved by the Institutional Review Board of Scripps Health, La Jolla, CA. Subject selection: The transthoracic echocardiogram (TTE) database at our institution was queried for studies performed between June 2009 and May 2011 for patients with heart failure. As over 20,000 echocardiograms per year are performed at our institution, in order to identify subjects with extremely low LVOT VTI, a cutoff LVOT VTI of no more than 10 cm was applied in order to limit the number of included studies.

Exclusion criteria included any one of the following: alternative causes for shock (including hypovolemia and sepsis), acute myocardial infarction, significant valvular disease affecting accurate estimation of forward cardiac output by LVOT VTI (i.e, severe aortic regurgitation) [5], significant tachycardia (defined as >120 beats per minute), and pulmonary arterial hypertension. Subjects with multiple TTEs were reviewed at time of earliest study and subsequent studies were excluded. Valvular disease was characterized according to guidelines from the American College of Cardiology [17]. Diagnosis of heart failure was established by review of the electronic medical record (EMR): clinical documentation of heart failure in an admission history and physical, discharge summary, or cardiologist’s note and/or referral to a dedicated heart failure clinic.

Because extremely low LVOT VTI was the focus of our investigation, a cut off of <10 cm was used for subject inclusion. Similar to previously described heart failure cohorts, our study population was predominantly male (72 out of 100), elderly (mean age, 73.5 years) with systolic CHF due to ischemic cardiomyopathy (mean EF, 28%). Our findings demonstrate that extremely diminished LVOT VTI was robustly associated with the combination of 12-month death and LVAD implantation. In the multivariate analysis, LVOT VTI was most predictive of adverse outcomes [HR 0.589 (95% CI 0.41 - 0.83), p = 0.003], hazard ratio of less than one indicating that higher LVOT VTI correlates with better outcomes, other significant variables being older age [HR 1.04 (95% CI 1.004 - 1.095, p = 0.033] and higher echo-derived systolic pulmonary artery pressure [HR 1.03 (95% CI 1.005 - 1.065, p = 0.022].

When comparing cohort tertiles, the unadjusted and adjusted hazard ratios for LVOT VTI were even more predictive, with an unadjusted mortality and LVAD likelihood ratio of 4.755 (95% CI 1.576 - 14.348) in the lowest LVOT VTI tertile compared with the rest of the study group and an adjusted likelihood ratio of 12.680 (95% CI 2.638 – 60.949).

Several reasons may explain why low LVOT VTI correlates closely with adverse clinical outcomes. LVOT VTI provides enhanced prognostic information over ejection fraction, as it focuses on forward cardiac output which at times maybe normal even in compensated heart failure patients with low ejection fraction. Low cardiac output is a known precursor to overt cardiogenic shock, multi-organ dysfunction and death [18]. Whereas the accuracy of Doppler derived cardiac output is primarily limited by errors in determining the cross sectional area of the LVOT, as defined by the formula πr ², utilizing LVOT VTI alone rather than Doppler derived cardiac output eliminates this source of error. In patients who are tachycardic due to cardiogenic shock and poor LV function, rapid heart rate partially offsets the decline LV function, allowing for maintenance of cardiac output in the setting of a sick ventricle, however LVOT VTI remains depressed. Thus, in cases of low cardiac output with compensatory tachycardia, LVOT VTI may be a very sensitive predictor of cardiogenic shock and impaired ability to meet systemic tissue perfusion and metabolic demands. Because LVOT VTI is an easily obtainable and reproducible measurement, we propose that LVOT VTI may be a useful and accessible tool to identify heart failure patients with very low cardiac output and who may benefit from advanced heart failure therapies appropriate for end-stage HF.

As numerous therapies emerge that increase cardiac output for patients with advanced heart failure [19], there is an ever greater need to identify those who stand to benefit most from such therapies [4]. LVOT VTI is an easily available non-invasive tool that identifies patients at highest risk for decreased survival at one year, thus allowing for earlier identification and advanced treatment.