Interatrial shunting for the treatment of heart failure: an on‐demand , self‐regulating left atrial pressure lowering system

This article refers to ‘One-year results of the first-in-man study investigating the Atrial Flow Regulator for left atrial shunting in symptomatic heart failure patients: the PRELIEVE study’ by C. Paitazoglou et al., published in this issue on pages 800–810. Two-time U.S. Open Title winner Curtis Strange said, ‘Under pressure, one of the most important things I have to remember to do is breathe.’ For millions of heart failure patients around the world, the opposite is true: under pressure, one of the things they cannot forget to do is breathe. In fact, breathing is frequently all that they can think about. Of course, the pressure we are talking about is left atrial pressure. In heart failure patients, regardless of their left ventricular ejection fraction, frequent and dynamic elevations in left atrial pressure occur during exercise, stress, and changes in salt and water intake and renal function. These elevations in left atrial pressure are causal for worsening heart failure symptoms, particularly for worsening shortness of breath, and increase the risk of morbidity and mortality. Conversely, chronic lowering of elevated left atrial pressure improves heart failure symptoms, morbidity, and possibly mortality as demonstrated in studies of implantable haemodynamic monitoring systems.1, 2 In these studies, left atrial pressure or pulmonary artery pressure as its surrogate were pharmacologically lowered, primarily through the use of pressure-guided changes in diuretic therapy, resulting in improved quality of life and fewer heart failure hospitalizations. Unfortunately, many patients do not tolerate or are refractory to pharmacological therapies that lower left atrial pressure, and pharmacological therapies cannot adequately address the so-called fast pathway leading to elevated left atrial pressure through rapid venous redistribution of blood volume.3 In addition, pressure-guided heart failure management has many delay and failure points, due to its reliance on patient adherence and physician compliance in taking and responding to pressure measurements, respectively. To address these shortcomings of pharmacological approaches to reduce left atrial pressure, the shunting of blood from the left atrium into the right atrium is currently under investigation as a treatment for heart failure, primarily through the use of investigational interatrial shunt devices or other catheter-based approaches to creating a communication between the cardiac atria. Once created, these shunts function as on-demand, self-regulating left atrial pressure lowering systems, requiring no patient adherence or physician compliance to work. Their operation is simply dependent on the pressure gradient between the left and right atrium. As left atrial pressure increases in response to any of the aforementioned conditions (exercise, stress, etc.), a small amount of excess left atrial volume is moved to the right atrium. This results in lowering of the left atrial pressure, due to the steepness of the left ventricular pressure–volume relationship in the failing heart. If the shunted volume is not too large, left atrial pressure lowering predominates over the increase in right-sided volume, and pulmonary artery and right heart pressures remain unchanged or may be lowered as well. To this end, the typical therapeutic interatrial shunt ratio (the ratio of pulmonary to system flow or Qp:Qs) goal is generally on the order of 1.2 or slightly greater. The proof of this concept has been demonstrated in an elegant chronic heart failure animal study and confirmed in human clinical trials.4-7 In the former animal study, interatrial shunting reversed the haemodynamic and echocardiographic phenotype of severe, progressive heart failure in sheep with ischaemic heart failure, demonstrating no untoward effects on the right heart or pulmonary circulation.4 In the latter human studies, interatrial shunting lowered left atrial pressure at rest and/or with exercise without increasing right heart or pulmonary artery pressures.5-7 Finally, these and other pilot studies provided evidence supporting not only the mechanism of action but also the potential safety and clinical effectiveness of interatrial shunting in heart failure.5-8 The results of these completed pilot studies of multiple interatrial shunt devices are strikingly concordant in demonstrating large improvements in quality of life, functional status, and exercise capacity in heart failure patients with reduced and preserved left ventricular ejection fractions (HFrEF and HFpEF, respectively). In this issue of the Journal, Paitazoglou and colleagues9 add to this evidence by extending their prior observations supporting the feasibly, safety, and potential effectiveness of interatrial shunting in 53 HFrEF and HFpEF patients followed for 1 year after shunt implantation. (Their prior report included the first 36 patients followed for 3 months, in the AFR-PRELIEVE study.7) Patients with New York Heart Association (NYHA) class III or ambulatory class IV heart failure, despite optimal guideline-directed medical therapy, with HFrEF (n = 24; ejection fraction 15–39%) or HFpEF (n = 29; ejection fraction ≥40% and N-terminal pro-B-type natriuretic peptide >125 pg/mL) and a pulmonary capillary wedge pressure ≥15 mmHg at rest or ≥25 mmHg during exercise, were enrolled in the study. Patients with severe pulmonary hypertension or advanced right heart failure were excluded, as was one patient who had a transseptal complication and two who had transseptal puncture failure prior to the device implant attempt. There was also one patient excluded from the study population after the device implant attempt, due to device embolization in the left atrium requiring surgical removal. This study demonstrated significant reduction in left atrial pressure (measured as the pulmonary capillary wedge pressure) at 3 months [−5 (−12, 0) mmHg, P = 0.0003], associated with improvements in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, NYHA class ranking, and 6-min walking distance (6MWD) at 1 year. The KCCQ overall summary score improved +14.9 (0.6, 38) points (P < 0.0001). To put this result into clinical context, a ≥ 5-point improvement in this quality of life score is considered clinically meaningful, and the typical improvement seen with effective drug therapies for heart failure is about 3 to 5 points. The only intervention for heart failure resulting in a similarly large improvement in this quality of life score is transvenous edge-to-edge mitral valve repair of moderately severe to severe secondary mitral regurgitation.10 NYHA class also improved significantly by one class ranking, and the 6MWD improved by +50 (−33, 113) m (P = 0.0198). The latter improvement represents a 25% improvement in walking distance from baseline, whereas a 10% improvement is generally considered to be clinically meaningful and associated with improved clinical outcomes. From the safety standpoint, no patient developed a stroke, worsening of right heart function, or a significant increase of pulmonary artery pressure. However, a mild dilatation of the right ventricle was observed in the HFpEF population. Finally, shunt patency was demonstrated in all patients for whom adequate imaging was obtained. This study illustrates the potential for interatrial shunting as a treatment for heart failure, in both HFrEF and HFpEF patients. It builds upon prior observations from these investigators and from others.5-8 Baseline demographics of the study patients were relatively typical of the advanced heart failure population with perhaps two notable exceptions: the age of the HFpEF population was younger [median (Q1, Q3) age 67 (60, 74) years] and the baseline 6MWD for all patients (HFrEF and HFpEF) was shorter [median (Q1, Q3) 6MWD 200 (100, 300) m] than might have been expected. For example, prior drug and device studies of NYHA class III or ambulatory class IV heart failure patients usually demonstrated a baseline median 6MWD of about 300 m. This observation raises the possibility that some other factor(s), such as a training effect with serial testing, may have accounted for at least some of the observed improvement in walking distance. Moreover, the absence of a parallel control group as well as patient and investigator knowledge of study assignment (open-label, observational trial design) limit the level of confidence one can have in these findings. Finally, the observation of right ventricular enlargement in the HFpEF patients studied raises concern regarding optimal shunt size. Across interatrial shunt studies, a variety of devices and approaches with a range of shunt sizes from about 5 to 10 mm are being explored. The best shunt size to optimize pressure–volume relationships in the heart remains to be determined. Despite these concerns, based on the totality of data available to date, including the results of the AFR-PRELIEVE trial, interatrial shunting remains one of the most promising investigational approaches to the treatment of heart failure. Two ongoing multinational, randomized, double-blind, controlled pivotal trials (REDUCE LAP-HF II and RELIEVE-HF in HFpEF and in HFrEF and HFpEF patients, respectively) should provide more definitive information on the safety and effectiveness of therapeutic interatrial shunting – an on-demand, self-regulating approach to left atrial pressure lowering – in heart failure patients. Conflict of interest: W.