Long-term prognosis analysis of PARACHUTE device implantation in patients with ischemic heart failure: a single-center experience of Chinese patients

Background Heart failure (HF) is one of the leading causes of mortality and morbidity. The PARACHUTE device is designed to partition for left ventricular (LV) apical aneurysm post extensive anterior myocardial infarction (MI). However, the long-term prognosis of the PARACHUTE device post-implantation is unclear. Methods From November 2015 to April 2017, six subjects with New York Heart Association Classes II, III and IV ischemic HF, LV ejection fraction between (LVEF) 15 and 40%; and LV anterior apical aneurysm were enrolled in our center. The cumulative event rates for MI, hospitalization, and mortality were documented. Further assessment of LVEF, LV end-diastolic diameter (LVEDD), and estimated pulmonary artery pressure were determined by echocardiography core laboratory. For quantitative data comparison, paired t-test was employed. Results Device implantation was successful in all six enrolled subjects, and acute device association adverse events were not observed. At 4.6 ± 1.7 years follow-up, major adverse cardiac events (MACEs) were found in 50% patients, and the survival rate was 86.7%. We observed that the LVEF was significantly elevated after deployment (46.00 ± 6.00% vs. 35.83 ± 1.47%, P = 0.009). Besides, the LVEDD elevated after MI (51.17 ± 3.71 vs. 62.83 ± 3.25, P < 0.001) was revealed, but the device sustained preserved LVEDD after implantation. Conclusion The PARACHUTE device is an alternative therapy for patients with severe LV maladaptive remodeling. However, the device seems to increase the HF ratio. Trial registration NCT02240940 Supplementary Information The online version contains supplementary material available at 10.1186/s13019-021-01484-0.


Introduction
Left ventricle (LV) maladaptive remodeling after acute myocardial infarction (MI) has been well documented in experimental and clinical trials [1,2]. During the past decades, the number of hospitalizations for acute MIs has increased significantly. Despite the treatment improvement in MI, the long-term prognosis of MI-related LV remodeling remains unfavorable.
The concept of percutaneous ventricular restoration (PVR) therapy of dilated LV is based on the premise of a dedicated partitioning device for LV volume reduction and geometric reconfiguration [3][4][5]. PARACHUTE® (CardioKinetix, Redwood City, CA, USA) is the first device designed for PVR, and it minimizes the risk of other invasive methods.
Previous clinical trials implied that the PARACHUTE device may reduce cardiac dimensions and end-diastolic wall stress, thereby benefitting patients with LV dilation post-MI. However, little is known about the long-term cardiac function, life quality, and major adverse cardiac events (MACEs) of PARACHUTE-implanted patients.
Therefore, we retrospectively collected the clinical and average 4.6 years follow-up data to analyze the PARA CHUTE device-related outcomes and complications, and we also performed a per-versu post-implantation pairwise comparison of patients' echocardiography parameter. In addition, we investigated the potential factor of an adverse event in these patients.

Study design and patient selection criteria
The Percutaneous Ventricular Restoration in Chronic Heart Failure due to Ischemic Heart Disease (PARA CHUTE) China (NCT02240940, https://clinicaltrials. gov/ct2/show/NCT02240940) is a prospective, nonrandomized observational study designed to assess the safety and efficacy of the PARACHUTE device. Clinical and echocardiographic follow-up was performed.
Inclusion criteria were as follows: enrolled cases were patients with symptomatic ischemic HF with NYHA Classes II, III, and IV. These patients were 18-75 years old with LV motion abnormalities secondary to anterior MI. LVEF ranged from 15 to 40%, which was measured by the 2D echocardiography core laboratory (core lab). All participants with myocardial ischemia underwent revascularization and received optimal and standard HF medical therapy for at least 3 months before enrollment.
The exclusion criteria were as follows: significant valvular stenosis or regurgitation, chronic obstructive pulmonary disease, end-stage renal disease requiring hemodialysis, cerebral vascular accident, or transient ischemic attacks occurring within 6 months. Selected computed tomography (CT) was applied for proper device size selection. All sites obtained approval from the Ethics Committee before the study began, and written informed consent was obtained for all patients at the appropriate time before involvement in this study. After the implantation of the device, clinical and echocardiographic follow-up was performed annually for up to 3 years.

Study device and procedure
Details of the device and procedure had been previously published [3][4][5]. In brief, the procedure was performed in a catheterization laboratory with the patients usually under conscious sedation. Multi-slice CT (Supplementary Figure 1) was implemented to provide accurate measurements and rule out LV apical thrombus, pseudochorda, or severe calcification. After the expansion of the device, the occlusive membrane provides a barrier to seal off the static chamber on the distal side of the device. All patients received low-dose aspirin and anticoagulation with warfarin for at least 12 months of postdevice implantation.

Transesophageal echocardiography
Patients underwent 3D-transthoracic echocardiography (TTE) and 2D-TEE with IE-33 Philips systems (Andover MA, USA) by using a 3D X5-1 PureWave matrix-array transducer. Images were digitally acquired for off-line reconstruction (for 3D-TEE images) and interpretation. 2D-TEE was used from basal to mid-esophageal levels.

Date collection and follow-up
All study-related data were collected on standardized case report forms [3][4][5] We assessed the successful delivery and deployment of the PARACHUTE device. The average of 4.6 years of follow-up data on MACEs was recorded. MACEs were defined as cardiac death, emergent cardiac surgery, cardiac tamponade, peripheral embolization, new or worsening HF, endocarditis or device infection, device migration or embolization. We collected echocardiography measurements, including LV end diastolic diameter (LVEDD), LLVEF, and estimated pulmonary artery pressure (PAP). Functional parameters such as NYHA functional class ranking were also determined. Data management was performed by contract research organization, and adverse events were adjudicated by an independent clinical events committee.

Statistical design and statistical analysis
The key efficacy evaluation was based on transthoracic TTE analysis from baseline to device implantation, including the follow-up data. The MACEs and efficacy analyses were performed on those who were discharged from the hospital after being treated with the study device. The following baseline characteristics were summarized using the mean ± standard deviation (SD) for continuous variables and counts and percentages for categorical variables. Paired t-test was conducted to compare the quantitative data; the signed-rank test was applied for the ranked data comparison. All statistical tests were performed using a two-sided test; P ≤ 0.05 was considered statistically significant. All analyses were performed using SPSS 21.0 (USA).

Patient characteristics
From November 2015 to April 2017, 139 patients with post-anterior MI were initially enrolled in our trial (Fig. 1). These patients were screened by 2D TEE and Doppler examinations. A total of 122 of these patients were ineligible, 98 subjects had not developed an aneurysm in the LV, and 24 patients had an LVEF less than 15% or over 40%. Device sizing and anatomical approval were granted by the central CT core lab. Seventeen patients received CT scan for proper PARACHUTE device selection; 11 were excluded for LV false tendons (four subjects), LV thrombosis (two subjects), and not being structurally fit for the device (three subjects); two patients withdrew their consent. Six patients were discharged with the PARACHUTE device and followed up for cardiac function and clinical outcomes. The mean follow-up time was 4.6 ± 1.7 years.
All the patients must have had a diagnosis of NYHA Class II, III, or IV before enrollment to be included in this study. Ischemic heart disease was present in all patients. All subjects with LV descending artery MI had a prior percutaneous coronary intervention. The average age of the patients was 55.7 ± 11.3 years old, the average time from an acute MI to PARACHUTE implantation was 13.5 ± 12.9 months, and BMI was 26.0 ± 2.0. Three patients had single-vessel occlusion, the rest had multivessel disease, and all revascularization was complete in their first hospitalization (data not shown). Five males and one female were involved. We hospitalized one patient for HF within 12 months. The baseline demographic data are shown in Table 1. All patients had LV post-MI aneurysm, and no patient received ICDs or CRTs.
As presented in Table 2, the PARACHUTE devices were implanted through the femoral artery of all the six subjects (Fig. 2a). The procedure was successful in six (100%) patients, without a perforation case. No major vascular complications were found, and no PARA CHUTE device was expanded or deployed improperly. In addition, no acute thrombosis and emergent surgery occurred during the procedure.
The procedure of the device implantation is briefly illustrated in Fig. 2. The PARACHUTE device was expanded and implanted in the LV apical wall. LV angiography was performed once again to evaluate the geometry of LV ( Fig. 2e and f). As displayed in Fig. 2, LV volume was remarkably reduced in the systole and diastole phases.

Clinical and functional outcomes
Patients in our center were followed up for 4.6 ± 1.7 years. Safety end-points are illustrated in Table 3 and Fig. 3. MACEs occurred in three (50%) patients (Fig. 3a). The most frequently reported MACEs were HF and unplanned interventional therapy. Three subjects (50%) received coronary artery intervention; one of them was diagnosed with non-ST elevation MI, other two have progressive angina attack. Three patients developed HF on the 85th, 418th, and 1599th days. on the 568th day due to progressively worsening HF. The device-related MI and emergent/selective cardiac or aortic surgery were not observed (Table 3).
Our center observed the successful delivery of the PARACHUTE device through 6 months follow-up without device-related MACEs. The medication therapy of the subjects was consistent from inclusion into the trial up to one-year follow-up. DAPT, Statin, Warfarin, and βblocker were 100% taken in all patients; ACEI/ARB and spironolactone were 83.3%. Even though all patients received warfarin for more than 12 months, device-related embolization was found in a patient by CT and TTE.
Our center analyzed echocardiographic parameters of these subjects at baseline and each time of follow-up, including the LVEF, LVEDD, and estimated PAP. We collected the baseline data after the first attack of anterior MI. Subsequently, data were obtained before the PARA CHUTE device implantation and 1 week, 6 months, 1 ± 0.25 year, 2 ± 0.5 years, and 3 ± 0.5 years after device implantation.
We further performed a per-verse post-implantation pairwise comparison of echocardiography. The results of TTE-based cardiac function assessment are shown in Fig. 4. Compared with the baseline, the LVEF was significantly reduced at the time when patients enrolled in the trial (50.67 ± 0.82% vs. 35.83 ± 1.47%, P < 0.001). PARACHUTE remarkably elevated LV systolic function in 1 week (35.8 ± 1.47% vs. 46.00 ± 6.0%, P = 0.009, illustrated in Fig. 4a and b). For the subjects without MACEs, compared with the one-week measurement, the LVEF demonstrated relatively sustained improvement when we referred to the latest follow-up (42.33 ± 3.51% vs. 43.67 ± 3.06%, P = 0.757). By contrast, patients with MACEs often showed a moderate decline (49.67 ± 6.03% vs. 35.67 ± 4.04%, P = 0.112).
Patients showed a significant chronic increase in LVEDD before the procedure (51.17 ± 3.71% vs.62.83 ± 3.25%, P < 0.001). After the implantation, TTE exhibited no pronounced change in LVEDD, and the progressive   LV enlargement was inhibited ( Fig. 4c and d). We further measured estimated PAP in Fig. 4e and f, except for the early death of one patient due to HF. The estimated PAP was comparable in each time evaluation. Notably, the device-related MACEs also contributed to the poor prognosis. Here, we found one case of embolization that may worsen the state of illness (Fig. 5). Figure 5a is an image captured immediately after PARA CHUTE implantation. The latest contrast-enhanced CT of the LV (Fig. 5b) showed the occurrence of deviceassociated embolization. We conducted a 3D TTE and Doppler scan to exclude device migration ( Fig. 5c and  d). Furthermore, MCE and LVO were employed to confirm the thrombus located in the LV apex ( Fig. 5e and f). These results suggested that the patients should continue to receive warfarin to prevent stroke, even though no embolization-associated adverse events are found. Moreover, long-term anticoagulant treatment may help prevent thrombus-related events.

Discussion
In this study, we demonstrated that PARACHUTE therapy could be beneficial for the maladaptive remodeling of patients with post-MI by restoring LV ejection and suppressing continuous and overwhelmed LV enlargement, thereby improving patients' long-term prognosis especially in LVEF-sustained preserved subjects. Limited by the size of cohort, the conclusion may not be robust, however, it could be an alternative treatment for specific group of anterior myocardial infarction patients. Typical LV dilation is common in patients with an anterior infarction [6]. As a consequence of anterior MI, the LV continuously develops geometrically from ellipsoid to spherical [7], accompanied with chamber dilation and wall motion abnormalities. The dilation of LV increased ventricle volume elevates filling pressure, resulting in the enhanced burden of remaining myocytes, progressive subendocardial myocardial ischemia [8], hemodynamic disorder such as functional mitral regurgitation [4], HF, and death [9]. Many studies have proven that LV remodeling is an independent clinical predictor of prognosis in patients with HF [10]. The beneficial effects of drugs or medical devices on LV remodeling have also been associated with reduced long-term mortality [11]. Therefore, effective and safe treatment strategies are urgently needed to restore LV function and improve outcomes of patients with HF.
To exert the maximum benefit effect to HF patients in this trial, restricted heart features were carefully evaluated, false tendons and ventricular thrombosis are the contraindications of the PARACHUTE procedure. Six eligible subjects were enrolled to the study, the Fig. 3 Cumulative incidence of cardiovascular events in PARACHUTE-implanted patients. a Cumulative event rates for the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure end-point. b, c, and d Cumulative myocardial infarction, hospitalization, and mortality, respectively. e Changes in functional capacity according to NYHA. MACEs, major adverse cardiovascular events; MI, myocardial infarction; HFH, hospitalization for heart failure. NYHA, New York Heart Association class cautiously HF patient selection also contribute to procedural safety eventually. The aforementioned studies [4,[12][13][14] suggested that the PARACHUTE device can reduce cardiac dimensions and end-diastolic wall stress and improve cardiac output. However, the three-year results indicated a reduction of LVEF and stroke volume. The PARACHUTE IV trial was terminated due to death or rehospitalization for worsening HF.
The device restored enrolled patients' LV systolic function, and this result was consistent with the findings of prior studies [4,5,13]. LVEF significantly improved from preimplantation to 7 days after deployment (35.83 ± 1.47% vs. 46.00 ± 6.00%, P = 0.009). The LVEDD and estimated PAP were relatively stable, which suggested that this therapy was effective and safe for patients. The improvement in NYHA functional class was also observed in other patients (illustrated in Fig. 3).
Patients with prior MI have a much higher risk to develop HF and multivessel coronary artery disease than their counterparts [15]. The device is designed to prevent maladaptive LV remodeling, which is helpless in inhibiting recurrent coronary attack. Therefore, Fig. 4 Transthoracic echocardiograph-based cardiac function assessment. Transthoracic echocardiography (TTE)-based cardiac function evaluation was performed at baseline (the first time for MI treatment); before the PARACHUTE device procedure; and at 1 week, 6 months, 1 year, 2 years, and 3 years after device implantation. a, c, and e Comparison of each time point for the left ventricular ejection fraction, left ventricular end-diastolic diameter, and estimated pulmonary artery pressure assessment, respectively. b, d, and f Changes in the TTE-based parameter measurement mentioned above. ***: P < 0.001, compared with baseline; ##: P < 0.01, compared with the PARACHUTE procedure; NS: not significant. mm: millimeter personalized treatment should be sought to decrease coronary risks. The HF that occurred in half of our enrolled patients may be partly because they selected suffered from severe cardiac remodeling, thereby enhancing the ratio of cardiac adverse events. However, the devicerelated MACEs also contributed to the poor prognosis.
As this clinical trial previously designed, all patients received low-dose aspirin and anticoagulation with warfarin for at least 12 months of post-device implantation. The duration of antiplatelet or anticoagulation is based on the spontaneous reendothelialization time. Extra anticoagulation is unnecessary when the implants are completely reendothelialized. The concept is also applicable to the PARACHUTE device. In color doppler flow imaging, we observed that blood flow crossed the device, suggesting it was not entirely reendothelialized even after 3 years, so thrombosis may be promoted. The evidence implies that the PARACHUTE device may need to be refined to fit the geometry of the dilated ventricle.
Despite the small number of patients in our center, we have the longest clinical observation of the PARACHUTE cohort in China. In this trial, the efficiency and safety of the PARACHUTE procedure were investigated, and longterm MACE and cardiac function were evaluated. These data add further evidence to PARACHUTE studies and prove that the ventricular partition device is relatively safe and may reduce long-term death. However, the PARA CHUTE device could increase the HF ratio.

Limitations
The study was limited by its small sample size; unblinded, single-arm nature; and single-center clinical observations. Given that it was conducted in selfcontrol mode and lacked a control group using standardized medical therapy or SVR, we could not rule out potential bias in the adjudication process. Furthermore, a robust conclusion could not be made without control group efficacy. c and d 3D-TTE and 2D-TEE were applied to exclude device migration, respectively. The white arrow indicates the implanted device. e and f Left ventricular thrombus confirmed by LVO and MCE, respectively. The white arrow points to the filling defect-implied LV apical thrombus