Impella in Acute Myocardial Infarction Complicated by Cardiogenic Shock: History and Current Controversies

Abstract

In this review, the authors discuss a brief history of the Impella mechanical circulatory support device, a mechanistic role for the device in the context of the underlying pathophysiology of acute myocardial infarction cardiogenic shock (AMI-CS), the current body of literature evaluating its role in AMI-CS, and upcoming efforts to identify a role more clearly for the device in AMI-CS.

Keywords: acute myocardial infarction, cardiogenic shock, mechanical circulatory support

Acute myocardial infarction (AMI), including non-ST-elevation myocardial infarction and ST-segment-elevation myocardial infarction (STEMI), is the most common cause of cardiogenic shock (CS). It is responsible for approximately 80% of cases of CS and develops in 8%-10% of patients who present with AMI.^1-3 Despite significant breakthroughs in recent decades, AMI-CS remains a formidable challenge for clinicians to diagnose and treat. The SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial demonstrated the benefit for revascularization in patients with AMI-CS, which now carries a class 1 recommendation from both American and European guidelines.^4-6

Definition of CS. Cardiogenic shock is generally defined as a state of end-organ hypoperfusion and dysfunction, secondary to cardiac dysfunction.⁷ Clinically, the end-organ dysfunction may manifest as persistent hypotension despite fluid administration, altered mental status, cold extremities, and a reduction in urine output. Objectively, a number of hemodynamic parameters are commonly used to assess for the presence of CS, including a systolic blood pressure of <90 mm Hg despite fluid administration, a cardiac index of <2.2 L/min/m², or a pulmonary capillary wedge pressure of >15 mm Hg.⁷ Historically, there has been significant heterogeneity in the definitions of CS used in the major randomized controlled trials (RCTs) of CS (Table 1). The lack of a unified definition of CS may have contributed to a lack of clinical equipoise among clinicians regarding the optimal management of these patients and may impede further research in the field.⁸ Furthermore, these definitions may require the calculation of hemodynamic parameters that may not always be practical in the clinical setting. Recognizing the need for a unified definition for CS, the Society for Cardiovascular Angiography and Interventions (SCAI) proposed a novel classification system for CS.⁹ The goal of this new classification system is to introduce a new unified system that is intuitive and easy to use at the bedside, allows for reclassification if needed, and allows clinicians to communicate with each other using a common lexicon. The scheme classifies CS from stage A (patients at risk of developing CS) to stage E (patients in advanced CS needing multiple interventions).

Therapies for CS. Currently available medical therapies for CS include vasopressors and inotropes.^1,7 While mortality from AMI-CS has decreased significantly due to prompt revascularization, it remains unacceptably high at around 40%, despite the use of vasopressors and inotropes.^2,3 As a result, mechanical circulatory support (MCS) devices are now being increasingly utilized in an effort to reduce the unacceptably high mortality from AMI-CS. For decades, the intra-aortic balloon pump (IABP) was the only short-term MCS device available for patients with CS and continues to be widely used today. However, the majority of currently available data, including the landmark IABP-SHOCK II trial (published in 2012), have shown that the IABP does not improve survival in AMI-CS.^10-12 Based on these data, its use in AMI-CS has been downgraded to a class III recommendation in the 2017 European Society of Cardiology guidelines, and a class IIb recommendation in the United States.^6,13 Its use has been declining consistently over the last decade.^14-16

The Impella pump. The continued high mortality of AMI-CS despite the use of medical therapies and IABP has been a major driver behind the growth and development of more advanced MCS devices, including the Impella system (Abiomed). The Impella is a catheter-based, microaxial, continuous-flow pump which utilizes the principles of the Archimedes screw.¹⁷ Developed in the 1990s, it is an improvement of its predecessor—the Hemopump, which was an axial flow system first developed in the 1980s—but failed to obtain Food and Drug Administration (FDA) approval and was eventually abandoned. The Impella is positioned across the aortic valve and aspirates blood from the left ventricular cavity and pumps it into the ascending aorta (Figure 1). It has several models, providing cardiac outputs ranging from 2.5 L/min (Impella 2.5), 3.0-4.0 L/min (Impella CP), 5.0 L/min (Impella 5 and Impella LD), and the Impella 5.5 with SmartAssist. The Impella 2.5 and CP models are implanted percutaneously, while the other models require surgical cutdown due to the larger device size. A version for right ventricular support (Impella RP) draws blood from the right atrium and pumps it into the main pulmonary artery.

The Impella 5.5 with SmartAssist is the latest iteration of the Impella pump and received FDA approval in 2019.¹⁸ It is designed for surgical use and is placed via the axillary artery or ascending aorta. It has a maximum speed of 33,000 rotations per minute and provides peak flows greater than 6 L/min. The SmartAssist software system incorporates multiple data points including real-time hemodynamic information via a fiberoptic pressure sensor and assists clinicians with positioning and weaning from the device.¹⁸

A mechanistic role for MCS in CS. Cardiogenic shock is a complex process, with a number of hemodynamic derangements that can be profound. Following AMI, a reduction in contractility (and thus stroke volume) leads to an elevation in left ventricular end-diastolic pressure (LVEDP), which in turn leads to elevated left atrial pressure, causing pulmonary congestion and hypoxia. Increased LVEDP also results in reduced coronary perfusion pressure and increased myocardial oxygen requirement due to increased wall tension.^19,20

The IABP and Impella target one or more of the above pathophysiologic processes. By way of counterpulsation, the IABP increases cardiac output and coronary perfusion by decreasing LVEDP, decreasing afterload, and increasing aortic diastolic pressure.^21,22 The Impella system mechanically “unloads” the left ventricle by actively pumping blood from the LV into the ascending aorta, providing significant hemodynamic support.¹⁷ It has been shown in animal studies to improve end-organ perfusion and reduce wall stress, myocardial oxygen consumption, and infarct size.^23,24 The LV unloading with Impella is associated with improved coronary perfusion pressure and LV ejection fraction, and a reduction in wall stress and ventricular filling pressures, along with an improvement in laboratory and clinical markers of severity of CS, such as blood lactate levels.^24,25 Moreover, compared with the IABP, the Impella has been shown to significantly improve cardiac output, mean arterial pressure, and reduce LVEDP.^26,27

Pressure-volume loops. The physiologic and hemodynamic derangements in CS are commonly portrayed in the form of pressure-volume loops (PVLs).^28,29 Normally, the PVL consists of a trapezoidal shape with a rounded top, portraying the stages of the cardiac cycle: isovolumic contraction, ejection, isovolumic relaxation, and relaxation/diastolic filling (Figure 2A). The width of the loop represents the stroke volume, the height the arterial blood pressure, and the loop area myocardial work (myocardial oxygen consumption). This loop is normally bounded by the end-systolic pressure-volume relationship (ESPVR) and the end-diastolic pressure-volume relationship (EDPVR) curves (Figure 2A). Following AMI, the ESPVR is shifted downward, indicating a decrease in contractility. This results in a reduction in stroke volume and blood pressure (Figure 2B).

The IABP and Impella have distinct effects on the PVL profile. The IABP, working in tandem with the cardiac cycle, reduces afterload and the pressure at which the aortic valve opens, thus causing a downward shift in the PVL. This is offset by an increase in stroke volume, which may not result in significant reduction in myocardial work, and thus the loop area remains relatively unchanged (Figure 2C).²⁹ In contrast, the Impella is a continuous-flow pump working independently of cardiac function. It causes a loss of the normal isovolumic periods, and the trapezoidal shape of the PVL is changed to a triangular form (Figure 2D). By unloading the LV, it also reduces the LVEDP, thus moving the PVL leftward. Finally, it also reduces myocardial oxygen demand, thus reducing the loop area.

Rise in Impella use. Since the Impella system gained initial FDA approval in 2008, it has steadily risen in popularity and is increasingly being used in the management of AMI-CS. Several studies, including our own, have shown an increase in Impella use in patients with AMI-CS over the last decade, accompanied by a parallel decrease in the use of IABP.^14-16 There are several reasons for its popularity. First, it is feasible to deploy rapidly under emergency situations. Second, the immediate ventricular unloading and improvement in hemodynamics and markers of shock severity, especially compared with the IABP, may be attractive to clinicians. Lastly, reasons for a rise in the device’s popularity may also include aggressive marketing campaigns and data from registry-based studies.³⁰

Impella approval by FDA. The approval process of the Impella by the FDA deserves mention as it has contributed significantly to both the widespread adoption of the device and the controversies surrounding its use. Briefly, the Medical Device Amendments Act of 1976 stipulated that the FDA classify all medical devices based on safety and effectiveness, and that all high-risk devices (class III), be evaluated through a rigorous premarket approval (PMA) process, which requires significant clinical study of device safety and effectiveness. An alternative pathway named the 510(k) pathway only requires manufacturers to demonstrate “substantial equivalence” to devices previously approved for a particular indication. The 510(k) pathway is less stringent than the PMA pathway and requires less clinical study for approval. It was initially established to allow certain medical devices to enter the market to potentially benefit patients, until a need was identified for PMA due to safety or efficacy concerns. Typically, all class III devices, including left ventricular assist devices such as the Impella system, require PMA prior to marketing, unless manufacturers demonstrate substantial equivalence to a device already on the market prior to the Medical Device Amendments Act of 1976, in which case devices can proceed to market under 510(k) clearance.^31-33

The Impella initially gained 510(k) approval in 2008 for a general indication of “partial circulatory support,” claiming substantial equivalence to its predecessor non-roller type cardiopulmonary bypass pumps, and Abiomed was not required to submit substantive clinical data demonstrating the efficacy and safety profile of its use in AMI-CS.³⁴ Several years later, in a subsequent review and reclassification process (the 515 Program Initiative) mandated by a change in policies, the FDA determined that the totality of available clinical data failed to support adequate safety and efficacy of the Impella system, and proposed that the Impella system retain class III classification and enter the PMA process.^31,33,35 This prompted Abiomed to seek PMA approval in 2015, for high-risk PCI, based on data from the PROTECT I and PROTECT II trials and the USpella registry.^36,37 In 2016, the Impella system received approval for use in AMI-CS and post-cardiotomy cardiogenic shock (PCCS) based on surgical data from the RECOVER I trial, the USpella registry, and a benchmark analysis comparing Impella with a ventricular assist device previously approved by the FDA for use in PCCS.³⁸

The RECOVER I study was a multicenter, single-arm, prospective study that evaluated the effect of Impella use in 16 patients with PCCS.³⁹ The primary composite endpoint of death or stroke at 30 days or discharge (whichever was longer) occurred in 13% of patients. From the USpella registry, 77 patients with PCCS were studied. In Kaplan-Meier survival analysis, 30-day survival among these patients was approximately 60%. In an additional analysis of the data, patients in whom Impella support was initiated prior to surgery had improved survival compared with patients in whom Impella support was initiated during or after surgery. In the benchmark analysis of patients with PCCS, 24 patients that received Impella were compared with 79 patients that received the AB5000 device. The AB5000 is a VAD that received FDA approval in 2003 for use in PCCS. Patients in the Impella cohort had improved 30-day survival (50% vs 15%; P<.01). Further details on these analyses are available in the Summary of Safety and Effectiveness Data document accompanying the PMA notification.³⁸

The FDA approval process for the Impella system has been controversial, as the device was given an indication for use in CS based on observational or single-arm studies, and not an adequately powered RCT with a control comparator (eg, IABP or standard medical therapy). Proponents argue that the initial FDA 510(k) approval of the device avoided a delay in introduction to clinical practice of a potentially life-saving therapy; critics contend that the approval process was not based on robust evidence from large randomized clinical trials and that the device was allowed to be introduced into clinical practice with limited data on its efficacy and safety.⁴⁰

Current evidence examining the role for Impella in AMI-CS. The majority of currently available data regarding the use of Impella in AMI-CS are limited to registries and large administrative databases. There have been only 3 RCTs (Table 2) comparing Impella with IABP in AMI-CS. In ISAR-SHOCK (Efficacy Study of LV Assist Device to Treat Patients With Cardiogenic Shock), Seyfarth et al randomized 25 patients with AMI-CS to either IABP or Impella 2.5. The Impella group had greater increases in cardiac index (+0.49 L/min/m² vs +0.11 L/min/m²; P=.02); 30-day mortality was similar between the 2 groups.⁴¹ The IMPRESS in STEMI (IMPella versus IABP REduceS infarct Size IN STEMI patients treated with primary PCI) trial aimed to study the impact of IABP vs Impella 2.5 on LV ejection fraction after primary PCI in pre-shock patients with anterior wall STEMI. Aiming to enroll a total of 130 patients, it was stopped early due to slow recruitment, after only 21 patients could be enrolled.⁴² In the IMPRESS in Severe Shock trial (2017), Ouweneel et al randomized 48 patients with AMI-CS to receive either Impella CP or IABP. There was no difference between the 2 groups in 30-day mortality (46% vs 50%; P=.92) or 6-month mortality (both 50%).¹⁰

Observational data on the Impella is primarily registry based, from both independent and industry-sponsored studies. Most independent studies tend to show that Impella may improve hemodynamics and laboratory markers of shock severity, but not survival, in patients with AMI-CS. An analysis of the Impella-EUROSHOCK registry utilizing Impella for AMI-CS observed a significant improvement in plasma lactate levels but 30-day mortality was still high at over 60%.⁴³ Schrage et al matched 237 patients with AMI-CS who received Impella to patients from the IABP-SHOCK II trial, observing no difference in 30-day ­mortality.⁴⁴ Alushi et al observed that Impella improved parameters of shock severity but was not associated with improved 30-day mortality compared with IABP.⁴⁵ Several meta-analyses comparing Impella to IABP in AMI-CS have also found no difference in mortality.^11,46,47

Data also exist (including industry-sponsored studies) that have shown a survival benefit with the use of Impella in AMI-CS. Most of these data indicate that deployment of Impella support early may be most beneficial. The USpella registry showed that early initiation of Impella 2.5 was associated with increased survival to hospital discharge, even after adjustment for confounding variables.⁴⁸ In a study of over 15,000 patients in the Impella quality improvement registry established by Abiomed, O’Neill et al observed early utilization of Impella was associated with favorable outcomes.⁴⁹ Basir et al showed that early initiation of Impella support along with invasive hemodynamic monitoring in AMI-CS was associated with improved hemodynamics and increased survival to discharge.^50,51

Recently, several studies have shown that despite an increase in the use of Impella for AMI-CS over time, there has not been a mortality benefit. Our work utilizing the National Inpatient Sample found an increase in Impella use among patients with AMI-CS from 2012-2015, with no difference in in-hospital mortality over the same time period.¹⁴ Utilizing the National Cardiovascular Data Registry (NCDR), Dhruva et al conducted a propensity score-matched analysis comparing IABP with Impella in AMI-CS, and observed that Impella use was associated with increased mortality and bleeding, regardless of timing of initiation of support.¹⁶ In a study of more than 48,000 patients receiving Impella or IABP support for PCI (including AMI-CS cases), Amin et al observed an increasing trend of Impella use over time, along with increased mortality, acute kidney injury, stroke, and costs associated with Impella use.¹⁵ Compared with IABP, Impella was associated with higher mortality, bleeding, AKI, and stroke. They also noted a wide variation in Impella utilization across hospitals, and that hospitals with higher utilization did not necessarily have better outcomes than lower-use hospitals.

As described above, the improvement of laboratory markers and hemodynamics with Impella use in AMI-CS may not always be accompanied by increased survival. There may be several reasons for this. The diagnosis of AMI-CS may not always be clear, and patients can present across a wide spectrum of severity, from symptoms of heart failure and preserved hemodynamics to hemodynamic collapse and profound multiorgan failure. Some studies have included “all-comers,” encompassing patients across the spectrum of severity of AMI-CS. The inclusion of all-comers with CS in trials and studies may not be appropriate to assess the role for Impella in AMI-CS, as MCS use in very ill patients in advanced stages of shock (ie, those with anoxic brain injury) may not result in meaningful clinical improvement.^15,16,40 Moreover, over 50% of patients with AMI-CS recover without MCS.⁷ Therefore, faced with such a diverse population of AMI-CS patients, it may be difficult for clinicians to identify which patients may benefit most from Impella use, and at which stage of AMI-CS. It is clear that appropriate patient selection appears to be critical. While most agree with the need to identify the right patient population in which to utilize the device, how exactly to accomplish this remains unclear and is a subject of active research, including the currently ongoing DanGer Shock trial.⁵² Lastly, timing of initiation of support is also controversial. A systemic inflammatory syndrome commonly develops late in the CS process, which is a process of pathologic systemic dilatation that may not respond favorably to mechanical LV unloading.⁷ Early and rapid initiation of MCS in patients with AMI-CS, even prior to revascularization, has been shown to be associated with improved survival, perhaps because these patients are in a stage of shock that is still responsive to mechanical support.^53,54

Complications associated with Impella use. Use of the Impella device is associated with several complications, including vascular complications, intravascular hemolysis, and ischemic/hemorrhagic stroke. The vascular complications are mainly related to the large-bore access sites used for implantation and the need for therapeutic anticoagulation while on support and include limb ischemia and bleeding/access-site hematomas. The reported incidence of limb ischemia (0.1%-10%) and bleeding (1%-50%)^55,56 reported in the literature varies widely, mainly due to differing definitions used in studies. Additionally, hemolysis is also of concern, resulting from the shear stress placed on blood cells by axial pumping by the device. The reported incidence of hemolysis reported in the literature is approximately 7%, while the incidence of stroke is approximately 3%-6%.⁵⁵

Based on the available clinical evidence, both the European Society of Cardiology and the American Heart Association/American College of Cardiology have put forth guidelines on the use of MCS devices in patients with AMI-CS (Table 3).

Cost-effectiveness of the Impella device. Cardiogenic shock is associated with high cost of treatment, given the resources and interventions involved with management in the acute care setting and outpatient follow-up. The economic impact of MCS devices can be variable depending on region, payer status, individual study characteristics, and local practice patterns. A study of the Canadian health system observed increased costs with Impella use than IABP use ($80,316 vs $56,055).⁵⁷ Similarly, Dhruva et al observed that hospitalization costs increased with increasing Impella use ($46,989 in 2004 to $51,202 in 2016).¹⁶ On the other hand, there are also data suggesting that the Impella device is a more cost-effective alternative to surgical forms of hemodynamic support. Maini et al observed that use of Impella in patients with CS reduced hospitalization cost by $53,850.⁵⁸ The economic impact of MCS devices has significant implications for healthcare systems and needs further study.

A debate. The rise of Impella use in AMI-CS has been accompanied by debate regarding the appropriate use of the device and ignited calls for further evidence generation to identify an appropriate indication for use. Some critics of the growing trend of the device’s use argue that this practice is driven by observational data from registries and anecdotal evidence rather than data from RCTs.^7,40,59 In contrast, some contend that the negative observational studies comparing Impella with IABP are subject to selection bias, and may mask a possible benefit from Impella use in AMI-CS. For example, statistical efforts to remove bias from studies (eg, propensity-score matching) may not account for residual confounding from unmeasured variables and may result in unbalanced comparisons, resulting in the Impella cohort being “sicker,” hence more likely to suffer complications or mortality, and thus portraying the Impella as ineffective.^60,61 Moreover, proponents argue that a lack of clinical benefit of Impella seen in most studies may perhaps be attributable to the fact that the support was initiated too late in the disease course, when patients were in refractory shock.⁶² Another issue has been the inclusion in some studies of patients with cardiac arrest, which is often accompanied by irreversible neurological damage due to prolonged hypoxia. Notably, over 90% of patients in the IMPRESS in Severe Shock trial had been resuscitated from cardiac arrest, and 46% died due to neurological damage compared with 29% from refractory CS.¹⁰

Opportunities for improvement. The Cardiac Safety Research Consortium ThinkTank has identified several of the issues discussed above as targets for improvement.³ What has become clear is that early identification of AMI-CS is critical, and outcomes may be improved if patients are identified and treated in the “pre-shock” stage, prior to the development of multiorgan failure, at which point any therapy may be futile. The recently introduced SCAI classification system for CS emphasized this pre-CS stage.⁹

The wide variation among hospitals in Impella use has also been identified as a target for improvement. There have been calls for the establishment of standardized protocols for the early diagnosis and treatment of AMI-CS, similar to those that led to improved outcomes for STEMI patients. These include early initiation of MCS and a “door-to-support” time target similar to the “door-to-balloon” concept for STEMI.^3,51,63 This would ideally include a multidisciplinary team-based approach to AMI-CS with input from interventional cardiologists, intensivists, cardiothoracic surgeons, and advanced heart-failure specialists.⁶⁴ One such initiative has been The National Cardiogenic Shock Initiative (NCSI). Formerly known as the Detroit Cardiogenic Shock Initiative, the NCSI has promoted the establishment of protocol-driven care of AMI-CS. One single-arm study from the NCSI found improved outcomes with the establishment of AMI-CS care delivered via such a model, compared with historical controls.⁵¹

An RCT for Impella in AMI-CS. While efforts such as the SCAI classification of CS are encouraging ­developments, the optimal role for Impella and other mechanical support devices in AMI-CS remains to be firmly defined. What has become increasingly clear over the last several years is that there is a dire need for large RCTs to properly evaluate the role of Impella in AMI-CS.

Randomized controlled trials have been scarce in the arena of mechanical circulatory support and AMI-CS for several reasons. Existing RCTs have been underpowered to detect a survival benefit of Impella use, mainly due to the fact that the low event rate of AMI-CS has meant that recruitment for trials has been slow.⁴² Furthermore, in a critical situation, it may not be feasible to obtain informed consent from family members for participation in a trial. The heterogeneity and variable presentation of CS after AMI has made inclusion and randomization challenging—over 50% of patients with AMI-CS may not show clinical signs of shock for several hours after initial presentation.³ Moreover, there are also variable diagnostic criteria for AMI-CS (Table 1) and lack of standardized protocols for Impella use. After the IMPRESS-in-STEMI trial had to be stopped prematurely due to slow patient recruitment, the authors noted that the wide spectrum of presentation of AMI-CS and lack of operator experience with Impella may have contributed to slow enrollment.⁴²

One encouraging development is the currently ongoing Danish-German Shock trial (DanGer Shock; NCT01633502). It is a prospective, multicenter, open-label RCT planning to randomize patients presenting with STEMI complicated by CS in a 1:1 fashion to immediate Impella CP support or conventional guideline-directed therapy. The study was originally initiated in Denmark, and planned to enroll 360 patients, with the first patient recruited in January 2013. It is subject to strict inclusion and exclusion criteria.⁵² Notably, patients with out-of-hospital cardiac arrest were excluded, as these patients typically die from irreversible neurologic injury, and would likely not benefit from a support device. While the strict inclusion and exclusion criteria allowed for selection of a more homogenous patient population most likely to derive benefit from Impella support, they also resulted in slow patient recruitment, with only 100 patients recruited by June 2018 in Denmark. The study was then expanded to Germany, in order to improve recruitment. Data collection for DanGer shock is expected to complete in September 2022. 

In addition to the ongoing DanGer Shock trial, Abiomed also recently announced its intent to conduct a similar trial (RECOVER-IV) examining the role of pre-PCI Impella support with conventional therapy (including non-Impella circulatory support devices) in AMI-CS patients. While the trial design is still being developed and exact study design has not been published, the trial is expected to follow the inclusion and exclusion criteria of the NCSI registry.⁶⁵ Further details regarding the DanGer Shock trial and NCSI registry are displayed in Table 4.

Conclusion

The Impella pump has rapidly become a popular MCS device utilized by clinicians in the battle against CS. While it is designed based on sound mechanistic principles acting on critical targets in the pathophysiology of CS and has shown promising results in preclinical and animal studies, human clinical studies have shown contradictory results. Despite lack of evidence of clinical benefit, clinical use of the device continues to increase, and thus the device has been controversial. Several RCTs are either ongoing or planned, and are expected to shed more light on the optimal role for Impella in CS.

Affiliations and Disclosures

From the ¹Tulane University Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana; ²Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute; ³Department of Internal Medicine, Cleveland Clinic, Cleveland, Ohio; and ⁴Heart, Vascular and Thoracic Department, Cleveland Clinic Akron General, Akron, Ohio.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript accepted February 11, 2022.

Address for correspondence: Ankur Kalra, MD, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, Cleveland Clinic, Regional Section of Interventional Cardiology at Cleveland Clinic Akron General, 224 West Exchange St, Suite 225, Akron, OH 44302. Email: kalraa@ccf.org

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