Transplant of stunned donor hearts rescued by pharmacological stress echocardiography: a “proof of concept” report

After legal declaration of brain death, marginal donors underwent baseline echocardiography for evaluation of regional wall motion, global ventricular function, and ventricular mass, according to American Society of Echocardiography recommendations [9].

Stress echocardiography was performed following the European Association of Echocardiography and American Society of Echocardiography [10, 11] protocol, using dipyridamole (0.84 mg/kg over 6 min). Echocardiographic images were continuously recorded and intermittently digitized. Regional wall motion score index was assessed and graded on a scale from 1 (normal) to 4 (dyskinetic) in each of the 17 segments at rest and after stress. LV wall motion score index was calculated by summing the scores and dividing the sum by 17. By definition, donors with abnormal stress echocardiographic results had fixed wall motion abnormalities and/or stress-induced wall motion abnormalities. We also considered changes in LV volumes as an index of global dysfunction, and pressure and volume changes as an index of LV elastance [6, 12]. At baseline and peak stress, the projections of the four chambers and of the two apical chambers were recorded to obtain LV end-systolic volume using the biplane Simpson rule [9] to calculate LV elastance (the ratio of systolic pressure by cuff sphygmomanometry to LV end-systolic volume) [12]. A decrease in LV elastance during stress was considered abnormal. In a previous study, this response was shown to be associated with moderate to severe coronary or myocardial abnormalities on cardiac autopsy verification [13]. Potential donors with normal stress echocardiography are considered suitable donors; recipients follow a routine treatment. We accepted a priori four stress echocardiographic criteria excluding a heart from eligibility as a donor: (1) new regional wall motion abnormalities (regional wall motion score > 1.0 in at least one segment), (2) abnormal regional or global LV dysfunction with fixed response to stress; (3) negative LV elastance variation during stress (stress value less than resting value), and (4) submaximal stress prematurely stopped because of non-diagnostic limiting effects (e.g., hemodynamic instability or hypotension with a decrease > 40 mmHg in systolic or diastolic blood pressure) before completion of the infusion. Each of the four criteria had a different rationale and target: a new-onset regional wall motion abnormality is a highly specific sign of a significant epicardial artery stenosis [10, 11]; a fixed response of abnormal regional or global LV function is a specific sign of an irreversibly damaged heart that will not recover, due to extensive necrosis or scarring, and is not eligible for transplant; a lack of hyperkinetic response with no increase in pressure/volume index is a sensitive marker of underlying cardiomyopathy [6], and a submaximal test loses diagnostic and prognostic power and falls within a gray zone unacceptable in the transplantation setting [10, 11]. Eligible organs were considered for transplantation [14]. Hearts that were not eligible underwent pathologic examination [13].

Eligible hearts (with normal echocardiographic findings) were retrieved using a standard technique and preserved with cold cardioplegic arrest and topical hypothermia. Primary graft failure after HT was defined as need for immediate post-HT mechanical circulatory support [3]. The recipients followed routine treatment and follow-up procedures. They underwent coronary angiography and intravascular ultrasound at the first month [3]. Focal and non-circumferential atherosclerosis with 50% stenosis in proximal segments of at least one coronary vessel was regarded as native and donor-transmitted coronary atherosclerosis [15]. Endomyocardial biopsies (EMBs) were taken for post-transplant rejection status surveillance. All transplanted hearts were followed, and any adverse event was monitored.

Hearts deemed unsuitable as a result of stress echocardiographic results were removed from donors and sent to the Pathology Department Center for a very detailed macroscopic and microscopic study [13]. Autopsies were performed by an experienced cardiac pathologist. Coronary atherosclerosis was graded as absent, subcritical, or significant. In accordance with the criteria of cardiac catheterization given above, significant atherosclerosis was defined as focal and non-circumferential atherosclerosis with 50% stenosis in proximal segments of at least one coronary vessel.

The stress echo results were abnormal in three donors: WMSI peak = 1.41 ± 0.30, with a flat-negative contractile reserve (Figures 1 and 2) (Additional files 1 and 2). At autopsy study (available in two), the donor with incomplete recovery of apical hypokinesia showed myocardial fibrosis with a mild DCM aspect (Table 1, donor #1); the donor with worsening of apical akinesia (Table 1, donor #3) showed a 90% LAD stenosis, multiple foci of coagulative necrosis associated with diffuse coagulative subendocardial myocytolysis (Figure 3).

The remaining three hearts showed reversible left ventricular resting abnormalities (Figures 4, 5, 6 and 7) (Additional files 3, 4 and 5). WMSI rest = 1.15 ± 0.13 vs peak = 1.04 ± 0.06. All had positive contractile reserve, with LV elastance increase during stress. These three hearts were transplanted uneventfully and underwent standard post TX coronary, angiography, IVUS and endomyocardial biopsies. The recipients were male, age 53 ± 4 years. No recipient had primary graft failure and all showed normal coronary vessel at 1-month post-TX coronary angiography: left ventricular function was normal at 1 month post-TX (LVEF = 57 ± 6%; WMSI = 1 ± 0). In the EMBs taken for post-transplant rejection status surveillance, no significant ischemic peritransplant injury was noted in two recipients (Table 1, donors #4 and #6) (Figure 6). The recipient of the donor heart with mild left ventricular hypertrophy and reversible septal hypokinesia (Table 1, donor #5) showed at EMBs mild peritransplant injury (Figure 8). The recipients were alive at 12-month median follow-up.

Left ventricular dysfunction is a common finding in patients with intracranial pathologies and brain stem death. In 147 patients with subarachnoid hemorrhage, global or regional LV dysfunction was found in 30 (20%) patients on echocardiography. Regional wall motion abnormalities tended to cover multiple arterial territories and occurred in the absence of coronary artery disease [20]. This frequency has been confirmed in a retrospective study of 66 patients with brain stem death, 28 (42%) of whom were found to have global or segmental LV dysfunction that was not predicted by clinical and electrocardiographic examination [21]. Secondly, left ventricular dysfunction documented on echocardiography in heart donors with BSD does not appear to correspond to any demonstrable pathological abnormality at postmortem [22]. Thirdly, there is clear evidence not only that donor hearts with mild abnormalities in LV function on rest echocardiography can be successfully transplanted but also that donor hearts with more severe regional wall abnormalities may improve immediately post-transplant [23]. The stress echo approach might also be applied to these potential heart donors with left ventricular wall motion abnormalities, since viability response during stress echo effectively recognizes viable tissue with non-fixed response, as opposed to necrotic response with scar and fixed wall motion abnormalities following inotropic challenge with either dobutamine or dipyridamole [24, 25].