Development and evolution of nuclear cardiology and cardiac PET in Canada.

Gated radionuclide angiography and myocardial perfusion imaging were developed in the United States and Europe in the 1970's and soon adopted in Canadian centers. Much of the early development of nuclear cardiology in Canada was in Toronto, Ontario and was quickly followed by new programs across the country. Clinical research in Canada contributed to the further development of nuclear cardiology and cardiac PET. The Canadian Nuclear Cardiology Society (CNCS) was formed in 1995 and became the Canadian Society of Cardiovascular Nuclear and CT Imaging (CNCT) in 2014. The CNCS had a major role in education and advocacy for cardiovascular nuclear medicine testing. The CNCS established the Dr Robert Burns Lecture and CNCT named the Canadian Society of Cardiovascular Nuclear and CT Imaging Annual Achievement Award for Dr Michael Freeman in memoriam of these two outstanding Canadian leaders in nuclear cardiology. The future of nuclear cardiology in Canada is exciting with the expanding use of SPECT imaging to include Tc-99m-pyrophosphate for diagnosis of transthyretin cardiac amyloidosis and the ongoing introduction of cardiac PET imaging.

Unexpected diagnosis of metastatic breast carcinoma in an endomyocardial biopsy done for cardiac allograft rejection evaluation.

We report a case of a 75-year-old female post orthotopic heart transplantation, who presented to the emergency department with a six-week history of shortness of breath, hand tremor and ultimately delirium. She had lobular breast carcinoma more than 5 years prior to her heart transplant, treated by lumpectomy followed by anthracycline based chemotherapy. The reason for her heart transplant was heart failure that was suspected to be from anthracycline cardiomyopathy, however, her explanted heart actually showed cardiac sarcoidosis. She was placed on long-term immunosuppression with tacrolimus, mycophenolate mofetil and prednisone. Two years after her heart transplant, she underwent bilateral mastectomies for recurrent breast cancer. Her neurological workup, including brain imaging (CT, MRI, LP and EEG) did not show any structural abnormalities, ischemia, mass or neurosarcoidosis as cause for delirium. Tacrolimus was held due to renal dysfunction and hemolytic anemia, and then she developed signs of right heart failure so an endomyocardial biopsy was carried out for suspected allograft rejection. The biopsy did not show any evidence of cellular or antibody medicated rejection; however, it demonstrated infiltration by bland appearing cells with signet ring morphology cells many of which showed intracytoplasmic mucin. The cells were strongly positive with cytokeratins AE1/3, CK7 and mammaglobin. The morphology and immunoprofile were consistent with metastatic lobular breast carcinoma and this was thought to be the cause of her clinical presentation with delirium, hemolytic anemia and renal dysfunction as a paraneoplastic syndrome.

HEARTBiT: A Transcriptomic Signature for Excluding Acute Cellular Rejection in Adult Heart Allograft Patients.

BACKGROUND: Nine mRNA transcripts associated with acute cellular rejection (ACR) in previous microarray studies were ported to the clinically amenable NanoString nCounter platform. Here we report the diagnostic performance of the resulting blood test to exclude ACR in heart allograft recipients: HEARTBiT. METHODS: Blood samples for transcriptomic profiling were collected during routine post-transplantation monitoring in 8 Canadian transplant centres participating in the Biomarkers in Transplantation initiative, a large (n = 1622) prospective observational study conducted between 2009 and 2014. All adult cardiac transplant patients were invited to participate (median age = 56 [17 to 71]). The reference standard for rejection status was histopathology grading of tissue from endomyocardial biopsy (EMB). All locally graded ISHLT ≥ 2R rejection samples were selected for analysis (n = 36). ISHLT 1R (n = 38) and 0R (n = 86) samples were randomly selected to create a cohort approximately matched for site, age, sex, and days post-transplantation, with a focus on early time points (median days post-transplant = 42 [7 to 506]). RESULTS: ISHLT ≥ 2R rejection was confirmed by EMB in 18 and excluded in 92 samples in the test set. HEARTBiT achieved 47% specificity (95% confidence interval [CI], 36%-57%) given ≥ 90% sensitivity, with a corresponding area under the receiver operating characteristic curve of 0.69 (95% CI, 0.56-0.81). CONCLUSIONS: HEARTBiT's diagnostic performance compares favourably to the only currently approved minimally invasive diagnostic test to rule out ACR, AlloMap (CareDx, Brisbane, CA) and may be used to inform care decisions in the first 2 months post-transplantation, when AlloMap is not approved, and most ACR episodes occur.

Incidental mammary fibromyoblastoma on 82Rb myocardial perfusion imaging.

82Rb is frequently used in PET myocardial perfusion imaging to detect ischemia. We present the case of a 64-year-old man referred for PET myocardial perfusion imaging to rule out ischemia. On PET images, an abnormal focus of uptake was present in the subcutaneous soft tissue overlying the right chest, which corresponded to a soft-tissue nodule on CT. This lesion was biopsied and proved to be a mammary fibromyoblastoma, an extremely rare and benign lesion. This case is presented to emphasize the importance of reviewing extracardiac structures on PET/CT myocardial perfusion studies.

Giant cell myocarditis in a patient with a spondyloarthropathy after a drug hypersensitivity reaction.

A young woman thought to have seronegative rheumatoid arthritis developed Stevens-Johnson syndrome after treatment with sulfasalazine; this resolved with prednisone. Later she was found to be HLA-B27-positive in keeping with a spondyloarthropathy. Soon afterward, she developed clinical myopericarditis and cardiogenic shock that responded initially to methylprednisolone and intravenous immunoglobulin, but recurred. An endomyocardial biopsy demonstrated active myocarditis with a mixed cell composition including rare giant cells, but not enough to classify it as giant cell myocarditis. Heart failure symptoms returned and she eventually required a heart transplant; the explanted heart showed giant cell myocarditis.

Cardiorenal syndrome and heart failure.

PURPOSE OF REVIEW: Concomitant anemia, heart failure, and renal disease can be seen in a large proportion of patients with heart failure. The purpose of this review is to discuss the current definitions and mechanisms involved in this pathophysiological relationship, as well as the potential management and treatment options available for these patients. RECENT FINDING: Dysfunctional heart can promote the dysfunction of the kidneys through a variety of pathophysiological mechanism, the reciprocal holds true as well. Heart failure has been considered as the most common type of cardiovascular complication seen in patients with renal failure. Central to this relationship lies anemia, which can be the result or the cause of either heart or kidney disease. SUMMARY: Cardiorenal syndrome is a complex condition, which requires the collaboration and resources from cardiology, cardiac surgery, nephrology, and critical care. Of great importance is recognizing the presence of cardiorenal syndrome and appreciating the impact it can play on treatment options and survival.

Relationship between natriuretic peptides and inflammation: proteomic evidence obtained during acute cellular cardiac allograft rejection in humans.

BACKGROUND: Cardiac natriuretic peptides (NPs) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are polypeptide hormones secreted by the heart. Previously, we found that BNP, but not ANF, plasma levels may increase during an acute cellular cardiac allograft rejection episode. In vitro, the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) produced a selective increase of BNP gene expression and secretion. Other pro-inflammatory cytokines had no such effects. METHODS: We identified cytokines associated with the selective upregulation of BNP during cardiac allograft rejection using a proteomics approach to measure 120 cytokines and related substances in the plasma of 16 transplant patients before, during and after an acute rejection episode. The values obtained were correlated with BNP plasma levels. Cytokines identified as being significantly related to BNP plasma levels were tested in neonatal rat ventricular cardiocytes in culture for their ability to selectively promote BNP secretion. The signaling pathway related to this phenomenon was pharmacologically characterized. RESULTS: Regulated-on-activation, normal T-expressed and secreted (RANTES), neutrophil-activating protein-2 (NAP-2) and insulin growth factor binding protein-1 (IGFBP-1) had significant correlations with BNP plasma levels during Grade 3A (Grade 2 revised [2R]) or above rejection as diagnosed by endomyocardial biopsy score according to the International Society for Heart and Lung Transplantation (ISHLT) grading system. In rat neonatal ventricular cardiocyte cultures, IGFBP-1 and RANTES were capable of promoting BNP, but not ANF secretion, as observed in rejecting patients. The BNP-promoting secretion activity of the identified cytokines was abolished by SB203580, a specific p38 MAP kinase inhibitor. CONCLUSIONS: This work shows that cytokines other than pro-inflammatory cytokines correlate with BNP plasma levels observed during acute cardiac allograft rejection, and that the substances identified have in common p38 signaling. This finding provides a unifying mechanistic explanation regarding the relationship between inflammation and cardiac hormone production in acute cardiac allograft rejection.

Cardiac actinomycosis: an unusual cause of an intracardiac mass.

Actinomycosis is a chronic disease characterized by abscess formation, tissue fibrosis, and draining sinuses that may involve the cervicofacial area, thorax, abdominopelvic region, or central nervous system. We describe a patient with cardiac actinomycosis presenting with pericardial disease and an intracardiac mass. The diagnosis failed to be obtained by pericardiocentesis, but was obtained after echocardiographically guided biopsy of the intracardiac mass. The patient recovered with long-term penicillin therapy. A review of the literature highlights the frequent pericardial presentation of cardiac actinomycosis, the potential difficulty in making the diagnosis, and the remarkable clinical response and good prognosis that can result when the correct diagnosis is made and appropriate antibiotic therapy administered.

Papillary fibroelastoma of the pulmonary valve.

There is a lack of information regarding the diagnosis and management of papillary fibroelastoma of the pulmonary valve due to the rarity of the tumour at this location. A case of pulmonary valve papillary fibroelastoma in a 60-year-old woman is reported and the approach for diagnosis and management is described.

Tricuspid valve chordal tissue in endomyocardial biopsy specimens of patients with significant tricuspid regurgitation.

OBJECTIVES: Tricuspid regurgitation is the most common valvular abnormality after orthotopic heart transplantation, with multiple etiologic factors implicated. The purpose of this study was to determine if the endomyocardial biopsy specimens of patients who developed significant tricuspid valve regurgitation (TVR) after cardiac transplantation had evidence of chordal tissue. METHODS: The echocardiograms of 98 patients who had cardiac transplantation between 1986 and 2002 were reviewed for evidence of significant TVR greater than mild. The biopsy specimens of all patients with significant TVR were then reviewed for histologic evidence of tricuspid chordal tissue and frequency and severity of rejection episodes. Clinical information collected included the presence of any systolic murmurs, significant dyspnea, and invasive hemodynamic measurements. RESULTS: The incidence of significant TVR was 19% (n = 19 patients). Histologic evidence of chordal tissue was present in 9 patients (47%) with significant TVR. Patients whose biopsy specimens evidenced chordal tissue tended to have a greater degree of TVR, but this was not statistically significant (odds ratio, 2.07; 95% confidence interval, 0.537-8.01, p = 0.32). There was no statistically significant difference in the number of biopsy specimens (p = 0.798), the number of rejection episodes (p = 0.73), or overall left or right ventricular systolic function between the patients with and without biopsy specimen evidence of chordal tissue disruption. Most of the patients with evidence of significant TVR after chordal tissue biopsy were clinically asymptomatic, with no significant change in their hemodynamics. CONCLUSION: Histologic evidence of chordal tissue in endomyocardial biopsy specimens was present in 47% of patients with significant TVR and did not relate to the number of biopsy procedures performed or the frequency of rejection episodes. This study provides histologic evidence that chordal tissue damage can occur after cardiac biopsy, resulting in significant TVR; however, it is clinically well tolerated by affected patients.

Neuroendocrine profiling of humans receiving cardiac allografts.

BACKGROUND: Several studies have investigated changes in circulating hormones and markers of cardiac status after heart transplantation in humans. As a result, plasma levels of various hormones and autocoids have been associated with cardiac allograft rejection status. However, no clear associations can be defined given the highly contradictory nature of the available literature. METHODS: In this study of 69 consecutive heart transplant patients followed for >2 years we examine the relationship between neurohumors potentially related to allograft rejection and endomyocardial biopsy grade of rejection (according to the ISHLT) and hemodynamic status. Markers assessed include brain natriuretic peptide (BNP), amino-terminal pro-BNP (N-BNP), atrial natriuretic factor (ANF), adrenomedullin, interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, troponin C and C-reactive protein. RESULTS: The highest plasma levels for most neurohumors were found shortly after surgery and showed a trend towards normalization with time. BNP and N-BNP were the only significantly elevated plasma analytes for patients with Grade 3 rejection as compared with other ISHLT grades. ANF plasma levels correlated with BNP and N-BNP in Grades 0 to 2, but not in Grade 3, suggesting that in this rejection grade the usual coordinated changes observed in BNP and ANF secretion no longer exist. Cardiac filling pressures were correlated with plasma BNP, N-BNP and ANF levels only for Grades 0 and 1. CONCLUSIONS: The timing of blood sampling after transplantation influences the level of the neurohumors measured, which may help explain the conflicting literature reports on the association between neurohumor levels and rejection grade. The significant increase in circulating levels of BNP and N-BNP observed in most cases of Grade 3 rejection occurred with no apparent relationship to post-transplantation time, which suggests a specific influence of acute rejection on BNP gene expression.

Issues influencing development of the Canadian Cardiovascular Information Network.

The 1995 Consensus Conference of the Canadian Cardiovascular Society on "Indications for and Access to Revascularization" recommended that Canadian centres with invasive cardiovascular facilities should participate in a national observational database that monitors the selection of patients, as well as evaluate outcomes. The Canadian Cardiovascular Society, the Heart and Stroke Foundation of Canada, and Health Canada with IBM as a partner, initiated a process to identify factors influencing the development of the Canadian Cardiovascular Information Network. IBM's "Business Discovery Methodology" was adapted for health care. Structured interviews with representatives of health organizations, cardiovascular databases and research institutes were conducted across Canada, followed by a workshop to identify goals, issues and challenges. Participants identified goals for a cardiovascular database (eg, evidence-based decision-making), project related issues (eg, respecting the integrity of existing databases) and health care related issues (eg, cardiac waiting lists). Challenges included initial mistrust between representatives of provincial cardiovascular databases and national agencies, and a lack of sustained funding. A Project Team was formed to address 'cardiac waiting lists'. Analysis of Alberta and Ontario data identified differences in definitions, such as when the waiting time for bypass surgery began, that impeded detailed comparisons. Development of a centralized national database was not feasible at this time for political, technical and financial reasons. However, provincial cardiovascular database representatives agreed to work together and to share aggregate data and analyses. A first step toward developing a national surveillance system for cardiovascular services will be achieving consensus about standardizing data definitions. This process will require sustained funding.

Ventricular assist devices as a bridge to cardiac transplantation: the Ottawa experience.

This article reports our experience with ventricular assist devices (VADs) as a bridge to cardiac transplantation. From 1991 to 2003, a total of 42 patients received a Thoratec VAD (Thoratec Laboratories Corporation Inc., Pleasanton, CA, U.S.A.) (Group T) and 12 patients received a Novacor VAD (WorldHeart Corporation, Ottawa, Canada) (Group N). Thirty Thoratec patients were transplanted compared to six in the Novacor group. Four more Novacor patients are still supported. Of the transplanted patients, 87% survived to hospital discharge in Group T and 67% in Group N. Infections affected 29% and 50% of Group T patients during support and post-transplantation, respectively, compared to 25% and 0%, respectively, in Group N. Neurologic complications affected 33% of patients in each group during support. Reopening rates for bleeding during support were 45% and 42% in Groups T and N, respectively. There were no significant differences in outcomes between the two groups. Our study demonstrated the effectiveness of VADs in bridging mortally ill cardiac patients to successful heart transplantation.

Giant cell myocarditis: clinical presentation, bridge to transplantation with mechanical circulatory support, and long-term outcome.

BACKGROUND: The multicenter Giant Cell Myocarditis Registry recorded 64 cases from 36 centers before 1996. The median transplant-free survival of 30 patients without immunosuppression was 3 months. Of 34 patients who received heart transplantations, 9 experienced recurrence of giant cell myocarditis in their transplanted hearts and 1 patient died. METHODS: We reviewed our experience in 340 heart transplantations since 1984. Unexpected giant cell myocarditis was found in the explanted hearts of 7 patients (6 men and 1 female, aged 18-65 years). RESULTS: The duration from the onset of symptoms to assist-device implant or transplantation ranged from 11 days to 9 years, whereas the time interval from referral or deterioration ranged from 2 days to 4 months. Four patients required mechanical circulatory support before surgery (total artificial hearts in 2 and left ventricular assist devices in 2), and 3 patients required inotropic drugs. Six patients are alive with no sign of recurrent giant cell myocarditis at 12 to 113 months after surgery. One patient died suddenly 75 months after surgery, and autopsy showed severe graft vascular disease with no recurrence of giant cell myocarditis. Surveillance, right ventricular endomyocardial biopsy specimens showed recurrent asymptomatic giant cell myocarditis in 3 patients at 5 to 13 months after surgery, and found recurrence in 1 patient 30 months after surgery. This patient received augmented immunosuppression. CONCLUSIONS: Giant cell myocarditis often is not diagnosed before transplantation. It can present as dilated cardiomyopathy with late deterioration, or it can present with rapid hemodynamic deterioration. In our experience, these patients can be bridged successfully to transplant with mechanical circulatory assist. Giant cell myocarditis may recur after transplantation but may respond to augmented immunosuppression.