Ross A. Davies

Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients

OBJECTIVES This study sought to analyze the outcomes of revascularization procedures in the treatment of allograft coronary disease. BACKGROUND Allograft vasculopathy is the main factor limiting survival of heart transplant recipients. Because no medical therapy prevents allograft atherosclerosis, and retransplantation is associated with suboptimal allograft survival, palliative coronary revascularization has been attempted. METHODS Thirteen medical centers retrospectively analyzed their complete experience with percutaneous transluminal coronary angioplasty, directional coronary atherectomy and coronary bypass graft surgery in allograft coronary disease. RESULTS Sixty-six patients underwent coronary angioplasty. Angiographic success (< or = 50% residual stenosis) occurred in 153 (94%) of 162 lesions. Forty patients (61%) are alive without retransplantation at 19 +/- 14 (mean +/- SD) months after angioplasty. The consequences of failed revascularization were severe. Two patients sustained periprocedural myocardial infarction and died. Angiographic restenosis occurred in 42 (55%) of 76 lesions at 8 +/- 5 months after angioplasty. Angiographic distal arteriopathy adversely affected allograft survival. Eleven patients underwent directional coronary atherectomy. Angiographic success occurred in 9 (82%) of 11 lesions. Two periprocedural deaths occurred. Nine patients are alive without transplantation at 7 +/- 4 months after atherectomy. Bypass graft surgery was performed in 12 patients. Four patients died perioperatively. Seven patients are alive without retransplantation at 9 +/- 7 months after operation. CONCLUSIONS Coronary revascularization may be an effective palliative therapy in suitable cardiac transplant recipients. Angioplasty has an acceptable survival in patients without angiographic distal arteriopathy. Because few patients underwent atherectomy and coronary bypass surgery, assessment of these procedures is limited. Angiographic distal arteriopathy is associated with decreased allograft survival in patients requiring revascularization.

Right and Left Ventricular Exercise Performance in Chronic Obstructive Pulmonary Disease: Radionuclide Assessment

Right and left ventricular pump performance was assessed at rest and during upright bicycle exercise in 30 patients with chronic obstructive pulmonary disease and in 25 normal control subjects. Right ventricular and left ventricular ejection fractions were ascertained noninvasively using first-pass quantitative radionuclide angiocardiography. The normal ventricular response to exercise was at least a 5% absolute increase in the ejection fraction of either ventricle. In patients the predominant cardiac abnormality involved performance of the right ventricle. Right ventricular ejection fraction was abnormal at rest in eight patients. Twenty-three patients demonstrated an abnormal right ventricular response to submaximal exercise. Airway obstruction and arterial hypoxemia were significantly more severe in patients with abnormal right ventricular exercise reserve than in those with normal reserve. Abnormal left ventricular performance was infrequent either at rest (four patients) or during exercise (six patients). Thus, this radionuclide technique allows noninvasive assessment of biventricular exercise reserve in chronic obstructive pulmonary disease.

Discoordinate Modulation of Natriuretic Peptides During Acute Cardiac Allograft Rejection in Humans

BACKGROUND Increased circulating levels of the cardiac polypeptide hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) may be observed after orthotopic cardiac transplantation. Both the hypertrophic and inflammatory processes in the allograft may contribute to this increase, but no mechanistic explanation has been suggested for this observation. METHODS AND RESULTS Plasma immunoreactive ANF and BNP determinations were performed in 10 consecutive transplant patients. These were correlated with degree of rejection as reflected by histopathological findings at serial endomyocardial biopsies. Three patients had associated hemodynamic measurements and blood samples 24 hours before and after transplantation. All rejection episodes that received treatment were accompanied by a marked increase in BNP plasma levels to > approximately 400 pg/mL. Steadily increasing BNP levels preceded overt rejection as assessed by histopathological criteria. The increase in plasma BNP was not always accompanied by an increase in ANF, which suggests the specific upregulation of BNP gene expression during acute rejection episodes. Treatment of the acute rejection episodes led to a substantial decrease of BNP plasma levels. CONCLUSIONS The significant selective increase in plasma BNP levels found in the present study has not been previously described. This finding provides a new insight into the mechanism of allograft rejection and the modulation of natriuretic peptide synthesis and release. Furthermore, although preliminary, the data suggest that BNP plasma levels could form the basis for a new, noninvasive screening test to predict acute cardiac allograft rejection. Because treatment with the antilymphocyte monoclonal antibody OKT3 (murine monoclonal antibody to the CD3 antigen of the human T-cell) decreased BNP plasma levels, cytokine production by T-cells may mediate the selective increase in circulating BNP.

Beat-to-beat left ventricular performance assessed from the equilibrium cardiac blood pool using a computerized nuclear probe.

SUMMARY The feasibility, accuracy and reproducibility of continuous beat-to-beat evaluation of left ventricular performance with a computerized nonimaging scintillation probe was assessed in 71 patients. This portable instrument has enough sensitivity to generate a real-time relative left ventricular volume curve using the labeled equilibrium blood pool without electrocardiographic gating. The probe was positioned at the left ventricular and background regions of interest using a systematic series of computerized algorithms and operator routines that were developed and standardized during the initial phase of this study. In each patient, left ventricular ejection fraction was calculated manually from the strip-chart recording in 10 consecutive sinus beats. Beat-to-beat left ventricular ejection fraction determined by the probe correlated well with first-pass studies obtained using a computerized multicrystal scintillation camera (r = 0.92). There was no systematic over- or underestimation, and the correlation was evident over a wide range of first-pass values (15–81%). There was excellent agreement between initial and repeat analyses (n = 58, r = 0.97) and between initial and repeat studies (n = 48, r = 0.94). The absolute variability of beat-to-beat ejection fraction measurements determined from all 710 beats was ± 5.9% (expressed in ejection fraction units as ± 2 SD). This technique should provide a reliable means of addressing pathophysiologic questions that require sampling of data directly on a beat-tobeat basis.

18F-FDG PET Imaging of Myocardial Viability in an Experienced Center with Access to 18F-FDG and Integration with Clinical Management Teams: The Ottawa-FIVE Substudy of the PARR 2 Trial

18F-FDG PET may assist decision making in ischemic cardiomyopathy. The PET and Recovery Following Revascularization (PARR 2) trial demonstrated a trend toward beneficial outcomes with PET-assisted management. The substudy of PARR 2 that we call Ottawa-FIVE, described here, was a post hoc analysis to determine the benefit of PET in a center with experience, ready access to 18F-FDG, and integration with clinical teams. Methods: Included were patients with left ventricular dysfunction and suspected coronary artery disease being considered for revascularization. The patients had been randomized in PARR 2 to PET-assisted management (group 1) or standard care (group 2) and had been enrolled in Ottawa after August 1, 2002 (the date that on-site 18F-FDG was initiated) (n = 111). The primary outcome was the composite endpoint of cardiac death, myocardial infarction, or cardiac rehospitalization within 1 y. Data were compared with the rest of PARR 2 (PET-assisted management [group 3] or standard care [group 4]). Results: In the Ottawa-FIVE subgroup of PARR 2, the cumulative proportion of patients experiencing the composite event was 19% (group 1), versus 41% (group 2). Multivariable Cox proportional hazards regression showed a benefit for the PET-assisted strategy (hazard ratio, 0.34; 95% confidence interval, 0.16–0.72; P = 0.005). Compared with other patients in PARR 2, Ottawa-FIVE patients had a lower ejection fraction (25% ± 7% vs. 27% ± 8%, P = 0.04), were more often female (24% vs. 13%, P = 0.006), tended to be older (64 ± 10 y vs. 62 ± 10 y, P = 0.07), and had less previous coronary artery bypass grafting (13% vs. 21%, P = 0.07). For patients in the rest of PARR 2, there was no significant difference in events between groups 3 and 4. The observed effect of 18F-FDG PET–assisted management in the 4 groups in the context of adjusted survival curves demonstrated a significant interaction (P = 0.016). Comparisons of the 2 arms in Ottawa-FIVE to the 2 arms in the rest of PARR 2 demonstrated a trend toward significance (standard care, P = 0.145; PET-assisted management, P = 0.057). Conclusion: In this post hoc group analysis, a significant reduction in cardiac events was observed in patients with 18F-FDG PET–assisted management, compared with patients who received standard care. The results suggest that outcome may be benefited using 18F-FDG PET in an experienced center with ready access to 18F-FDG and integration with imaging, heart failure, and revascularization teams.

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.

In vivo and in vitro examination of the functional significances of novel lamin gene mutations in heart failure patients

Context: Lamin A/C (LMNA) gene variations have been reported in more than one third of genotyped families with dilated cardiomyopathy (DCM). However, the relationship between LMNA mutation and the development of DCM is poorly understood. Methods and results: We found that end stage DCM patients carrying LMNA mutations displayed either dramatic ultrastructural changes of the cardiomyocyte nucleus (D192G) or nonspecific changes (R541S). Overexpression of the D192G lamin C dramatically increased the size of intranuclear speckles and reduced their number. This phenotype was only partially reversed by coexpression of the D192G and wild type lamin C. Moreover, the D192G mutation precludes insertion of lamin C into the nuclear envelope when co-transfected with the D192G lamin A. By contrast, the R541S phenotype was entirely reversed by coexpression of the R541S and wild type lamin C. As lamin speckle size is known to be correlated with regulation of transcription, we assessed the SUMO1 distribution pattern in the presence of mutated lamin C and showed that D192G lamin C expression totally disrupts the SUMO1 pattern. Conclusion: Our in vivo and in vitro results question the relationship of causality between LMNA mutations and the development of heart failure in some DCM patients and therefore, the reliability of genetic counselling. However, LMNA mutations producing speckles result not only in nuclear envelope structural damage, but may also lead to the dysregulation of cellular functions controlled by sumoylation, such as transcription, chromosome organisation, and nuclear trafficking.

Measurement of left ventricular ejection fraction by acoustic quantification and comparison with radionuclide angiography

Left ventricular (LV) ejection fraction (EF) is an important measure of systolic function, with radionuclide angiography being the accepted standard for its determination. Echocardiography is ideal for repeated measurements of EF, but most methods are either subject to error in the presence of regional wall abnormalities or require cumbersome off-line analysis. Acoustic quantification is a recently introduced method that allows for the continuous on-line display of LV cavity dimensions, but the on-line algorithm for the measurement of EF has not been validated against an independent standard in the clinical setting. This study attempted to validate acoustic quantification in the determination of EF by comparison with off-line echocardiographic analysis and radionuclide angiography in 54 patients referred for this latter procedure. Acoustic quantification correlated well with off-line analysis in both the apical 4-chamber (r = 0.89, n = 43) and 2-chamber (r = 0.86, n = 26) views. Similarly, it also correlated well with radionuclide angiography in the 4-chamber (r = 0.81, n = 44) and 2-chamber (r = 0.83, n = 26) views. The correlation between the 2 methods was further improved when only the last 30 patients were assessed (r = 0.91, n = 25 for 4-chamber views; r = 0.86, n = 16 for 2-chamber views). The correlation was worse in patients with regional asynergy (r = 0.69, n = 17 for 4-chamber views; r = 0.76, n = 10 for 2-chamber views). Moreover, acoustic quantification tended to underestimate EF when compared with radionuclide angiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Improvement in cardiac performance by oral long-acting theophylline in chronic obstructive pulmonary disease

Although oral theophylline is a widely used bronchodilator in chronic obstructive pulmonary disease (COPD), its effects upon cardiac performance have not been fully established. The effect of slow release oral theophylline upon right ventricular and left ventricular ejection fraction was evaluated using first-pass quantitative radionuclide angiocardiography in 15 patients with COPD. After 72 hours of therapy, oral theophylline significantly increased right ventricular ejection fraction (42% to 48%, p less than 0.005). In 7 of 10 patients with depressed baseline right ventricular performance, including two with cor pulmonale, right ventricular ejection fraction normalized (greater than or equal to 45%). After long-term therapy, an average of 16 weeks, right ventricular fraction also increased (43% to 48%, p less than 0.005). Left ventricular ejection fraction improved significantly from 64% to 68% (p less than 0.05) at 72 hours and from 61% to 65% (p less than 0.025) after long-term therapy. These data indicate that oral theophylline produces a sustained modest enhancement of resting biventricular performance in COPD.

Exercise Left Ventricular Performance in Patients with Chest Pain, Ischemic-Appearing Exercise Electrocardiograms, and Angiographically Normal Coronary Arteries

Left ventricular performance was evaluated using first-pass radionuclide angiocardiography in 31 patients with chest pain, an ischemic-appearing exercise electrocardiogram, and angiographically normal coronary arteries at rest and during maximal upright bicycle exercise. Thallium-201 (201 TI) imaging was done in all patients after treadmill exercise and in selected patients after ergonovine provocation. Resting left ventricular performance was normal in all patients. An abnormal ejection fraction response to exercise was detected in 12 of 31 patients. Regional dysfunction was present during exercise in four patients, all of whom also had abnormal global responses. Three of these 12 patients and two additional patients had exercise-induced 201 TI perfusion defects. In all nine patients who underwent ergonovine testing, there was no suggestion of coronary arterial spasm. Thus, left ventricular dysfunction during exercise, in the presence of normal resting performance, was found in a substantial number of patients with chest pain, an ischemic-appearing exercise electrocardiogram, and normal coronary arteries.