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1.  Cardiovascular Pharmacogenomics: The Future of Cardiovascular Therapeutics? 
Responses to drug therapy vary from benefit to no effect to adverse effects which can be serious or occasionally fatal. Increasing evidence supports the idea that genetic variants can play a major role in this spectrum of responses. Well-studied examples in cardiovascular therapeutics include predictors of steady-state warfarin dosage, predictors of reduced efficacy among patients receiving clopidogrel for drug eluting stents, and predictors of some serious adverse drug effects. This review summarizes contemporary approaches to identifying and validating genetic predictors of variability in response to drug treatment. Approaches to incorporating this new knowledge into clinical care, and the barriers to this concept, are addressed.
PMCID: PMC3529768  PMID: 23200096
2.  Bucindolol, systolic blood pressure, and outcomes in systolic heart failure: a prespecified post hoc analysis of BEST 
In the Beta-Blocker Evaluation of Survival Trial (BEST) trial, systolic blood pressure (SBP) ≤120 mm Hg was an independent predictor of poor prognosis in ambulatory patients with chronic systolic heart failure (HF). Because SBP is an important predictor of response to beta-blocker therapy, the BEST protocol had pre-specified a post hoc analysis to determine if the effect of bucindolol varied by baseline SBP.
In the BEST, 2706 patients with chronic systolic (left ventricular ejection fraction <35%) HF and New York Heart Association class III (92%) or IV (8%) symptoms and receiving standard background therapy were randomized to receive either bucindolol (n=1354) or placebo (n=1354). Of these, 1751 had SBP ≤120 mm Hg and 955 had SBP >120 mm Hg at baseline.
Among patients with SBP >120 mm Hg, all-cause mortality occurred in 28% and 22% of patients receiving placebo and bucindolol, respectively (hazard ratio when bucindolol was compared with placebo, 0.77; 95% confidence interval, 0.59–0.99; P=0.039). In contrast, among those with SBP ≤120 mm Hg, 36% and 35% of patients in the placebo and bucindolol groups died, respectively (hazard ratio, 0.95; 95% confidence interval, 0.81–1.12; P=0.541). Hazard ratios (95% confidence intervals) for HF hospitalization associated with bucindolol use were 0.70 (0.56–0.89; P=0.003) and 0.82 (0.71–0.95; P=0.008) for patients with SBP >120 and ≤120 mm Hg, respectively.
Bucindolol, a nonselective beta-blocker with weak alpha-blocking properties, significantly reduced HF hospitalization in systolic HF patients regardless of baseline SBP. However, bucindolol reduced mortality only in those with SBP >120 mm Hg.
PMCID: PMC3769783  PMID: 21982425
Bucindolol; systolic blood pressure; outcomes; heart failure
3.  There Is Power in Numbers—Even/Especially in Genomic Medicine 
PMCID: PMC3674099  PMID: 22326711
4.  Pulmonary Endarterectomy Surgery- A Technically Demanding Cure for WHO Group IV Pulmonary Hypertension: Requirements for Centers of Excellence and Availability in Canada 
PMCID: PMC3555483  PMID: 22019277
chronic thromboembolic pulmonary hypertension (CTEPH); pulmonary embolism; registries; pulmonary vascular resistance; pulmonary hypertension
8.  A Changing World 
PMCID: PMC3006096  PMID: 21165358
11.  Two novel mutations of the MYBPC3 gene identified in Chinese families with hypertrophic cardiomyopathy 
The Canadian Journal of Cardiology  2010;26(10):518-522.
Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular disorders. Mutations in the MYBPC3 gene are one of the most frequent genetic causes of HCM.
To screen MYBPC3 gene mutations in Chinese patients with HCM, and analyze the correlation between the genotype and the phenotype.
The 35 exons of the MYBPC3 gene were amplified by polymerase chain reaction in the 11 consecutive unrelated Chinese pedigrees. The sequences of the products were analyzed and the mutation sites were determined. The clinical data of genotype-positive families were collected, and the correlation between genotype and phenotype was analyzed.
Two mutations of the MYBPC3 gene were confirmed among 11 pedigrees. A frameshift mutation (Pro459fs) was identified in exon 17 in family H8, and a splice mutation (IVS5+5G→C) was identified in intron 5 in family H3. These two mutations were first identified in Chinese patients with familial HCM and were absent in 110 chromosomes of healthy controls. Seven known polymorphisms were found in the cohort.
Compared with what was reported abroad, the MYBPC3 gene is a common pathogenic gene responsible for HCM in Chinese patients, and the phenotypes of these two mutations in their respective families may have their own clinical characteristics.
PMCID: PMC3006099  PMID: 21165360
Familial hypertrophic cardiomyopathy; Genotype; Mutation; MYBPC3; Phenotype
12.  Trends in postacute myocardial infarction management and mortality in patients with diabetes. A population-based study from 1995 to 2001 
The Canadian Journal of Cardiology  2010;26(10):523-531.
To compare trends in coronary revascularization use and case fatality rate (CFR) following acute myocardial infarction in patients with and without diabetes.
A retrospective study of 77,552 patients, 20 years of age or older (25% with diabetes), who were hospitalized for a first acute myocardial infarction in the province of Quebec between April 1995 and December 2001 was conducted. Administrative databases were used to identify patients and assess outcomes.
Compared with patients without diabetes, patients with diabetes underwent more coronary artery bypass graft (CABG) surgeries (11.1% versus 8.3%; P<0.0001) but fewer percutaneous coronary interventions (17.1% versus 20.2%; P<0.0001). The use of percutaneous coronary intervention increased substantially over time in both populations, driven mainly by an increase during the index admission (20.6% versus 16.6% per year; P=0.1144 in patients with and without diabetes, respectively). The use of CABG during the index admission increased markedly among patients with diabetes compared with those without (10.3% versus 5.3% per year; P=0.0072); however, at one-year following discharge, CABG use remained stable in patients with diabetes and fell in those without (−0.7% versus −5.3% per year; P=0.2046). Concomitantly, patients with diabetes presented a similar decline in CFR compared with patients without diabetes. The decline was more pronounced during the index admission (−5.0% versus −4.1% per year; P=0.282) than at one-year following discharge (−2.5% versus −2.5% per year; P=0.629) in patients with and without diabetes, respectively. However, fatal outcome remained higher in patients with diabetes than without, with an adjusted RR of 1.21 (95% CI 1.18 to 1.24) at one-year follow-up.
Overall, coronary revascularization use and CFR improved over time in patients with diabetes. Nevertheless, the mortality rate in patients with diabetes remains higher than in patients without diabetes, indicating that additional progress is required to improve the poorer prognosis in this population.
PMCID: PMC3006100  PMID: 21165361
Acute myocardial infarction; Diabetes mellitus; Mortality; Revascularization
13.  Patient-prosthesis mismatch in the mitral position affects midterm survival and functional status 
The Canadian Journal of Cardiology  2010;26(10):532-536.
The definition and incidence of patient-prosthesis mismatch (PPM) in the mitral position are unclear.
To determine the impact of PPM on late survival and functional status after mitral valve replacement with a mechanical valve.
Between 1992 and 2005, 714 patients (mean [± SD] age 60±10 years) underwent valve replacement with either St Jude (St Jude Medical Inc, USA) (n=295) or Carbomedics (Sulzer Carbomedics Inc, USA) (n=419) valves. There were 52 concomitant procedures (50 tricuspid annuloplasties, 25 foramen oval closures and 20 radiofrequency mazes). The mean clinical follow-up period was 4.4±3.3 years. The severity of PPM was established with cut-off values for an indexed effective orifice area (EOAi) of lower than 1.2 cm2/m2, lower than 1.3 cm2/m2 and lower than 1.4 cm2/m2. Parametric and nonparametric tests were used to determine predictors of outcome.
The prevalence of PPM was 3.7%, 10.1% and 23.5% when considering values of lower than 1.2 cm2/m2, lower than 1.3 cm2/m2 and lower than 1.4 cm2/m2, respectively. When considering functional improvement, patients with an EOAi of 1.4 cm2/m2 or greater had a better outcome than those with an EOAi of lower than 1.4 cm2/m2 (OR 1.98; P=0.03). When building a Cox-proportional hazard model, PPM with an EOAi of less than 1.3 cm2/m2 was an independent predictive factor for midterm survival (HR 2.24, P=0.007). Other factors affecting survival were age (HR 1.039), preoperative New York Heart Association class (HR 1.96) and body surface area (HR 0.31).
In a large cohort of patients undergoing mitral valve replacement with mechanical prostheses, PPM defined as an EOAi of lower than 1.3 cm2/m2 significantly decreased midterm survival. This level of PPM was observed in 10.2% of patients. Patients with an EOAi of 1.4 cm2/m2 or greater had greater improvement of their functional status.
PMCID: PMC3006101  PMID: 21165362
Mitral valve; Prosthesis; Surgery; Valvuloplasty
14.  Knowledge of heart disease and stroke among cardiology inpatients and outpatients in a Canadian inner-city urban hospital 
The Canadian Journal of Cardiology  2010;26(10):537-541.
Heart disease and stroke are leading causes of death in North America. Nevertheless, in 2003, the Heart and Stroke Foundation of Canada reported that nearly two-thirds of Canadians have misconceptions regarding heart disease and stroke, echoing the results of similar American studies. Good knowledge of these conditions is imperative for cardiac patients who are at greater risk than the general population and should, therefore, be better educated. The present study evaluated the awareness of heart disease and stroke among cardiac patients to assess the efficacy of current education efforts.
Two hundred fifty-one cardiac inpatients and outpatients at St Michael’s Hospital (Toronto, Ontario) were surveyed in July and August 2004. An unaided questionnaire assessed respondents’ knowledge of cardiovascular risk factors, symptoms of heart attack and stroke, and actions in the event of cardiovascular emergency. Demographic data and relevant medical history were also obtained.
Cardiac patients demonstrated relatively adequate knowledge of heart attack warning symptoms. These patients also demonstrated adequate awareness of proper actions during cardiovascular emergencies. However, respondents were not aware of the most important risk factors for cardiovascular disease. Knowledge of stroke symptoms was also extremely poor. Socioeconomic status, and personal history of heart attack and stroke were positively correlated with good knowledge.
Future patient education efforts should address the awareness of the important cardiovascular risk factors and knowledge of cardiovascular warning symptoms (especially for stroke), as well as inform patients of appropriate actions during a cardiovascular emergency. Emphasis should be placed on primary and secondary prevention, and interventions should be directed toward low-income cardiac patients.
PMCID: PMC3006102  PMID: 21165363
Heart attack; Myocardial infarction; Prevention; Public health education; Stroke
15.  Could a high-fat diet rich in unsaturated fatty acids impair the cardiovascular system? 
The Canadian Journal of Cardiology  2010;26(10):542-548.
Dyslipidemia results from consumption of a diet rich in saturated fatty acids and is usually associated with cardiovascular disease. A diet rich in unsaturated fatty acids is usually associated with improved cardiovascular condition.
To investigate whether a high-fat diet rich in unsaturated fatty acids (U-HFD) – in which fatty acid represents approximately 45% of the total calories – impairs the cardiovascular system.
Male, 30-day-old Wistar rats were fed a standard (control) diet or a U-HFD containing 83% unsaturated fatty acid for 19 weeks. The in vivo electrocardiogram, the spectral analysis of heart rate variability, and the vascular reactivity responses to phenylephrine, acetylcholine, noradrenaline and prazosin in aortic ring preparations were analyzed to assess the cardiovascular parameters.
After 19 weeks, the U-HFD rats had increased total body fat, baseline glucose levels and feed efficiency compared with control rats. However, the final body weight, systolic blood pressure, area under the curve for glucose, calorie intake and heart weight/final body weight ratio were similar between the groups. In addition, both groups demonstrated no alteration in the electrocardiogram or cardiac sympathetic parameters. There was no difference in the responses to acetylcholine or the maximal contractile response of the thoracic aorta to phenylephrine between groups, but the concentration necessary to produce 50% of maximal response showed a decrease in the sensitivity to phenylephrine in U-HFD rats. The cumulative concentration-effect curve for noradrenaline in the presence of prazosin was shifted similarly in both groups.
The present work shows that U-HFD did not impair the cardiovascular parameters analyzed.
PMCID: PMC3006103  PMID: 21165364
Cardiovascular; High-fat diet; Obesity; Unsaturated fatty acid
16.  Recurrent myopericarditis with extensive ulcerative colitis 
The Canadian Journal of Cardiology  2010;26(10):549-550.
A 26-year-old man with ulcerative colitis was independently evaluated in different emergency rooms on two occasions, separated by six years, for episodes of severe chest pain consistent with myopericarditis. Cardiac enzyme and electrocardiographic changes were accompanied by extensive colonic inflammatory changes. Treatment with corticosteroids led to resolution. While his cardiac findings were initially believed to be caused by a previously reported drug hypersensitivity to mesalamine (5-aminosalicylate), sulphasalazine was tolerated. Recurrent myopericarditis with ulcerative colitis appears to be rare, but responsive to steroids. It may occur more often than is currently appreciated and may lead to fatal arrhythmias or cardiac failure.
PMCID: PMC3006104  PMID: 21165365
5-Aminosalicylates; Inflammatory bowel disease; Myocarditis; Pericarditis; Ulcerative colitis
17.  The accuracy of the physical examination for the detection of lower extremity peripheral arterial disease 
The Canadian Journal of Cardiology  2010;26(10):e346-e350.
Peripheral arterial disease (PAD) is a major risk factor for adverse cardiovascular events. There has been a definite push for wider use of the ankle-brachial index (ABI) as a simple screening tool for PAD. Perhaps this has occurred to the detriment of a thorough physical examination.
To assess the accuracy of the physical examination to detect clinically significant PAD compared with the ABI.
PADfile, the PAD module of CARDIOfile (the Kingston Heart Clinic’s cardiology database [Kingston, Ontario]), was searched for all patients who underwent peripheral arterial testing. Of 1619 patients, 1236 had all of the necessary data entered. Patients’ lower limbs were divided into two groups: those with a normal ABI between 0.91 and 1.30, and those with an abnormal ABI of 0.90 or lower. Peripheral pulses were graded as either absent or present. Absent was graded as 0/3, present but reduced (1/3), normal (2/3) or bounding (3/3). Femoral bruits were graded as either present (1) or absent (0). Using the ABI as the gold standard, the sensitivity, specificity, negative predictive value (NPV), positive predictive value and overall accuracy were calculated for the dorsalis pedis pulse, the posterior tibial pulse, both pedal pulses, the presence or absence of a femoral bruit and, finally, for a combination of both pedal pulses and the presence or absence of a femoral bruit.
In 1236 patients who underwent PAD testing and who underwent a complete peripheral vascular physical examination (all dorsalis pedis and posterior tibial pulses palpated and auscultation for a femoral bruit), the sensitivity, specificity, NPV, positive predictive value and accuracy for PAD were 58.2%, 98.3%, 94.9%, 81.1% and 93.8%, respectively.
The clinical examination of the peripheral arterial foot pulses and the auscultation for a femoral bruit had a high degree of accuracy (93.8%) for the detection or exclusion of PAD compared with the ABI using the cut-off of 0.90 or lower. If both peripheral foot pulses are present in both lower limbs and there are no femoral bruits, the specificity and NPV of 98.3% and 94.9%, respectively, make the measurement of the ABI seem redundant. The emphasis in PAD detection should be redirected toward encouraging a thorough physical examination.
PMCID: PMC3006105  PMID: 21165366
Ankle-brachial index; Peripheral arterial disease; Physical examination
18.  Toxic shock syndrome: A rare complication to enhanced external counterpulsation 
The Canadian Journal of Cardiology  2010;26(10):e351-e352.
Enhanced external counterpulsation (EECP) is known to reduce angina pectoris in patients in whom revascularization is not possible. The therapy is associated with few adverse effects. A case with a previously unknown complication – toxic shock syndrome – that occurred twice in an EECP-treated patient is described. Toxic shock syndrome initially resembles the state of septic shock. Early recognition of the syndrome and initiation of therapy is of vital importance to prevent rapid progression and a possibly fatal outcome. Awareness of this condition among cardiologists offering EECP is essential.
PMCID: PMC3006106  PMID: 21165367
EEC; Enhanced external counterpulsation; Toxic shock syndrome; TSS
19.  Echocardiographic tools for pacemaker optimization of ventricular function in an infant following surgical repair for double outlet right ventricle 
The Canadian Journal of Cardiology  2010;26(10):e353-e355.
A case of an infant, following surgical repair for double outlet right ventricle, who developed low cardiac output syndrome and complete heart block that required insertion of a pacemaker is presented. The infant underwent optimization of his ventricular function to determine whether pacing the right ventricle or left ventricle or both would improve cardiac function. Using standard two-dimensional echocardiography and Doppler imaging, tissue synchronization imaging, and two-dimensional speckle-tracking strain analysis, improvement in cardiac output and function was demonstrated. The present case highlights the usefulness of newer echocardiographic techniques in pacemaker optimization in the acute postoperative setting.
PMCID: PMC3006107  PMID: 21165368
Congenital heart disease; Tissue and strain Doppler echocardiography
22.  Daily low-dose folic acid supplementation does not prevent nitroglycerin-induced nitric oxide synthase dysfunction and tolerance: A human in vivo study 
Continuous treatment with nitroglycerin (GTN) causes tolerance and endothelial dysfunction, both of which may involve endothelial nitric oxide synthase (eNOS) dysfunction. eNOS dysfunction may be linked to depletion of tetrahydrobiopterin, and folic acid may be involved in the regeneration of this cofactor. It has been demonstrated that 10 mg/day folic acid supplementation prevents the development of GTN tolerance and GTN-induced endothelial dysfunction. However, the efficacy of daily lower-dose folic acid supplementation for preventing these phenomena has not been investigated.
To determine the effect of 1 mg/day folic acid supplementation on responses to sustained GTN therapy.
On visit 1, 20 healthy male volunteers were randomly assigned to receive either oral folic acid (1 mg/day) or placebo for one week in a double- blind study. All subjects also received continuous transdermal GTN (0.6 mg/h). On visit 2, forearm blood flow was measured using venous occlusion strain-gauge plethysmography in response to incremental intra-arterial infusions of acetylcholine, N-monomethyl-L-arginine and GTN. Subjects in both groups displayed significantly decreased responses to acetylcholine and N-monomethyl-L-arginine infusions compared with a control group that received no treatment. Responses to GTN were also significantly diminished in both groups (P<0.05 for all).
The present data demonstrate that daily supplementation with 1 mg folic acid does not prevent the development of GTN-induced eNOS dysfunction or tolerance.
PMCID: PMC2989350  PMID: 21076717
Acetylcholine; Blood flow; Endothelial dysfunction; Folic acid; Nitric oxide synthase; Nitroglycerin; Superoxide
23.  Mechanical circulatory support with the ABIOMED BVS 5000: The Toronto General Hospital experience 
Acute hemodynamic collapse resulting in cardiogenic shock and impending end-organ failure is usually associated with certain death. The introduction of short-term mechanical circulatory support (MCS) devices offers potential therapy to these critically ill patients. The BVS 5000 device (ABIOMED Inc, USA) is widely used in the United States, but rarely in Canada, where device reimbursement remains a barrier.
To present the Toronto General Hospital’s (Toronto, Ontario) initial five-year experience with this device to highlight the indications for use, common complications and overall success rates.
The institutional MCS database from 2001 to 2006 was reviewed, and 18 patients who received 30 devices in a variety of configurations were identified. The most common support configuration consisted of biventricular support (n=12), followed by isolated left ventricular support (n=4) and isolated right ventricular support in two recipients of an implantable long-term left ventricular assist device. Overall survival to device explant or transplant was 55% (n=10), of which five (50%) were successfully discharged from the hospital. The overall survival from device implant to hospital discharge was 28% (five of 18). The most common cause of death was multisystem organ failure.
MCS with the ABIOMED BVS 5000 can successfully resuscitate critically ill patients; however, earlier institution of this device would avoid irreversible end-organ injury, and lead to higher rates of device explant and hospital discharge. Short-term MCS devices should be available in all cardiac surgical centres in Canada to permit stabilization and evaluation of the acutely ill cardiac patient and subsequent management in a heart transplant facility.
PMCID: PMC2989351  PMID: 21076718
Acute cardiogenic shock; Transplantation; Ventricular assist device
24.  Time course of early changes in plasma markers of collagen turnover following percutaneous transluminal coronary angioplasty 
Marked changes occur in the collagen framework of the heart following acute ischemia, which is associated with adverse ventricular remodelling. Plasma markers of collagen turnover are useful in the assessment of remodelling and have predictive value, but their exact temporal dynamics following ischemia are unclear.
To characterize the early temporal dynamics of plasma markers of collagen turnover in a human model of coronary artery occlusion.
Fourteen patients undergoing elective percutaneous coronary intervention (PCI) to a single coronary artery were recruited in addition to a control group of eight patients undergoing elective diagnostic coronary arteriography. Sequential assessment of plasma levels of procollagen type I carboxyterminal propeptide and C-telopeptide for type I collagen (CITP) as markers of synthesis and degradation, respectively, was performed over a 16 h period.
The ischemic burden in the PCI group was high, with 13 of the 14 patients demonstrating transient ST segment shift or positive troponin. Mean plasma levels of CITP on admission were 3.1 ng/mL and 3.0 ng/mL in the PCI and control groups, respectively (P value nonsignificant). There was a sequential increase in plasma CITP following PCI, peaking at 4.7 ng/mL at 16 h (P<0.01), with no change in the control group. There were no significant changes in plasma levels of procollagen type I carboxyterminal propeptide in either group.
Plasma levels of CITP demonstrated early temporal dynamics of collagen degradation following transient coronary artery occlusion supporting the use of plasma markers of collagen turnover as an early tool in the assessment of the remodelling process following myocardial ischemia.
PMCID: PMC2989352  PMID: 21076719
Angioplasty; Collagen; Remodelling
25.  Utility of three-dimensional echocardiography in assessing and predicting response to cardiac resynchronization therapy 
Cardiac resynchronization therapy (CRT) can be a valuable treatment for heart failure. However, there are high nonresponse rates using current CRT inclusion criteria.
To assess the value of three-dimensional echocardiography (3DE) in predicting response to CRT.
Functional assessments and 3DE were performed in heart failure patients pre-CRT, 24 h post-CRT and six to 12 months after CRT. The dyssynchrony index (DI) was calculated as the SD of the time to minimum volume in 16 left ventricle segments corrected by heart rate. Response to CRT was defined as functional improvement (alive at late follow-up with improvement by one New York Heart Association class) and a decrease in left ventricular end-systolic volume by 15% or greater at six to 12 months follow-up.
A total of 53 patients were enrolled. Average 3DE acquisition time was less than 5 min. Seventy-two per cent of patients showed functional improvement, while 43% showed functional and echocardiographic evidence of response. Baseline DI and the decrease in DI at 24 h were both correlated with reverse remodelling. Responders had higher baseline DI values compared with nonresponders (mean 16.8 versus 7.1, P<0.001), and showed a greater decrease in DI values at 24 h (mean decrease 7.9 versus 0.7, P<0.001). All responders had baseline DI values of greater than 10 (negative predictive value of 100%). A decrease in the DI value by more than 5 at 24 h in patients with a baseline DI of greater than 10 identified responders with a positive predictive value of 83%.
3DE may be valuable in predicting response to CRT. A baseline DI cut-off of greater than 10 in our patients excluded reverse remodelling to CRT. In addition, the decrease in DI at 24 h had a high positive predictive value for long-term response to CRT.
PMCID: PMC2989353  PMID: 21076720
Biventricular pacing; Cardiac resynchronization therapy; Dyssynchrony; Heart failure; Three-dimensional echocardiography; Ventricular remodelling

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