Statin-Associated Muscle Adverse Events: Update for clinicians.

Statins are potent medications which reduce low-density lipoprotein cholesterol (LDL-C) levels. Their efficacy in cardiovascular risk reduction is well established and indications for their use are expanding. While statins are generally well tolerated and safe, adverse events are relatively common, particularly statin-associated muscle adverse events (SaMAEs), which are the most frequently encountered type of adverse event. Recent guidelines and guideline updates on SaMAEs and statin intolerance have included revised definitions of SaMAEs, incorporating new evidence on their pathogenesis and management. As SaMAEs emerge as a therapeutic challenge, it is important for physicians to be aware of updates on management strategies to ensure better patient outcomes. The majority of patients who are considered statin-intolerant can nevertheless tolerate some forms of statin therapy and successfully achieve optimal LDL-C levels. This review article discusses the recent classification of SaMAEs with emphasis on pathogenesis and management strategies.

A Plaque Disruption Index Identifies Patients with Non-STE-Type 1 Myocardial Infarction within 24 Hours of Troponin Positivity.

BACKGROUND: Markers of plaque destabilization and disruption may have a role in identifying non-STE- type 1 Myocardial Infarction in patients presenting with troponin elevation. We hypothesized that a plaque disruption index (PDI) derived from multiple biomarkers and measured within 24 hours from the first detectable troponin in patients with acute non-STE- type 1 MI (NSTEMI-A) will confirm the diagnosis and identify these patients with higher specificity when compared to individual markers and coronary angiography. METHODS: We examined 4 biomarkers of plaque destabilization and disruption: myeloperoxidase (MPO), high-sensitivity interleukin-6, myeloid-related protein 8/14 (MRP8/14) and pregnancy-associated plasma protein-A (PAPP-A) in 83 consecutive patients in 4 groups: stable non-obstructive coronary artery disease (CAD), stable obstructive CAD, NSTEMI-A (enrolled within 24 hours of troponin positivity), and NSTEMI-L (Late presentation NSTEMI, enrolled beyond the 24 hour limit). The PDI was calculated and the patients' coronary angiograms were reviewed for evidence of plaque disruption. The diagnostic performance of the PDI and angiography were compared. RESULTS: Compared to other biomarkers, MPO had the highest specificity (83%) for NSTEMI-A diagnosis (P<0.05). The PDI computed from PAPP-A, MRP8/14 and MPO was higher in NSTEMI-A patients compared to the other three groups (p<0.001) and had the highest diagnostic specificity (87%) with 79% sensitivity and 86% accuracy, which were higher compared to those obtained with MPO, but did not reach statistical significance (P>0.05 for all comparisons). The PDI had higher specificity and accuracy for NSTEMI-A diagnosis compared to coronary angiography (P<0.05). CONCLUSIONS: A PDI measured within 24 hour of troponin positivity has potential to identify subjects with acute Non-ST-elevation type 1 MI. Additional evidence using other marker combinations and investigation in a sufficiently large non-selected cohort is warranted to establish the diagnostic accuracy of the PDI and its potential role in differentiating type 1 and type 2 MI in patients presenting with troponin elevation of uncertain etiology.

HeartWare ventricular assist device as a bridge to heart transplantation in a patient with congenitally corrected transposition of the great arteries and dextrocardia.

Congenitally corrected transposition of the great arteries (ccTGA) is a rare condition with prevalence of <0.5%. Dextrocardia is reported among 20% of them. Among patients with ccTGA, heart failure is a common presentation, especially in the fourth or fifth decade of life and survival is dismal without heart transplantation. A left ventricular assist device (LVAD) is considered for bridge to transplantation if early heart transplantation is not available or as destination therapy for patients ineligible for heart transplant. Our patient had ccTGA and dextrocardia, after which he developed failure of a systemic ventricle and severe systemic atrioventricular valve, subpulmonic atrioventricular valve and aortic valve regurgitation along with paroxysmal atrial fibrillation. A third-generation ventricular assist device HeartWare ventricular assist device (HVAD, HeartWare, Inc., Framingham, MA, USA) was implanted as a bridge to transplantation with concomitant aortic valve replacement with a bioprosthetic valve. There is no prior publication on HVAD implantation in patient having both ccTGA and dextrocardia. Our case report includes the patient's summary and literature review encompassing limited experience of LVADs in patients with ccTGA and dextrocardia.

Contractile reserve induced with dobutamine echocardiography predicts outcome in patients with left ventricular dysfunction and mitral regurgitation.

BACKGROUND AND AIM OF THE STUDY: The appropriate management of patients with mitral regurgitation (MR) and left ventricular dysfunction (LVD) is controversial. The study aim was to determine whether the presence of contractile reserve (CR) assessed by dobutamine stress echocardiography (DSE) was associated with improved outcomes. METHODS: Death and heart transplantation were analyzed as the primary outcomes associated with the presence of CR. A total of 125 consecutive patients (96 males, 29 females; mean age 60 +/- 12 years) with left ventricular ejection fraction (LVEF) < or = 35% and hemodynamically significant MR underwent DSE between 1999 and 2005. CR was defined as an increase in LVEF of > or = 10% during dobutamine infusion. RESULTS: Among 125 patients, 55 (43.0%) showed evidence of CR. Within five years after DSE, 24 patients (34.3%) in the CR- group and seven (12.7%) in the CR+ group had died or required heart transplantation (p < 0.01, log rank). After adjusting for age, baseline LVEF, NYHA class and moderate/severe tricuspid regurgitation (TR), CR remained an independent predictor of time to death or heart transplantation (HR 0.34; 95% CI: 0.15-0.76, p < 0.01). Improvement in the degree of MR was present at one year in 85.0% of CR+ patients, and in 62.5% of CR- patients (p = 0.03). An improvement of 5% in LVEF was noted in the CR+ group, compared to 0% in the CR- group (p = 0.04). CONCLUSION: In patients with advanced LVD and severe MR, CR detected by DSE was associated with significant reductions in the risk of death and heart transplantation.

A successful 4S heart transplantation.

Donor recipient matching is paramount to successful heart transplantation. The presence of allosensitization decreases the transplant candidate's donor pool, prolongs the time to transplantation, and increases the post-transplant mortality and morbidity. Various strategies are applied to reduce antibody loads with mixed results being reported. The development of a new listing criterion by the Canadian Cardiac Transplant Network (CCTN) for sensitized patients may overcome this problem by increasing the odds that a given recipient receives an organ from an appropriately matched donor. The success of this case gives hope to patients and provides insights into the treatment of sensitized patients.

The impact of dietary changes and dietary supplements on lipid profile.

With a growing number of dietary interventions that claim to improve lipid profile, it is important to ensure that these claims are evidence based. The objective of this study was to make recommendations for dietary regimens by analyzing their effectiveness and the level of evidence. We searched MEDLINE as well as the Cochrane Database of Systematic Reviews for nutritional studies. Meta-analyses and randomized controlled trials published in English and including data on the effect on blood lipid levels were used. Randomized controlled trials were included if they were at least 4 weeks in duration and had a minimum of 50 participants. We identified 22 different dietary interventions and reviewed 136 studies published between January 1990 and December 2009 that met our inclusion criteria. Our literature review showed that to improve lipid profile, the following regimens can be recommended fully: Mediterranean and Portfolio diets; low-fat diet; diet high in soy protein, fibre, or phytosterols; whole grain foods, and omega-3 fatty acid supplementation. The consumption of nuts, a diet high in carbohydrates and protein, green tea, and red wine, as well as the supplementation with policosanol and red yeast rice extract, can be considered for improvement of the lipid profile, while the supplements of guggulipid, garlic, chromium, vitamin C, magnesium-pyridoxal-phosphate-glutamate, tocotrienols, and absorbitol cannot be recommended.

Elevated N-terminal pro-brain natriuretic peptide in Mycobacterium tuberculosis pulmonary infection without myocardial dysfunction.

Increased levels of N-terminal pro-brain natriuretic peptide (NT pro- BNP) in infectious settings may not reflect myocardial depression. In addition to NT pro-BNP measurement, clinical assessment remains a valuable tool for diagnosis and prognosis of heart failure. A case of excessively increased NT pro-BNP level associated with Mycobacterium tuberculosis infection that was not indicative of myocardial dysfunction is described.

Performance of limited sampling strategies for predicting mycophenolic acid area under the curve in thoracic transplant recipients.

BACKGROUND AND METHODS: Eight limited sampling strategies (LSSs) for estimating mycophenolic acid area under the concentration-time curve (4 developed from lung transplant recipients at our center, 4 developed for heart transplant recipients from other research groups) were evaluated in 27 heart or heart-kidney transplant patients. RESULTS: The LSSs from our lung transplant patients performed well when applied to the heart transplant population, with percent bias and percent precision within the acceptable limit of +/-15%. CONCLUSIONS: The LSSs developed at our center are robust enough to be applied to both lung and heart transplant populations. Application of LSSs from other research groups yielded less optimal results, reinforcing the need to re-establish or re-validate LSSs for each specific center.

Accuracy of a provincial prescription database for assessing medication adherence in heart failure patients.

BACKGROUND: British Columbia's central prescription database, PharmaNet, is often used for both clinical and research applications. However, PharmaNet details prescription transactions, not actual medication consumption, resulting in many potential sources of inaccuracy when the information is assumed to reflect population or individual drug utilization. OBJECTIVE: To assess the accuracy of PharmaNet for adherence assessment in patients with heart failure who are taking beta-blockers. METHODS: A 6-month prospective, longitudinal assessment of adherence to the prescribed beta-blocker regimen was carried out using both PharmaNet data and the Medication Event Monitoring System (MEMS) for each patient enrolled. The limit of agreement between the 2 adherence assessment methods was assessed using the Bland-Altman approach. RESULTS: Fifteen of 58 patients initially enrolled in the study were excluded, most due to misuse of MEMS or failure to return the MEMS vial despite thorough follow-up. For the 43 patients included in the final analysis, mean +/- SD adherence was 97.8 +/- 11.8% when assessed by PharmaNet and 97.1 +/- 7.3% when MEMS was used. However, the limit of agreement, reported as the mean of the differences +/- 2SD, was 6.8 +/- 18.5%, indicating a moderate-to-high level of agreement between the 2 methods when the confidence interval is taken into consideration. CONCLUSIONS: These results suggest that PharmaNet data accurately reflect medication adherence for most patients. The MEMS system proved unreliable in several cases, illustrating the difficulty of identifying a gold standard for adherence assessment.

Eosinophilic myocarditis: case series and review of literature.

Although the etiology of eosinophilic myocarditis (EM) is not always apparent, several causes are identified, including hypersensitivity to a drug or substance, with the heart as the target organ. However, symptoms and signs of hypersensitivity are not found in all patients. EM can lead to progressive myocardial damage with destruction of the conduction system and refractory heart failure. The present report describes three cases of biopsy-proven EM with different presentations, including acute coronary syndrome, cardiogenic shock and newly diagnosed heart failure. In one patient, hypersensitivity to sumatriptan was suspected to be the underlying cause. All patients responded well to treatment with steroids, angiotensin-converting enzyme inhibitors and beta-blockers. There was a complete recovery of the ventricular function in all cases.

Effectiveness of high-intensity interval training for the rehabilitation of patients with coronary artery disease.

We found that interval training provides an effective means to improve the cardiovascular fitness and health status of highly functional patients with coronary artery disease. We also revealed that interval training improves anaerobic tolerance to a greater extent than the traditional exercise training model without increasing the risk to the patient. This research supports the implementation of interval training for highly functional patients with coronary artery disease.

Self-reported Morisky score for identifying nonadherence with cardiovascular medications.

BACKGROUND: The Morisky medication adherence scale is a commonly used adherence screening tool. It is composed of 4 yes/no questions about past medication use patterns and is thus quick and simple to use during drug history interviews. OBJECTIVE: To evaluate the use of the self-reported Morisky score as a screening tool for identifying patients who have been nonadherent with chronic cardiovascular medications. METHODS: Patients who had taken an angiotensin-converting enzyme inhibitor or lipid-lowering agent for at least 3 consecutive months were interviewed using a structured questionnaire including the Morisky scale. Nonadherence was defined as taking < 80% of chronic cardiovascular medications based on prescription refill data over the previous 14 months. RESULTS: Forty-nine of 377 (13%) patients were categorized as nonadherent; however, only 12 (3%) patients had Morisky scores suggesting a high likelihood of nonadherence (3 or 4). While the Morisky score was a significant independent predictor of nonadherence by multivariate analysis, there was no threshold score or individual question that yielded concurrent high sensitivity and positive predictive values (PPVs) for identifying nonadherent patients. The internal consistency of the questions was low (alpha 0.32), as were item-to-total score correlations, suggesting that the individual questions were not measuring the same attribute. CONCLUSIONS: Using the Morisky scale to identify patients who have been nonadherent with chronic cardiovascular medications may be reasonable in some settings; however, the threshold score would have to be chosen based on a trade-off between sensitivity and PPV. These results were likely influenced by the low rate of nonadherence in this cohort. Rewording the questions, increasing the number of questions, and the use of graded response options may improve consistency.

Novel mutations in the TRIM37 gene in Mulibrey Nanism.

Mulibrey nanism is an autosomal recessive prenatal-onset growth disorder of unknown pathogenesis. The main clinical features are pre- and postnatal growth failure, characteristic dysmorphic craniofacial features, heart disease, and hepatomegaly. Five truncating mutations in the TRIM37 gene have previously been reported in Mulibrey nanism patients. The TRIM37 protein encodes a novel protein of unknown function. It contains a tripartite motif (TRIM, also denoted the RING-B-box-Coiled-coil or RBCC domain) and a TRAF (tumor necrosis factor-receptor associated factor) domain. TRIM37 localizes to peroxisomes classifying Mulibrey nanism as a peroxisomal disorder. Here we have characterized the genomic structure of the TRIM37 gene, which has 24 exons spanning approximately 109 kb of genomic DNA. Further, we report six novel disease-associated mutations, five of which predict a truncated protein: c.745C>T (p.Gln249X), c.1411C>T (p.Arg471X), c.2056C>T (p.Arg686X), and an 8.6 kb genomic deletion (c.1314+507_1668-207del resulting in p.Arg439fsX4). The sixth mutation (c.965G>T) is the first missense mutation (p.Gly322Val) associated with Mulibrey nanism. It affects the TRAF domain of TRIM37 and results in altered subcellular localization of the mutant TRIM37 protein, further suggesting that it is pathogenic.

Mycophenolate pharmacokinetics in early period following lung or heart transplantation.

BACKGROUND: The available pharmacokinetic and pharmacodynamic data on mycophenolic acid (MPA), the pharmacologically active metabolite of mycophenolate mofetil (MMF), are derived largely from renal transplant patients, not thoracic transplant recipients. OBJECTIVE: To evaluate, in a pilot study, the pharmacokinetics of MPA at 3 different times in the early period (up to the first 9 mo) following lung or heart transplantation. METHODS: Nine patients were entered into this open-label study. Upon administration of a steady-state morning MMF dose, blood samples were collected at 0, 20, 40, 60, and 90 minutes and at 2, 4, 6, 8, 10, and 12 hours after the dose at 3 times (denoted as sampling periods 1, 2, and 3) in the early posttransplant period. Total MPA concentrations were measured by a validated HPLC method with ultraviolet detection and followed by ultrafiltration of pooled samples for unbound MPA concentrations. Pharmacokinetic parameters (maximal concentration [C(max)], dose-normalized C(max), time to C(max), minimum concentration, predose concentration, AUC, dose-normalized AUC, free fraction, free AUC) were calculated by traditional noncompartmental methods. RESULTS: Patient characteristics included 7 men and 2 women, 5 lung and 4 heart transplant recipients, mean +/- SD age 53 +/- 11 years, and weight 77 +/- 14 kg. All patients were receiving prednisone and cyclosporine (with the exception of 2 pts. on tacrolimus during sampling periods 2 and 3). Sampling periods 1, 2, and 3 occurred on posttransplant days 15 +/- 13, 56 +/- 33, and 125 +/- 73, respectively. No significant differences were found between sampling periods in any pharmacokinetic parameter. Drug exposure as evaluated by AUC was 39.95 +/- 44.86, 25.24 +/- 25.68, and 43.96 +/- 38.67 micro g*h/mL during sampling periods 1, 2, and 3, respectively, (p > 0.05). CONCLUSIONS: As of September 26, 2003, this is the first study to systematically evaluate MPA pharmacokinetics in thoracic transplant recipients at 3 different time points during the early posttransplant period. Wide interpatient variability in MPA pharmacokinetics was observed, thus emphasizing the need to individualize dosing of MMF and to further evaluate important pharmacokinetic/pharmacodynamic parameters and endpoints that impact on clinical outcomes. Further studies involving more patients and pharmacodynamic outcomes are underway to help identify optimal MMF strategies.

Churg-Strauss syndrome with myocarditis manifesting as acute myocardial infarction with cardiogenic shock: case report and review of the literature.

A patient with a two-year history of worsening asthma presented with chest pain and shortness of breath. She developed cardiogenic shock. Analysis of blood chemistry detected increased troponin I concentration. Her electrocardiographic changes were consistent with a diagnosis of anteroseptal myocardial infarction. However, angiography showed normal coronary arteries. Left ventriculography showed severe mitral regurgitation and global hypokinesis. Peripheral eosinophilia was detected. Subsequent endomyocardial biopsy showed myocarditis with prominent eosinophil and plasma cell components. Churg-Strauss syndrome was diagnosed based on her history of asthma, evidence of peripheral eosinophilia and results of endomycardial biopsy. Treatment with a high dose of corticosteroids was initiated. As symptoms of heart failure improved - without recurrence of cardiac and respiratory symptoms - the dose of corticosteroids was gradually reduced. Eight months after her original presentation, she developed urticarial lesions on her abdomen and legs, with muscle soreness but no other associated symptoms. She was treated with a combination of prednisone and dapsone. After the diagnosis of Churg-Strauss syndrome, the patient remained symptom free with a normal ejection fraction for 15 months while taking prednisone.

Edge-to-edge repair for functional mitral regurgitation: an echocardiographic study of the hemodynamic consequences.

BACKGROUND AND AIM OF THE STUDY: The study aim was to characterize changes in mitral valve area and flow, and left ventricular (LV) size and function, following edge-to-edge (E-E) repair for severe functional mitral regurgitation (MR). The possibility that preoperative dobutamine stress echocardiography (DSE) might be used to predict post-repair recovery in LV function was also examined. METHODS: Seventeen patients underwent preoperative transthoracic echocardiography (TTE) and DSE, intraoperative transesophageal echocardiography, and three-month postoperative TTE. RESULTS: After repair, mitral valve area was reduced from 8.5 +/- 1.9 cm2 to 3.8 +/- 0.9 cm2 by planimetry (p < 0.0001) and to 2.9 +/- 0.9 cm2 by pressure half-time. Valve area by pressure half-time correlated with the planimetered area (r = +0.55), but was consistently lower (p = 0.004). Sixxteen of 17 patients had mean transmitral gradients <5 mmHg. Postoperative LV end-diastolic diameter improved from 72 +/- 11 to 64 +/- 10 mm (p < 0.01), and end-systolic diameter from 56 +/- 14 to 46 +/- 12 mm (p < 0.05). Mean ejection fraction improved from 25 +/- 12% before repair to 38 +/- 17% after repair (p < 0.02) in patients with evidence of LV function improvement on DSE, but was unchanged (15 +/- 5% versus 17 +/- 5%, p = NS) in patients without evidence of improvement. Postoperatively, 13 patients had no or mild MR, and two patients had moderate MR. There was one perioperative death. CONCLUSION: E-E repair, in combination with ring annuloplasty, reduces LV cavity dimensions and functional MR severity, without causing significant valve stenosis. Improvement on DSE may predict those patients in whom EF will improve following repair.