Opinions, hopes and concerns regarding pharmacogenomics: a comparison of healthy individuals, heart failure patients and heart transplant recipients.

It is not yet known whether healthy individuals and patients with a chronic disease have similar attitudes towards pharmacogenomics. Thus we conducted a survey of 175 healthy volunteers, 175 heart failure (HF) patients and 100 heart transplant recipients to compare their opinions on this subject. Most participants (>90%) stated that they would accept pharmacogenomic testing and expressed high hopes regarding its potential applications. Overall, interest for pharmacogenomics was shared equally among the three groups. In contrast, after adjusting for age, gender, education and income, healthy individuals were more likely to voice concerns about potential employment (P=0.008 vs HF, odds ratio (OR)=2.93, confidence interval (CI)=1.33-6.47; P=0.010 vs Transplant, OR=2.46, CI=1.24-4.90) and insurance discrimination (P=0.001 vs HF, OR=5.58, CI=2.01-15.48; P<0.001 vs Transplant, OR=4.98, CI=2.03-12.21) and were possibly more worried by confidentiality issues. These findings highlight the need for strict legislation and proper educational strategies directed at the general population to facilitate the clinical implementation of pharmacogenomics.

Management of the extravasation of anti-neoplastic agents.

BACKGROUND: Extravasation is a potentially severe complication that can occur during the administration of chemotherapy. The scarcity of evidence available makes it difficult to develop an optimal management scheme. The purpose of this guideline is to review the relevant scientific literature on the prevention, management, and treatment of extravasation occurring during the administration of chemotherapy to cancer patients. METHOD: A scientific literature review was conducted using the PubMed search tool. The period covered was from database inception to April 2014, inclusively. Since the literature on extravasation treatment is often empirical, anecdotal, and controversial, the review also identified clinical practice guidelines and expert consensuses published by relevant international organizations and cancer agencies. RESULTS: Identification of potential risk factors and preventive measures can reduce the risk of extravasation. Recognition and management of symptoms are crucial in patients with this complication. Provision of adequate instruction to personnel responsible for administering chemotherapy and to patients on recognizing symptoms, preventing, and managing extravasation is essential. Extravasation can be treated with dry warm or cold compresses and various antidotes such as dimethyl sulfoxide, dexrazoxane, hyaluronidase, or sodium thiosulfate, depending on the agent that has caused extravasation. Patient monitoring to assess the progression or regression of symptoms and to thus take the appropriate measures is necessary. CONCLUSION: Several strategies must be established to ensure that extravasation is recognized and properly managed. Given the evidence available at this time, the Comité de l'évolution des pratiques en oncologie (CEPO) has made recommendations for clinical practice in Quebec.

Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction.

Matrix metalloproteinase-9 (MMP-9) is prominently overexpressed after myocardial infarction (MI). We tested the hypothesis that mice with targeted deletion of MMP9 have less left ventricular (LV) dilation after experimental MI than do sibling wild-type (WT) mice. Animals that survived ligation of the left coronary artery underwent echocardiographic studies after MI; all analyses were performed without knowledge of mouse genotype. By day 8, MMP9 knockout (KO) mice had significantly smaller increases in end-diastolic and end-systolic ventricular dimensions at both midpapillary and apical levels, compared with infarcted WT mice; these differences persisted at 15 days after MI. MMP-9 KO mice had less collagen accumulation in the infarcted area than did WT mice, and they showed enhanced expression of MMP-2, MMP-13, and TIMP-1 and a reduced number of macrophages. We conclude that targeted deletion of the MMP9 gene attenuates LV dilation after experimental MI in mice. The decrease in collagen accumulation and the enhanced expression of other MMPs suggest that MMP-9 plays a prominent role in extracellular matrix remodeling after MI.

Cystatin C deficiency in human atherosclerosis and aortic aneurysms.

The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves breakdown of the elastic laminae. Elastolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage, but whether endogenous local inhibitors counterbalance these proteases is unknown. We show here that, whereas cystatin C is normally expressed in vascular wall smooth muscle cells (SMCs), this cysteine protease inhibitor is severely reduced in both atherosclerotic and aneurysmal aortic lesions. Furthermore, increased abdominal aortic diameter among 122 patients screened by ultrasonography correlated inversely with serum cystatin C levels. In vitro, cytokine-stimulated vascular SMCs secrete cathepsins, whose elastolytic activity could be blocked when cystatin C secretion was induced by treatment with TGF-beta(1). The findings highlight a potentially important role for imbalance between cysteine proteases and cystatin C in arterial wall remodeling and establish that cystatin C deficiency occurs in vascular disease.

Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice.

BACKGROUND: Extracellular matrix synthesis and degradation contribute to the morphological changes that occur after myocardial infarction (MI). METHODS AND RESULTS: We tested the hypothesis that inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling in experimental MI. Seventy-one male FVB mice that survived ligation of the left anterior coronary artery were randomized to a broad-spectrum MMP inhibitor (CP-471,474) or placebo by gavage. Echocardiographic studies were performed before randomization (within 24 hours of surgery) and 4 days later and included short-axis imaging at the midpapillary and apical levels. Infarction as defined by wall motion abnormality was achieved in 79% of the procedures (n=56), and mortality rate during the 4-day protocol was 23% (9 of 36 on treatment vs 7 of 35 on placebo; P=NS). Baseline end-diastolic and end-systolic dimensions and areas were similar (P=NS) between treated and placebo groups. At follow-up, infarcted mice allocated to MMP inhibitor had significantly smaller increases in end-systolic and end-diastolic dimensions and areas at both midpapillary and apical levels compared with infarcted mice allocated to placebo (all P<0.05). In addition, infarcted animals that received MMP inhibitor had no change in fractional shortening (-3+/-13%), whereas animals that received placebo had a decrease in fractional shortening (-12+/-12%) (P<0.05). In an analysis stratified by baseline end-diastolic area, the effects of MMP inhibition on the changes in end-systolic area and end-diastolic area were most prominent in animals that had more initial left ventricular dilatation (both P<0.05). CONCLUSIONS: -Administration of an MMP inhibitor attenuates early left ventricular dilation after experimental MI in mice. Further studies in genetically altered mice and other models will improve understanding of the role of MMPs in left ventricular remodeling.

Remodeling of atrial dimensions and emptying function in canine models of atrial fibrillation.

OBJECTIVES: Atrial tachycardia-induced remodeling (ATR) and ventricular tachypacing-induced heart failure (HF) create experimental substrates for atrial fibrillation (AF), and both have been reported to produce atrial dilation and hypocontractility. The relative importance of changes in atrial size and contractility in the two models is unknown. This study compared changes in atrial dimensions and emptying in ATR versus HF dog models and related them to AF promotion. METHODS: In ATR dogs (n=11), the right atrium (RA) was paced at 400/min for 42 days. In HF dogs (n=10), the right ventricle was paced at 240 bpm for 2 weeks, followed by 3 weeks at 220 bpm. Transthoracic echocardiography was performed at baseline and weekly thereafter. At a terminal electrophysiological study, RA effective refractory period (ERP) was recorded and AF induced repeatedly by atrial burst pacing to measure mean AF duration (DAF). RESULTS: Left atrial (LA) systolic area increased by 10.0% in ATR versus 48.2% in HF dogs (P=0.008), with significant time-dependent changes in HF (P=0.0001), but not ATR (P=0.16). LA diastolic area increased over time in both groups (P=0.004, 0.0001 for ATR and HF respectively), but increases were much larger in CHF (80.2%) compared to ATR (24.2%, P=0.0002). Similar findings were obtained for RA. Fractional area shortening (FAS) decreased by 19.4% (ATR) versus 41.8% (HF, P=0.007) in LA and 13.7% (ATR) versus 33.7% (HF, P=0.03) in RA. RA ERP correlated with DAF in ATR dogs (r=-0.79, P<0.001), but not in HF dogs (r=0.20, P=NS). DAF and diastolic areas of RA and LA were highly correlated (r=0.71, 0.77; P<0.01 for each) in HF dogs, but not in ATR dogs (r=-0.18, 0.29; P=NS). CONCLUSIONS: Remodeling of atrial size and emptying function is much greater in HF than in ATR. Whereas in ATR, electrophysiological remodeling is of prime importance in AF promotion, structural remodeling (as reflected in changes in atrial size and contraction) appears much more important in HF-induced AF.

Comparison of nitroglycerin lingual spray and sublingual tablet on time of onset and duration of brachial artery vasodilation in normal subjects.

This study compared the rapidity of onset, the magnitude, and the duration of action of 2 short-acting nitroglycerin preparations using high-resolution brachial ultrasound. Both sublingual tablet and lingual spray formulations caused maximal vasodilation at 3 minutes; however, the spray provided faster (at 2 minutes), greater, and more prolonged (15 minutes) vasodilation than the tablet.

Therapeutic potential of angiotensin II receptor antagonists.

The circulating renin-angiotensin system plays an important role in cardiovascular homeostasis. More importantly, the local tissue renin angiotensin plays a pivotal role in cell growth and remodelling of cardiomyocytes and on the peripheral arterial vasculature. In addition, the renin angiotensin system is related to apoptosis, control of baroreflex and autonomic responses, vascular remodelling and regulation of coagulation, inflammation and oxidation. The cardioprotective and vascular protective effects of the angiotensin receptive blockade appears to be related to selective blockade of the angiotensin II (A-II) Type I (AT(1)) receptors. However, there is now growing evidence showing that some of the effects of AT-II receptor blockers (ARBs) are related to the activation of the kinin pathways. This paper will review some of the recent mechanisms related to the cardiovascular effects of angiotensin and more specifically of ARBs. This paper will present the novel data on the role of ARB in the development of atherosclerosis, vascular remodelling, coagulation balance and autonomic regulation. Finally, the role of ARBs, used alone or in combination with ACE inhibitor in patients with heart failure, will be discussed.

Characterization of the natural history of cervical heterotopic heart transplantation with echocardiography.

BACKGROUND: Limitations of the dog model of orthotopic heart transplantation to study rejection include the need for extracorporeal circulation and transfusions. Heterotopic cervical heart transplantation may improve on these limitations. It is not known whether the natural history after heterotopic transplant is similar to that after orthotopic grafting. METHODS: Twenty-one dogs underwent cervical heterotopic heart transplantation. Serial echocardiographic studies were performed 1 to 3 hours after surgery, at 24 hours, 48 hours later, and immediately before killing (5 to 7 days). RESULTS: LV diastolic and systolic areas were elevated immediately after transplantation (4.95+/- 1.49 cm2 and 3.36+/-1.18 cm2 respectively) but decreased at 24 hours (3.93+/-1.20 cm2, p = 0.0003 and 2.44+/-0.96 cm2, p = 0.16). Thereafter, a progressive increase in LV diastolic and systolic areas was observed until sacrifice (5.53+/-2.20 cm2 and 4.59 +/-2.14 cm2, p < 0.001 vs 24 hours). LV fractional area shortening (FAS) and fractional volume change were depressed immediately after transplantation (28.2+/- 12.8% and 40.4+/-12.3%, respectively), but increased at 24 hours (35.7+/-10.0%,p = 0.11 and 50.3+/-4.0%,p = 0.02). FAS decreased at 48 hours to 19.6+/-11.1% (p = 0.01 vs 24 hours). The centractility indexes were markedly reduced before killing (FAS = 14.0+/-8.2% and LVEF = 18.4+/-1.3%, p < 0.0005 vs 24 hours). The thickness of the interventricular septum increased from 11.9+/-2.0 mm at baseline to 14.4+/-4.2 mm before sacrifice (p = 0.007). CONCLUSION: The evolution of dogs after heterotopic cervical heart transplant is comparable to that after the more standard orthotopic graft. Considering its multiple practical advantages including the easy echocardiographic follow-up, heterotopic transplantation may become a very practical model to use for the study of rejection after heart transplantation.

Severe aortic regurgitation immediately after mitral valve annuloplasty.

We report a case of severe aortic regurgitation occurring immediately after the insertion of a mitral annuloplasty ring. On transesophageal echocardiography, regurgitation was found to originate from the retracted left coronary cusp. On direct examination, part of the aortic wall was folded, but no suture could be identified. It was reasoned that tension created by the ring caused the retraction. The problem was corrected by releasing three sutures on the ring. Postoperative course was uneventful.

Obstruction of left ventricular outflow tract by vegetation and periaortic abscess.

Echocardiography is the modality of choice for the noninvasive recognition of vegetations and abscesses that complicate endocarditis. Vegetation size is highly variable, and it has been suggested that large vegetations are related to a more complicated course. The case we present is unusual in that the echocardiographically detected vegetation was very large, highly mobile, and caused severe obstruction of the left ventricular outflow tract, which led to impaction and cardiac arrest.

Seasonal congestive heart failure mortality and hospitalisation trends, Quebec 1990-1998.

STUDY OBJECTIVE: To describe seasonal congestive heart failure (CHF) mortality and hospitalisations in Quebec, Canada between 1990-1998 and compare trends in CHF mortality and morbidity with those in France. DESIGN: Population cohort study. SETTING: Province of Quebec, Canada. PATIENTS: Mortality data were obtained from the Quebec Death Certificate Registry and hospitalisation from the Quebec Med-Echo hospital discharge database. Cases with primary ICD-9 code 428 were considered cases of CHF. RESULTS: Monthly CHF mortality was higher in January, declined until September and then rose steadily (p<0.05). Hospital admissions for CHF declined from May until September (moving averages analysis p<0.0001). Seasonal mortality patterns observed in Quebec were similar to those observed in France. CONCLUSION: CHF mortality in Quebec is highest during the winter and declines in the summer, similar to observations in France and Scotland. This suggests that absolute temperatures may not necessarily be that important but increased CHF mortality is observed once environmental temperatures fall below a certain "threshold" temperature. Alternatively better internal heating and warmer clothing required for survival in Quebec may ameliorate mortality patterns despite colder external environments.

Remnants of the right valve of the sinus venosus presenting as a right atrial mass on transthoracic echocardiography.

Three patients were referred for suspicion of intracardiac tumour on transthoracic echocardiography. In all patients, the mass appeared as a nonobstructive oval structure measuring approximately 12 x 4 mm, located near the posterior third of the interatrial septum in the right atrium in the apical four-chamber view. The characteristics of the mass were not those of a Eustachian valve or a Chiari network. Multiplane transesophageal echocardiography performed in each of these patients did not reveal a tumour but rather a fibrous band in the right atrium, extending from the inferior to the superior vena cava. These findings are consistent with remnants of the right valve of the sinus venosus. Inclusion of a persistent right valve of the sinus venosus in the differential diagnosis of a right atrial mass can alleviate concern and spare an unnecessary transesophageal examination when the typical transthoracic echocardiographic characteristics are identified.

Prolonged distress and clinical deterioration before pericardial drainage in patients with cardiac tamponade.

OBJECTIVE: To determine whether patients with cardiac tamponade are subject to delays and clinical deterioration before undergoing echocardiography and pericardial drainage. DESIGN: Retrospective study. SETTING: The Montreal Heart Institute, Montreal, Quebec, a cardiology referral centre. PATIENTS: The charts of 50 patients who presented with tamponade were reviewed. Intervals between the appearance of symptoms, consultation, echocardiography and drainage were noted. The presence of clinical deterioration before drainage was evaluated. Causes for delays were investigated. RESULTS: Previous cardiac surgery (74%) was the most common etiology of tamponade. Symptoms were present 6.6+/-5.8 days before consultation. The delay between consultation and echocardiography was 1.2+/-2.0 days (range 0 to 12), and that between echocardiography and drainage was 0.8+/-0.9 days (range 0 to four). Patients underwent drainage 1. 9+/-2.5 days (range 0 to 16) after the initial consultation. Deterioration of the clinical status was noted in 34% of patients before pericardial drainage. An error in the initial diagnosis was present in 36% of patients; the majority of these were incorrectly diagnosed with heart failure. Another 44% of patients had no mention of either a working diagnosis in the chart at admission or the desire to rule out tamponade on the request for echocardiography. CONCLUSION: The proper diagnosis does not appear to be initially considered in up to 80% of patients who present with cardiac tamponade. Clinical deterioration occurs in approximately a third of patients during the interval between consultation and pericardial drainage.

Patient assessment for cardiac resynchronization therapy: Past, present and future of imaging techniques.

It has been proposed that dyssynchrony assessment before cardiac resynchronization therapy (CRT) implantation could help predict response to CRT. It is known that up to 40% of patients who receive a CRT device for established indications do not respond to CRT. Great expectations came from the Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study, which would finally identify the ultimate echocardiographic dyssynchrony criteria to help select responders. The recently published PROSPECT trial failed to identify an ideal parameter of dyssynchrony. Patient selection for CRT should involve a multimodal approach, and new promising tools are being investigated in that view. The present review integrated new data coming from the exciting field of imaging with currently available evidence to generate a stepwise approach to patient selection.

Elimination of threshold-induced distortion in the power spectrum of narrow-band laser speckle.

The distortion in the power spectrum of narrow-band laser speckle that results from irradiance thresholding is quantified. A method for compensation of this distortion is presented. An optimal threshold level is presented that simplifies the compensation method.

Effects of intensity thresholding on the power spectrum of laser speckle.

Spatial-frequency filtering of laser-speckle patterns has proved to be a useful tool in the measurement of the modulation transfer function for focal plane arrays. Intensity thresholding of the laser-speckle patterns offers nearly an order of magnitude savings in digital storage space. The effect of this thresholding on the spatial-frequency power spectral density of the speckle pattern is investigated. An optimum threshold level is found that minimizes distortion of the power spectrum for the classes of speckle data used for modulation transfer function testing.

Transvenous catheter ice mapping and cryoablation of the atrioventricular node in dogs.

While radiofrequency catheter ablation is very effective, it does not allow for prediction of success prior to full delivery of the energy. We investigated the use of cryoablation using a new catheter on the AV node to determine (1) if a successful site might be identified prior to the ablation itself, and (2) the parameters of cryoablation of the AV node using a new cryocatheter. In eight dogs, the cryoablation catheter was advanced to the AV node to produce transient high degree AV block by lowering the temperature to a minimum of -40 degrees C (ice mapping). Transient high degree AV node block was obtained in seven of eight animals at a mean temperature of -39.9 +/- 11.6 degrees C. No significant pathological modification was found in all animals but one and, in all cases, electrophysiological parameters of the AV node measured before, 20 minutes, 60 minutes, and up to 56 days after cryoapplication were not significantly different. In the 12 other dogs, after ice mapping, cryoablation of the AV node was attempted with a single freeze-thaw cycle in 6 dogs (group I) and a double freeze-thaw cycle in the other 6 dogs (group II). Chronic complete AV block was obtained in only one animal in group I compared to all animals in group II. Ablation of the AV node is effective with a double freeze-thaw cycle using a percutaneous catheter cryoablation system. Ice mapping of the area allows for identification of the targeted site.

Cardiac-directed overexpression of wild-type alpha1B-adrenergic receptor induces dilated cardiomyopathy.

Using transgenesis as a paradigm, we show here that alpha1-adrenergic receptors (alpha1AR) play an important role in cardiac homeostasis. Cardiomyocyte-specific overexpression of the alpha(1B)AR subtype resulted in the development of dilated cardiomyopathy and death at ~9 mo of age with typical signs of heart failure. Histological analyses showed the enlargement of all four cardiac chambers and cardiomyocyte disarray in the failing hearts. Transgenic animals showed increased left ventricular areas, as assessed by echocardiography. In addition, a progressive decrease in left ventricular systolic function was revealed. The abundance and activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) were reduced, and the ratio of phospholamban to SERCA2 was increased. alpha-Myosin heavy chain (MHC) mRNA was less abundant in older transgenic ventricles, whereas beta-MHC was induced in the failing hearts. Titin mRNA abundance was decreased at 9 mo, whereas atrial natriuretic factor mRNA was elevated at all times. This model mimics structural and functional features of idiopathic dilated cardiomyopathy. The results of this study suggest that chronic alpha1AR activity is deleterious for cardiac function.