Global Cardiology Science and Practice - Volume 2015, Issue 1

The decrease in cardiovascular death rates in the United States has been slower in blacks than whites, especially in patients < 65 years of age. The Dallas Heart Study was designed as a single-site, multiethnic, population-based probability sample to produce unbiased comparison of cardiovascular health among multiple ethnicities.

The 21st century has seen a paradigm shift to inhaled therapy, for both systemic and local drug delivery, due to the lung's favourable properties of a large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including non-invasive route of administration, low metabolic activity, control environment for systemic absorption and avoids first bypass metabolism. However, because the lung is one of the major ports of entry, it has multiple clearance mechanisms, which prevent foreign particles from entering the body. Although these clearance mechanisms maintain the sterility of the lung, clearance mechanisms can also act as barriers to the therapeutic effectiveness of inhaled drugs. This effectiveness is also influenced by the deposition site and delivered dose. Particulate-based drug delivery systems have emerged as an innovative and promising alternative to conventional inhaled drugs to circumvent pulmonary clearance mechanisms and provide enhanced therapeutic efficiency and controlled drug release. The principle of multiple pulmonary clearance mechanisms is reviewed, including mucociliary, alveolar macrophages, absorptive, and metabolic degradation. This review also discusses the current approaches and formulations developed to achieve optimal pulmonary drug delivery systems.

Comprehensive and precise assessment of left ventricular (LV) systolic and diastolic function is necessary to establish, or exclude, heart failure as a cause or component of dyspnea. Echocardiography with Doppler readily assesses LV diastolic function; advantages include that echocardiography is non-invasive, does not require radiation, is portable, rapid, readily available, and in competent hands, can provide an accurate and comprehensive assessment of LV systolic and diastolic function. Correct assessment of LV diastolic function is relevant in patients with both depressed and preserved LV ejection fraction (EF ≥ 50%, and < 50%, respectively). Tissue Doppler (TD) imaging has been useful in demonstrating impaired LV relaxation in the setting of preserved LVEF, which, in the setting of increased cardiac volume, can result in elevated LV filling pressures, and dyspnea due to diastolic heart failure. TD imaging is not always critical in patients with depressed LVEF, since such patients by definition have impaired LV relaxation, and thus significant increases in volume will result in increases in LV filling pressure due to impaired LV compliance. Thus, in depressed LVEF, transmitral flow velocities (E and A, and E/A) and deceleration time, pulmonary venous Doppler, left atrial volume, and pulmonary artery (PA) pressures suffice for the accurate assessment of LV filling pressures. Overall, diastolic assessment by echo-Doppler can be readily achieved in by using a comprehensive diastolic assessment—incorporating many 2-dimensional, conventional and tissue Doppler variables—as opposed to relying on any single, diastolic parameter, which can lead to errors.

In the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study, dronedarone use was associated with an excess risk of stroke, cardiovascular death and hospitalizations. However, an increased level in the serum digoxin level was observed in the dronedarone arm, as it is a potent inhibitor of the P-glycoprotein transport system. The PALLAS subanalysis suggests that digoxin-dronedarone interaction was responsible for the higher arrhythmic death rate observed in the trial. These data are consistent with several other studies that demonstrate the potential hazard of the use of digoxin in heart failure and/or atrial fibrillation. One must consider other safer alternatives before prescribing digoxin in atrial fibrillation patients.

Lipoprotein associated phospholipase A2 (Lp-PLA2) - an enzyme with several pro-inflammatory properties - has been hypothesized to be involved in the pathogenesis of atherosclerosis and plaque vulnerability. Lp-PLA2 activity has been demonstrated to be an independent predictor of coronary heart disease (CHD) and ischemic stroke. However, it has been recently reported that carriers of loss of function variants in PLA2G7 gene (encoding Lp-PLA2) had no lower CHD risk than non-carriers. The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY), and the Stabilization of Plaque Using Darapladib - Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies are two phase III, randomized, placebo-controlled, clinical trials that were conducted to evaluate the clinical efficacy and safety of the Lp-PLA2 inhibitor (darapladib), against a background of optimal medical therapy, in patients with stable CHD and acute coronary syndrome, respectively. In both studies, darapladib failed to reduce the risk of major coronary events as compared to placebo. In addition, darapladib was associated with significantly higher rates of drug discontinuation, and adverse side effects such as diahrrea and malodorous feces, urine, and skin, as compared to placebo. These data suggest that Lp-PLA2 may be a biomarker of vascular inflammation rather than a causal pathway of cardiovascular (CV) diseases. It also challenges the notion that inhibition of Lp-PLA2 is a worthwhile approach in patients with CHD. Alternate therapies that target inflammation are awaited to reduce residual risk in patients with CV diseases.

Early pharmacological interventions on transgenic models of hypertrophic cardiomyopathy (HCM) using angiotensin receptor blockers (ARBs) may be effective in preventing development of clinical phenotype or causing phenotype regression in early stages of disease. In the clinical setting, however, the effects of ARBs on HCM phenotype have been less consistent. INHERIT (INHibition of the renin angiotensin system in hypertrophic cardiomyopathy and the Effect on hypertrophy—a Randomised Intervention Trial with losartan) was designed to assess the effect of 100 mg of losartan in promoting the regression of LV hypertrophy in HCM. The primary end-point of the study was the reduction in LV mass assessed by MRI or computed tomography. After 12 months, no reduction in LV mass was observed in the losartan arm, and there was no difference in LV mass change with the placebo arm. The same was true for all secondary endpoints. The implications of these findings are discussed in the light of further, ongoing study targeting the HCM phenotype.

Atrial fibrillation ablation is a complex and challenging procedure. Appropriate patient selection is the most critical step to ensure safe and successful atrial fibrillation ablation procedure. The DECAAF study (Delayed-Enhancement MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation) showed that atrial tissue fibrosis, as estimated by delayed enhancement magnetic resonance imaging, was independently associated with recurrent arrhythmia post atrial fibrillation ablation. Magnetic resonance imaging also detected left atrial volume and shape. Integrating the data provided by magnetic resonance imaging into the pre-procedural planning is crucial.

In developing countries, rheumatic fever and carditis still constitutes a major public health problem. Patients have special characteristics that differ from those with rheumatic mitral valve disease we still see in developed countries. They are usually young, poor, uneducated, and have low compliance to prophylaxis / therapy. In addition, they usually have great difficulty in accessing medical care. In these situations, the rate of complications associated to valve replacement is significantly increased. Alternatively, mitral valve repair is now known to achieve better long-term results in this pathology, but this was not widely recognized three or four decades ago, when first reports showed worse results after repair of rheumatic regurgitation than with degenerative valves. This has been reported by several groups in developing countries in different continents, with high incidence of repairs and excellent long term results. It is, therefore, becoming increasingly clear that, although, the results may not compare to those obtained with degenerative pathology, repair of rheumatic valves, when feasible, is the procedure of choice, especially in these underprivileged populations.

The heart is subject to multiple sources of stress. To maintain its normal function, and successfully overcome these stresses, heart muscle is equipped with fine-tuned regulatory mechanisms. Some of these mechanisms are inherent within the myocardium itself and are known as intrinsic mechanisms. Over a century ago, Otto Frank and Ernest Starling described an intrinsic mechanism by which the heart, even ex vivo, regulates its function on a beat-to-beat basis. According to this phenomenon, the higher the ventricular filling is, the bigger the stroke volume. Thus, the Frank-Starling law establishes a direct relationship between the diastolic and systolic function of the heart. To observe this biophysical phenomenon and to investigate it, technologic development has been a pre-requisite to scientific knowledge. It allowed for example to observe, at the cellular level, a Frank-Starling like mechanism and has been termed: Length Dependent Activation (LDA).

In this review, we summarize some experimental systems that have been developed and are currently still in use to investigate cardiac biophysical properties from the whole heart down to the single myofibril. As a scientific support, investigation of the Frank-Starling mechanism will be used as a case study.

We report on the case of 5-year-old girl with severe tricuspid regurgitation following previous repair of double outlet right ventricle with subaortic ventricular septal defect, performed through trans-atrial approach using detachment of tricuspid valve leaflet. The severe tricuspid regurgitation was found to be due to dehiscence at the site of the previous detachment and was repaired using a pericardial patch. In this report, we discuss the relative merits and risks of using this technique.

Background: Left ventricular outflow tract obstruction (LVOT) is an independent predictor of adverse outcome in hypertrophic cardiomyopathy (HCM). It is of major importance that the provocation modalities used are validated against each other. Aim: To define the magnitude of LVOT gradients provocation during both isosorbide dinitrate (ISDN) inhalation and treadmill exercise in non-obstructive HCM and analyze the correlation to the electromechanical delay using speckle tracking. Methods: We studied 39 HCM pts (64% males, mean age 38 ± 13 years) regional LV longitudinal strain and electromechanical delay (TTP) was analyzed at rest using speckle tracking. LVOT gradient was measured at rest and after ISDN then patients underwent a treadmill exercise echocardiography (EE) and LVOT gradient was measured at peak exercise. Results: The maximum effect of ISDN on LVOT gradient was obtained at 5 minutes, it increased to a significant level in 12 (31%) patients, and in 14 (36%) patients using EE, with 85.6% sensitivity & 100% specificity. Patients with latent obstruction had larger left atrial volume and lower E/A ratio compared to the non-obstructive group (p < 0.01). LVOTG using ISDN was significantly correlated with that using EE (p < 0.0001), resting LVOTG (p < 0.0001), SAM (p < 0.0001), EF% (p < 0.02) and regional electromechanical delay but not related to global LV longitudinal strain. Using multivariate regression, resting LVOTG (p = 0.006) & TTP mid septum (p = 0.01) were found to be independent predictors of latent LVOT obstruction using ISDN. Conclusion: There is a comparable diagnostic value of nitrate inhalation to exercise testing in provocation of LVOT obstruction in HCM. Latent obstruction is predominantly dependent on regional electromechanical delay.

We recently performed next generation sequencing (NGS) genetic screening in 11 consecutive and unrelated Tunisian HCM probands seen at Habib Thameur Hospital in Tunis in the first 6 months of 2014, as part of a cooperative study between our Institutions. The clinical diagnosis of HCM was made according to standard criteria. Using the Illumina platform, a panel of 12 genes was analyzed including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2 and MYL3), troponin-T (TNNT2), troponin-I (TNNI3), troponin-C (TNNC1), alpha-tropomyosin (TPM1), alpha-actin (ACTC1), alpha-actinin-2 (ACTN2) as well as alfa-galactosidase (GLA), 5′-AMP-activated protein (PKRAG2), transthyretin (TTR) and lysosomal-associated membrane protein-2 (LAMP2) for exclusion of phenocopies. Our preliminary data, despite limitations inherent to the small sample size, suggest that HCM in Tunisia may have a peculiar genetic background which privileges rare genes overs the classic HCM-associated MHY7 and MYBPC3 genes.