The non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients with high-normal renal function - A systematic review.

Non-vitamin K antagonist oral anticoagulants (NOACs) have revolutionized treatment of atrial fibrillation. Although benefits of anticoagulation therapy are clear, a minority of patients still experience treatment inefficacy or harm. All NOACs have varying degree of renal clearance, which may significantly affect plasma concentrations. Pivotal clinical trials have explored the effects of dose reduction in patients with chronic renal disease. None of these have, however, specifically addressed the need for a dose up-titration in patients with renal hyperfiltration, in whom lower drug plasma levels are to be expected. A signal for lower efficacy in this patient subset has recently emerged. We systematically assessed the peer-reviewed scientific literature on this topic, including a recently reported randomized pharmacokinetic study in renal hyperfiltrators also reporting on ischemic and bleeding events. We conclude that the reduction in NOAC plasma levels in AF patients with renal hyperfiltration is limited in extent and, does not translate into a clinically meaningful reduction in efficacy for NOACs as compared to vitamin K antagonists (VKAs) in such patients. At the current state of knowledge, NOAC current dosing should not be altered in patients with high-normal renal function.

Myocardial ischemia: From disease to syndrome.

Although current guidelines on the management of stable coronary artery disease acknowledge that multiple mechanisms may precipitate myocardial ischemia, recommended diagnostic, prognostic and therapeutic algorithms are still focused on obstructive epicardial atherosclerotic lesions, and little progress has been made in identifying management strategies for non-atherosclerotic causes of myocardial ischemia. The purpose of this consensus paper is three-fold: 1) to marshal scientific evidence that obstructive atherosclerosis can co-exist with other mechanisms of ischemic heart disease (IHD); 2) to explore how the awareness of multiple precipitating mechanisms could impact on pre-test probability, provocative test results and treatment strategies; and 3) to stimulate a more comprehensive approach to chronic myocardial ischemic syndromes, consistent with the new understanding of this condition.

Cardiovascular Risk Factors and Timing of Anthracyclines and Trastuzumab Cardiac Toxicity.

BACKGROUND/AIM: Cardiovascular risk factors (CVRFs) predict cardiotoxicity in cancer patients but their role in late cardiac toxicity is less clear. PATIENTS AND METHODS: This was a retrospective analysis of patients treated with anthracyclines (A) and/or trastuzumab (T) and a correlation with early (≤5 years) or late (>5 years) cardiac toxicity, and baseline CVRFs and CVRFs at toxicity time. RESULTS: A total of 610 patients were included, 422 with (Group A) and 188 without (Group B) baseline CVRFs. In group A toxicity incidence was 4.7% with all events during treatment or immediately after [mean onset time 0.7 years (range=0.2-1.6)]. Events rate was 3.2% in group B with all events after five years [mean time onset 6.9 years (range=5.2-7.5)]. All group B patients who developed late cardiac toxicity presented with CVRFs at the time of toxicity not reported before. CONCLUSION: CVRFs could predict late cardiac toxicity and their control should be part of the survivorship program.

Integrated quadruple stress echocardiography.

Stress echocardiography (SE) is an established diagnostic technique. For 40 years, the cornerstone of the technique has been the detection of regional wall motion abnormalities (RWMA), due to the underlying physiologically-relevant epicardial coronary artery stenosis. In the last decade, three new parameters (more objective than RWMA) have shown the potential to integrate and complement RWMA: 1) B-lines, also known as ultrasound lung comets, as a marker of extravascular lung water, measured using lung ultrasound with the 4-site simplified scan symmetrically of the antero-lateral thorax on the third intercostal space, from mid-axillary to anterior axillary and mid-clavicular line; 2) left ventricular contractile reserve (LVCR), assessed as the peak stress/rest ratio of left ventricular force, also known as elastance (systolic arterial pressure by cuff sphygmomanometer/end-systolic volume from 2D echocardiography); 3) coronary flow velocity reserve (CFVR) on left anterior descending coronary artery, calculated as peak stress/rest ratio of diastolic peak flow velocity assessed using pulsed-wave Doppler. The 4 parameters (RWMA, B-lines, LVCR and CFVR) now converge conceptually, logistically, and methodologically in the Integrated Quadruple (IQ)-SE. IQ-SE optimizes the versatility of SE to include in a one-stop shop the core "ABCD" (asynergy+B-lines+contractile reserve+Doppler flowmetry) protocol. It allows a synoptic assessment of parameters mirroring the epicardial artery stenosis (RWMA), interstitial lung water (B-lines), myocardial function (LVCR) and small coronary vessels (CFVR). Each variable has a clear clinical correlate, different and complementary to all others: RWMA identify an ischemic vs. non-ischemic heart; B-lines a wet vs. dry lung; LVCR a strong vs. weak heart; CFVR a warm vs. cold heart. IQ-SE is highly feasible, with minimal increase in the imaging and analysis time, and obvious diagnostic and prognostic impact also beyond coronary artery disease - especially in heart failure. Large scale effectiveness studies with IQ-SE are now under way with the Stress Echo 2020 Study, and will provide the necessary evidence base prior to large scale acceptance of the technique.

Acetylation contributes to hypertrophy-caused maturational delay of cardiac energy metabolism.

A dramatic increase in cardiac fatty acid oxidation occurs following birth. However, cardiac hypertrophy secondary to congenital heart diseases (CHDs) delays this process, thereby decreasing cardiac energetic capacity and function. Cardiac lysine acetylation is involved in modulating fatty acid oxidation. We thus investigated what effect cardiac hypertrophy has on protein acetylation during maturation. Eighty-four right ventricular biopsies were collected from CHD patients and stratified according to age and the absence (n = 44) or presence of hypertrophy (n = 40). A maturational increase in protein acetylation was evident in nonhypertrophied hearts but not in hypertrophied hearts. The fatty acid ß-oxidation enzymes, long-chain acyl CoA dehydrogenase (LCAD) and ß-hydroxyacyl CoA dehydrogenase (ßHAD), were hyperacetylated and their activities positively correlated with their acetylation after birth in nonhypertrophied hearts but not hypertrophied hearts. In line with this, decreased cardiac fatty acid oxidation and reduced acetylation of LCAD and ßHAD occurred in newborn rabbits subjected to cardiac hypertrophy due to an aortocaval shunt. Silencing the mRNA of general control of amino acid synthesis 5-like protein 1 reduced acetylation of LCAD and ßHAD as well as fatty acid oxidation rates in cardiomyocytes. Thus, hypertrophy in CHDs prevents the postnatal increase in myocardial acetylation, resulting in a delayed maturation of cardiac fatty acid oxidation.

Integration of Wall Motion, Coronary Flow Velocity, and Left Ventricular Contractile Reserve in a Single Test: Prognostic Value of Vasodilator Stress Echocardiography in Patients with Diabetes.

BACKGROUND: Coronary flow velocity reserve (CFVR) and left ventricular contractile reserve (LVCR) have demonstrated prognostic importance in patients with diabetes. The aim of this study was to investigate the prognostic contribution of combined evaluation of CFVR and LVCR in patients with diabetes with nonischemic stress echocardiography. METHODS: Three hundred seventy-five patients with diabetes (mean age, 68 ± 9 years) with nonischemic dipyridamole stress echocardiography underwent assessment of CFVR of the left anterior descending coronary artery (prospectively) and LVCR with left ventricular force (retrospectively) in a multicenter study. RESULTS: On receiver operating characteristic analysis, LVCR ≤ 1.1 was the best prognostic predictor and was considered an abnormal value. CFVR was abnormal (≤2) in 139 patients (37%), LVCR in 156 (42%), neither in 157 (42%), and both in 77 (21%). During a median follow-up period of 16 months, 86 major adverse cardiac events occurred: 16 deaths, 13 myocardial infarctions, and 57 revascularizations. Multivariate prognostic indicators were CFVR ≤ 2 (P < .0001), age (P = .03), and LVCR ≤ 1.1 (P = .04). The 3-year rate of major adverse cardiac events was 63% in patients with both abnormal CFVR and LVCR, 42% in those with abnormal CFVR only, 19% in those with abnormal LVCR only, and 10% in patients with both normal CFVR and LVCR. The 3-year hard event rate was 3% in patients with both normal CFVR and LVCR, fivefold higher in patients with abnormal CFVR or LVCR only, and ninefold higher in patients with both abnormal CFVR and LVCR. CONCLUSIONS: Patients with diabetes with nonischemic dipyridamole stress echocardiography may still have significant risk in presence of abnormal CFVR and/or LVCR, which assess the underlying, largely unrelated, microvascular and myocardial components of coronary circulation.

Trimetazidine and Other Metabolic Modifiers.

Treatment goals for people with chronic angina should focus on the relief of symptoms and improving mortality rates so the patient can feel better and live longer. The traditional haemodynamic approach to ischaemic heart disease was based on the assumption that increasing oxygen supply and decreasing oxygen demand would improve symptoms. However, data from clinical trials, show that about one third of people continue to have angina despite a successful percutaneous coronary intervention and medical therapy. Moreover, several trials on chronic stable angina therapy and revascularisation have failed to show benefits in terms of primary outcome (survival, cardiovascular death, all-cause mortality), symptom relief or echocardiographic parameters. Failure to significantly improve quality of life and prognosis may be attributed in part to a limited understanding of ischaemic heart disease, by neglecting the fact that ischaemia is a metabolic disorder. Shifting cardiac metabolism from free fatty acids towards glucose is a promising approach for the treatment of patients with stable angina, independent of the underlying disease (macrovascular and/or microvascular disease). Cardiac metabolic modulators open the way to a greater understanding of ischaemic heart disease and its common clinical manifestations as an energetic disorder rather than an imbalance between the demand and supply of oxygen and metabolites.

Pharmacological Agents Targeting Myocardial Metabolism for the Management of Chronic Stable Angina : an Update.

Despite continuous advances in myocardial revascularization procedures and intracoronary devices, patients with ischemic heart disease (IHD) still experience worse prognosis and poor quality of life (QoL). Indeed, chronic stable angina (CSA) is a common disease with a large burden on healthcare costs. Traditionally, CSA is interpreted as episodes of reversible myocardial ischemia related to the presence of stable coronary artery plaque causing myocardial demand/supply mismatch when myocardial oxygen consumption increases. Accordingly, revascularization procedures are performed with the aim to remove the flow limiting stenosis, whereas traditional medical therapy (hemodynamic agents) aims at reducing myocardial oxygen demands. However, although effective, none of these treatment strategies or their combination is either able to confer symptomatic relief in all patients, nor to reduce mortality. Failure to significantly improve QoL and prognosis may be attributed at least in part to this "restrictive" understanding of IHD. Despite for many years myocardial metabolic derangement has been overlooked, recently it has gained increased attention with the development of new pharmacological agents (metabolic modulators) able to influence myocardial substrate selection and utilization thus improving cardiac efficiency. Shifting cardiac metabolism from free fatty acids (FA) towards glucose is a promising approach for the treatment of patients with stable angina, independently of the underling disease (macrovascular and/or microvascular disease). In this sense cardiac metabolic modulators open the way to a "revolutionary" understanding of ischemic heart disease and its common clinical manifestations, where myocardial ischemia is no longer considered as the mere oxygen and metabolites demand/supply unbalance, but as an energetic disorder. Keeping in mind such an alternative approach to the disease, development of new pharmacological agents directed toward multiple metabolic targets is mandatory.

Stress Testing After Complete and Successful Coronary Revascularization.

BACKGROUND: Noninvasive stress tests play a determinant role in the initial management of patients with chronic angina. Nonetheless, their use in the same patient population is considered inappropriate within 2 years after percutaneous coronary intervention (PCI). Indeed, early abnormal results correlate less well with angiographic control and are attributed to a number of confounding factors. We prospectively assessed prevalence and impact on the quality of life of abnormal stress test results in a highly selected patient population. METHODS: Patients with no cardiac comorbidities who underwent successful and complete PCI with stenting for typical angina and had an abnormal exercise stress test (EST) under guideline-directed medical treatment were administered the Seattle Angina Questionnaire (SAQ). Clinical evaluation, EST, and the SAQ were repeated at 1, 6, and 12 months after the index PCI. RESULTS: One hundred ninety-eight patients qualified and were included in the study (mean age, 64 years; 79% men). Although the majority had normal EST results or an increased threshold to angina, at 1 month after the index PCI, 29% of patients still had an abnormal result. At 6 and 12 months, 31% and 29% of patients had abnormal results, respectively. Quality-of-life assessment by the SAQ showed consistent results, with persistent angina in one third of patients. Control angiography documented a critical lesion, attributable to in-stent coronary restenosis, in only 8% of patients. CONCLUSIONS: When stress testing is systematically performed after PCI, the prevalence of abnormal results is high and is associated with impaired quality of life. Prognostic significance along with the underlying pathophysiological mechanisms of such findings should be investigated.

Prediction of Post Percutaneous Coronary Intervention Myocardial Ischaemia.

Following revascularisation the majority of patients obtain symptom relief and improved quality of life. However, myocardial ischaemia may recur or persist in a significant patient subset. Symptom recurrence is usually attributed to inaccurate evaluation of epicardial stenosis, incomplete revascularisation or stent failure and disease progression. However, technological advances with modern imaging and/or physiological evaluation of epicardial plaques have not solved this issue. Conversely, recent clinical studies have shown that abnormal coronary vasomotion and increased myocardial resistance are frequent determinants of post-percutaneous coronary intervention (PCI) myocardial ischaemia. Strategies to enhance prediction of post-PCI angina include proper selection of patients undergoing revascularisation, construction of clinical prediction models, and further invasive evaluation at the time of coronary angiography in those with high likelihood.

Activating PPARα prevents post-ischemic contractile dysfunction in hypertrophied neonatal hearts.

RATIONALE: Post-ischemic contractile dysfunction is a contributor to morbidity and mortality after the surgical correction of congenital heart defects in neonatal patients. Pre-existing hypertrophy in the newborn heart can exacerbate these ischemic injuries, which may partly be due to a decreased energy supply to the heart resulting from low fatty acid ß-oxidation rates. OBJECTIVE: We determined whether stimulating fatty acid ß-oxidation with GW7647, a peroxisome proliferator-activated receptor-α (PPARα) activator, would improve cardiac energy production and post-ischemic functional recovery in neonatal rabbit hearts subjected to volume overload-induced cardiac hypertrophy. METHODS AND RESULTS: Volume-overload cardiac hypertrophy was produced in 7-day-old rabbits via an aorto-caval shunt, after which, the rabbits were treated with or without GW7647 (3 mg/kg per day) for 14 days. Biventricular working hearts were subjected to 35 minutes of aerobic perfusion, 25 minutes of global no-flow ischemia, and 30 minutes of aerobic reperfusion. GW7647 treatment did not prevent the development of cardiac hypertrophy, but did prevent the decline in left ventricular ejection fraction in vivo. GW7647 treatment increased cardiac fatty acid ß-oxidation rates before and after ischemia, which resulted in a significant increase in overall ATP production and an improved in vitro post-ischemic functional recovery. A decrease in post-ischemic proton production and endoplasmic reticulum stress, as well as an activation of sarcoplasmic reticulum calcium ATPase isoform 2 and citrate synthase, was evident in GW7647-treated hearts. CONCLUSIONS: Stimulating fatty acid ß-oxidation in neonatal hearts may present a novel cardioprotective intervention to limit post-ischemic contractile dysfunction.

Effect of fatty acids on human bone marrow mesenchymal stem cell energy metabolism and survival.

Successful stem cell therapy requires the optimal proliferation, engraftment, and differentiation of stem cells into the desired cell lineage of tissues. However, stem cell therapy clinical trials to date have had limited success, suggesting that a better understanding of stem cell biology is needed. This includes a better understanding of stem cell energy metabolism because of the importance of energy metabolism in stem cell proliferation and differentiation. We report here the first direct evidence that human bone marrow mesenchymal stem cell (BMMSC) energy metabolism is highly glycolytic with low rates of mitochondrial oxidative metabolism. The contribution of glycolysis to ATP production is greater than 97% in undifferentiated BMMSCs, while glucose and fatty acid oxidation combined only contribute 3% of ATP production. We also assessed the effect of physiological levels of fatty acids on human BMMSC survival and energy metabolism. We found that the saturated fatty acid palmitate induces BMMSC apoptosis and decreases proliferation, an effect prevented by the unsaturated fatty acid oleate. Interestingly, chronic exposure of human BMMSCs to physiological levels of palmitate (for 24 hr) reduces palmitate oxidation rates. This decrease in palmitate oxidation is prevented by chronic exposure of the BMMSCs to oleate. These results suggest that reducing saturated fatty acid oxidation can decrease human BMMSC proliferation and cause cell death. These results also suggest that saturated fatty acids may be involved in the long-term impairment of BMMSC survival in vivo.

Pharmacological approaches to coronary microvascular dysfunction.

In recent decades coronary microvascular dysfunction has been increasingly identified as a relevant contributor to several cardiovascular conditions. Indeed, coronary microvascular abnormalities have been recognized in patients suffering acute myocardial infarction, chronic stable angina and cardiomyopathies, and also in patients with hypertension, obesity and diabetes. In this review, we will examine pathophysiological information needed to understand pharmacological approaches to coronary microvascular dysfunction in these different clinical contexts. Well-established drugs and new pharmacological agents, including those for which only preclinical data are available, will be covered in detail.

Myocardial deformation analysis in contrast echocardiography: first results using two-dimensional cardiac performance analysis.

BACKGROUND: Contrast echocardiography (CE) provides closer agreement with magnetic resonance imaging (MRI) for left ventricular (LV) volumes and ejection fraction (EF) than noncontrast echocardiography. However, the feasibility and role of myocardial deformation analysis on contrast echocardiographic images have not been well established. The aim of this study was to assess the feasibility of deformation analysis on CE using a new software tool that provides simultaneous measurements for LV volumes and EF. METHODS: Data from 52 patients who were recruited for the Alberta Heart Failure Etiology and Analysis Research Team Study (34 men; mean age, 64 ± 9 years) and underwent CE and MRI were considered. Contrast bolus injections were administered for optimal endocardial definition. Offline LV volume analysis was performed by standard manual tracing. A single frame was traced manually for two-dimensional (2D) cardiac performance analysis (CPA), which automatically calculated LV volumes, EF, and global longitudinal strain (GLS). Volumes obtained with 2D CPA were compared with those measured with standard CE and MRI. GLS from noncontrast echocardiographic recordings was also calculated with 2D CPA and compared with CE-derived and MRI-derived GLS. RESULTS: Tracing of contrast echocardiographic images with 2D CPA was possible in 49 out of 52 patients, and measurements correlated well with standard CE and MRI (EF: r = 0.93, P < .001, and r = 0.85, P < .001, respectively). Mean GLS from noncontrast echocardiographic and contrast echocardiographic recordings was -13.4 ± 5.8 and -15.3 ± 4.64, respectively (P = .056), and the latter correlated well with MRI-derived GLS (r = 0.78 vs 0.81, respectively). CONCLUSIONS: Simultaneous volumetric and deformation analysis on contrast echocardiographic recordings is feasible and reproducible. While volumes and EF obtained with the new software compare well with those obtained from standard CE and MRI, GLS from CE shows a good correlation with strain measured with MRI.