Consideration Regarding the Analysis of Randomized Controlled Trials in the Era of Evidence-based Medicine.

ABSTRACT: Analysis of randomized controlled trials (RCTs) is the cornerstone of evidence-based medicine, therapeutic guidelines and ultimately daily practice. However, 2 issues contribute to cloud the analysis of RCTs. Industry-sponsored RCTs aim at capturing as large indications as possible and clinicians rely excessively on P value statistical significance for the evaluation of the findings. To be most valuable to practitioners, analysis of RCTs needs to provide absolute risk reduction, number of patients needed to treat, fragility index along with the estimation of lost to follow-up patients, and outcome postponement (gain in survival time). We analyzed few major cardiovascular RCTs and assessed the robustness of their findings. Our suggested analytic parameters may be further used in future systematic reviews and meta-analyses.

Toward safe inotropic therapy.

The use of currently available positive inotropic agents is associated with an unfavorable clinical outcome. The disappointment with positive inotropic therapy is to some extent foreseeable as currently available inotropic agents may precipitate ventricular arrhythmias due to a diastolic rise in intracellular [Ca], trigger/worsen myocardial ischemia due to an increased oxygen demand, and foster fuel deprivation from an energy starved heart. Safe use of presently available inotropic agents and development of novel inotropic agents must ensure that they are not associated with a diastolic rise in intracellular [Ca], an increase in myocardial oxygen consumption, and energy expenditure. Agents that improve left ventricular systolic performance through prolongation of left ventricular ejection time and not through increased myocardial contractility, that is, myosin activators, may be associated with a favorable outcome as they do not affect diastolic intracellular [Ca], myocardial oxygen demand, and presumably fuel expenditure.

Patient-Centered Heart Failure Therapy.

Simultaneous initiation of quadruple therapy with angiotensin receptor-neprilysin inhibitor, beta-adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor aims at prompt improvement and prevention of readmission in patients hospitalized for heart failure with reduced ejection fraction. However, titration of quadruple therapy is time consuming. Lengthy up-titration of quadruple therapy may negate the benefit of early initiation. Quadruple therapy should start with a sodium glucose cotransporter 2 inhibition and a mineralocorticoid antagonist, as both enable safe decongestion and require minimal or no titration. Depending on the level of decongestion and clinical characteristics, patients receive an angiotensin receptor-neprilysin inhibitor or a beta-adrenergic receptor blocker to be titrated after hospital discharge. Outpatient addition of an angiotensin receptor-neprilysin inhibitor to a beta-adrenergic receptor blocker or vice versa completes the quadruple therapy scheme. By focusing on decongestion and matching intervention to patients' profile, the present therapeutic sequence allows rapid implementation of quadruple therapy at fully recommended doses.

Acute myocardial infarction spurred by myopericarditis in a young female patient: Coxsackie B2 to blame.

Myocardial virus infection may mimic but also trigger acute myocardial infarction.The present paper reports an exceedingly rare presentation of an acute myocardial infarction in a very young female associated with Coxsackie B2 virus infection. A 17-year-old woman with no prior medical history presented to the Cardiac Intensive Care unit with chest pain, ST segment elevation and increased cardiac troponin with pericardial effusion one week after experiencing febrile viral gastroenteritis. Given the age and health of the patient, myocarditis was initially presumed. Coronary angiography and cardiac magnetic resonance imaging studies, however, demonstrated an acute posterior myocardial infarction related to a right coronary artery thrombosis. Serological studies disclosed a concurrent Coxsackie B2 virus infection. The patient made a successful recovery with subsequent minor left ventricular dysfunction at long-term follow-up. Coxsackie B2 myocarditis might have triggered a coronary artery spasm and subsequent thrombosis.

Exercise-induced functional mitral regurgitation in heart failure and preserved ejection fraction: a new entity.

We report here the worsening of functional mitral regurgitation (MR) during dynamic exercise Doppler echocardiography in four female patients with heart failure and preserved ejection fraction. MR worsened concomitantly to an increase in systolic mitral tenting area and in E/E(a) ratio, whereas local left ventricular (LV) remodelling was not substantially aggravated by exercise. We accordingly suggest that exercise-induced increase in LV filling or left atrial pressure that in turn leads to increase in mitral tenting area worsens functional MR during exercise.

Contractile pattern of inverted Takotsubo cardiomyopathy: illustration by two-dimensional strain.

We report a case of a 25-year-old man who was admitted to our emergency department for brain trauma, with electrocardiographic and echocardiographic features suggestive of inverted Takotsubo cardiomyopathy. Using myocardial strain obtained from bidimensional acquisitions, we describe the myocardial abnormalities in this patient presenting with this yet under-recognized syndrome.

The effect of ageing on cardiac remodelling and hospitalization for heart failure after an inaugural anterior myocardial infarction.

AIMS: Following myocardial infarction (MI), both age and left ventricular (LV) remodelling are associated with an increased risk of adverse events. We tested the hypothesis that the increased incidence of heart failure following MI in elderly patients is associated with a greater propensity for LV remodelling. METHODS AND RESULTS: We monitored 266 patients with anterior MI. Echocardiographic studies were performed at hospital discharge, at 3 months, and at 1 year following hospitalization for MI. A clinical follow-up examination was performed after 3 years. Left ventricular remodelling was documented by an increase in LV end-diastolic volume after 1 year. Left ventricular end-diastolic and end-systolic volumes did not differ with age for all time points studied. Left ventricular remodelling was observed in 31, 26, 34, and 34% of patients <48, 48-57, 58-71, and >71 years of age, respectively. The 3 year heart-failure hospitalization rates were 1.9, 1.5, 11.0, and 20.3% for patients <48, 48-57, 58-71, and >71 years of age, respectively. Hospitalization for heart failure was more frequent in older patients. CONCLUSION: We found that age was a major determinant of subsequent re-hospitalization for heart failure. However, we found no significant association between age and the LV remodelling process.

Exercise does not enhance the prognostic value of Doppler echocardiography in patients with left ventricular systolic dysfunction and functional mitral regurgitation at rest.

BACKGROUND: Functional mitral regurgitation (MR) is a powerful predictor of poor prognosis in patients with chronic heart failure (CHF) due to left ventricular systolic dysfunction (LVSD). However, severity of MR varies with dynamic exercise. Accordingly, we sought to assess the prognostic value of exercise-induced changes in functional MR in patients with LVSD and functional MR at rest. METHODS: One hundred four patients with chronic heart failure due to LVSD (ejection fraction [EF] < 45%) and functional MR at rest underwent conventional continuous 2-dimensional Doppler echocardiography at rest and during maximal symptom-limited exercise. The primary end point of the study was all-cause mortality. The median follow-up period was 20 months. RESULTS: Fifty-six patients (54%) had ischemic cardiomyopathy. When feasible, all 56 patients with ischemic cardiomyopathy had undergone revascularization procedures before enrollment into the study. In the whole patient cohort, resting LV end-diastolic volume was 205 +/- 76 mL and EF was 26% +/- 9%. Univariate predictors of death were functional class (New York Heart Association), LV EF, LV end-diastolic volume, resting mitral effective regurgitant orifice, mitral E deceleration time, tricuspid annular plane systolic excursion < or = 14 mm, systolic blood pressure, LV EF, and trans-tricuspid pressure gradient response to exercise. Exercise-induced change in mitral effective regurgitant orifice did not predict survival (HR 0.99, 95% CI 0.94-1.04, P = .63). By Cox multivariate analysis, resting LV end-diastolic volume and tricuspid annular plane systolic excursion < or = 14 mm were the independent predictors of death. CONCLUSIONS: Exercise Doppler echocardiography does not refine the predictive value of resting Doppler echocardiography in patients with LVSD and functional MR at rest.

Left ventricular remodeling is associated with the severity of mitral regurgitation after inaugural anterior myocardial infarction--optimal timing for echocardiographic imaging.

BACKGROUND: Although mitral regurgitation (MR) has been associated with an increased risk of death and heart failure after myocardial infarction (MI), the relationship between post-MI MR and left ventricular (LV) remodeling has not been entirely clarified. In addition, the optimal timing for assessing MR after MI remains unknown. METHODS: Post-MI MR was assessed by Doppler echocardiography at hospital discharge (baseline) and after 3 months in 261 patients with an inaugural anterior MI. We studied LV remodeling during a 1-year period and clinical follow-up after 3 years, according to MR severity at baseline and at 3 months. RESULTS: Left ventricular remodeling was demonstrated as an increase in LV end-diastolic volume from 56 +/- 15 mL/m(2) at baseline to 63 +/- 19 mL/m(2) at 1 year (P < .0001). MR severity at baseline was not significantly associated with LV remodeling. By contrast, MR severity at 3 months was a strong indicator of LV remodeling. There was a graded increase in the proportion of patients with a >20% increase in LV end-diastolic volume between baseline and 1 year according to MR severity at 3 months (no MR: 21%, mild MR: 32%, moderate/severe MR: 60%) (P = .008). Both MR at baseline and at 3 months were associated with death or rehospitalization for heart failure by univariate analysis (P = .014 and P < .0001, respectively). By multivariable analysis, MR at baseline was not an independent predictor of adverse outcome (P = .66). By contrast, MR at 3 months was independently associated with adverse outcome with a hazard ratio of 2.23 (1.02-4.91 [P = .04]). CONCLUSIONS: After an inaugural anterior MI, MR is associated with LV remodeling and adverse clinical outcome. For prognostic purpose, the optimal timing for assessing MR is the chronic post-MI stage rather than the early post-MI period.

Left ventricular abnormal response during dynamic exercise in patients with heart failure and preserved left ventricular ejection fraction at rest.

BACKGROUND: The mechanisms that contribute to limit functional capacity are incompletely understood in patients with preserved resting ejection fraction (HFpREF). We assessed left ventricular (LV) systolic response to dynamic exercise in patients with HFpREF and in patients with similar comorbidities to HFpREF patients but without history or evidence of heart failure. METHODS AND RESULTS: Twenty-five HFpREF patients in steady-state clinical condition without significant coronary artery disease and 25 hypertensive controls underwent exercise echocardiography. At rest, systolic pulmonary artery pressure, left atrial area, E/A and E/e' ratios were greater in patients with HFpREF than in control patients, whereas peak systolic mitral annular velocity was lower in HFpREF patients. The exercise-induced changes in LVEF, forward stroke volume, and cardiac output were significantly lower in HFpREF compared with control patients (-4 +/- 8 vs. +6 +/- 6 %, P = .001; -4 +/- 9 vs. +10 +/- 10 mL, P < .0001, and 1.6 +/- 1.2 vs. 3.5 +/- 1.8 L/min, P < .0001, respectively). Exercise-induced changes in effective arterial elastance significantly differed in HFpREF and control patients (0.5 +/- 0.6 vs. -0.2 +/- 0.5 mm Hg/mL, P < .0001). In addition, 7 of the 25 HFpREF patients developed functional mitral regurgitation during exercise and none in controls. CONCLUSIONS: When compared with patients with similar comorbidities but without history or evidence of heart failure, patients with HFpREF experience greater arterial stiffening and thereby a deterioration of global LV systolic performance during dynamic exercise.

Septic pseudo-aneurysm of the left main trunk in a dialysis patient.

This case report relating the association between a septic pseudo-aneurysm of the left trunk and myocardial infarction underscores the importance of early non-invasive imaging when acute myocardial infarction is associated with frank clinical or biological signs of systemic sepsis.

Prognostic importance of tissue Doppler-derived diastolic function in patients presenting with acute coronary syndrome: a bedside echocardiographic study.

AIMS: We sought to evaluate the prognostic value of bedside tissue Doppler derived diastolic function in patients presenting with acute coronary syndrome (ACS) on top of major clinical predictors of mortality and routine laboratory testings. METHODS AND RESULTS: Bedside Doppler echocardiography and laboratory tests were prospectively performed in 239 consecutive patients (mean age 62 +/- 14, 69% men) admitted for ACS. Ratio of early transmitral flow (E) to early mitral annulus velocities (e') was calculated. The study endpoint was cardiac death. The median follow-up period was 2 years. E/e' was >15 in 39 patients. Multivariate predictors of E/e' > 15 were older age, diabetes, non-ST-segment elevation ACS, and decreased LV ejection fraction (LVEF). Survival free from cardiac death was lower in patients with E/e' ratio >15 (P = 0.01). History of coronary artery disease, lower creatinine clearance, higher glycemia on admission, decreased LVEF, and E/e' >15 were independent predictors of cardiac death. CONCLUSION: Bedside Doppler echocardiography provides prognostic information on top of major clinical predictors of mortality and routine laboratory testings in patients presenting with ACS.

A prospective evaluation of left ventricular remodeling after inaugural anterior myocardial infarction as a function of gene polymorphisms in the renin-angiotensin-aldosterone, adrenergic, and metalloproteinase systems.

BACKGROUND: Left ventricular remodeling (LVR) is a strong predictor of cardiovascular events after myocardial infarction (MI). Although several factors have been shown to influence LVR, interindividual variability exists. Some studies have suggested that gene polymorphisms may be associated with LVR, but these studies were limited by either a retrospective design or the inclusion of limited patient numbers. The present study was designed to prospectively assess the impact of gene polymorphisms on LVR. METHODS: We included 266 patients with inaugural anterior MI. Systematic echocardiographic follow-ups were performed at 3 months and at 1 year after MI. The polymorphisms were selected using a candidate gene approach based on LVR pathophysiology. We analyzed 14 polymorphisms in 3 different systems: the renin-angiotensin-aldosterone system (ACE I/D, RAT1 1166A/C, angiotensinogen M235T, CYP11B2 -344C/T), the adrenergic system (beta1AR Ser49Gly, beta1AR Gly389Arg, beta2AR Gly16Arg, beta2AR Gln27Glu, beta2AR Thr164Ile, alpha2cAR Del322-325), and the metalloproteinase (MMP) system (-1607 1G/2G MMP-1, -1306 C/T MMP-2, -1171 5A/6A MMP-3, -1562 C/T MMP-9). RESULTS: Left ventricular remodeling was documented by a progressive increase in end-diastolic volume from 56.5 +/- 14.9 mL/m2 at baseline to 62.8 +/- 18.8 mL/m2 at 1 year (P < .0001). End-diastolic volume at baseline, 3 months, or 1 year did not differ significantly among genotypes for any polymorphism. The change in end-diastolic volume from baseline to 1 year was also similar among genotypes for all polymorphisms. CONCLUSIONS: Left ventricular remodeling after MI is not associated with common polymorphisms in the renin-angiotensin-aldosterone, adrenergic, or MMP systems.

Relation of admission white blood cell count to left ventricular remodeling after anterior wall acute myocardial infarction.

We investigated whether a high white blood cell (WBC) count on admission for acute myocardial infarction (AMI) may be associated with a higher risk of subsequent left ventricular (LV) remodeling. We included 107 patients with anterior AMI. Echocardiographic studies were performed at hospital discharge, at 3 months, and at 1 year after AMI. LV remodeling (>20% increase in end-diastolic volume) was observed in 27% of patients. WBC counts during hospitalization were higher in patients who subsequently underwent LV remodeling (p = 0.003 for WBC count on admission). The increase in end-diastolic volume from baseline to 1 year was greater for patients in the higher tertile of WBC count on admission (p = 0.04). When adjusting for baseline clinical and echocardiographic characteristics by multivariate analysis, WBC count on admission was independently associated with LV remodeling (odds ratio 1.23, 95% confidence interval 1.04 to 1.45, p = 0.018). In conclusion, a high WBC count on admission for AMI is an independent predictor of LV remodeling, even when predischarge echocardiographic variables are taken into account.

Steady endothelial nitric oxide synthase expression in heart failure.

BACKGROUND: Vascular nitric oxide (NO)-mediated vasodilation is reduced in the limb vasculature of patients with chronic heart failure. Depressed gene expression of vascular endothelial NO synthase has been reported in experimental models of heart failure. We sought to investigate endothelial NO synthase (eNOS) mRNA expression in the skeletal muscle vasculature of patients with chronic heart failure (CHF) and in controls. METHODS AND RESULTS: Transcript levels for eNOS were measured and normalized to von Willebrand factor gene expression level, in samples of skeletal muscle from patients with CHF (n = 20) and healthy subjects (n = 7). CHF was not associated with a decrease in eNOS expression. There was a trend towards an increased expression in NYHA class IV patients. Similar results were found when normalized to GAPDH mRNA levels. CONCLUSION: Vascular endothelial dysfunction that is observed in patients with severe heart failure does not appear to be related to a specific decrease in the expression of the gene encoding for endothelial NOS.

Current knowledge and recent development on management of peripartum cardiomyopathy.

Heart failure with left ventricular dysfunction occurring during pregnancy or during the post-partum period in patients without history of cardiovascular disease defines peripartum cardiomyopathy (PPCM). PPCM carries a high morbidity and mortality rate as well as the possibility of recovery ad integrum. Its incidence shows ethnic variations, with a greater prevalence of the disease among women with African descent. Pathogenesis of PPCM remains poorly understood. Both "oxidative stress-prolactin axis" and "anti-angiogenic-signaling excess" hypotheses are currently being investigated. Novel diagnostic strategies and biomarkers are currently being evaluated. Besides conventional treatment of heart failure, targeted therapies such as pharmacological prolactin blockade are under evaluation. The aim of this short review is to highlight current management as targeted therapy has far been disappointing.

Left ventricular remodeling after anterior wall acute myocardial infarction in modern clinical practice (from the REmodelage VEntriculaire [REVE] study group).

Left ventricular (LV) remodeling after acute myocardial infarction (AMI) has been well described in previous studies. However, there is a paucity of data on the incidence of and risk factors for LV remodeling in modern clinical practice that incorporates widespread use of acute reperfusion strategies and almost systematic use of "antiremodeling" medications, such as angiotensin-converting enzyme inhibitors and beta blockers. We enrolled 266 patients with anterior wall Q-wave AMI who had >or=3 segments of the infarct zone that were akinetic on echocardiography before discharge. Echocardiographic follow-up was performed 3 months and 1 year after AMI. LV volumes, ejection fraction, wall motion score index, and mitral flow velocities were determined in a blinded analysis at a core echocardiographic laboratory. Acute reperfusion was attempted in 220 patients (83%; primary angioplasty in 29% and thrombolysis in 54%). During hospitalization, 99% of patients underwent coronary angiography and 87% underwent coronary stenting of the infarct-related lesion. At 1 year, 95% of patients received an antiplatelet agent, 89% a beta blocker, 93% an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, and 93% a statin. Echocardiographic follow-up was obtained in 215 patients. There was recovery in LV systolic function as shown by a decrease in wall motion score index and an increase in ejection fraction. There was a significant increase in end-diastolic volume (EDV; 56.4 +/- 14.7 ml/m2 at baseline, 59.3 +/- 15.7 ml/m2 at 3 months, 62.8 +/- 18.7 ml/m2 at 1 year, p <0.0001). LV remodeling (>20% increase in EDV) was observed in 67 patients (31%). Peak creatine kinase level, systolic blood pressure, and wall motion score index were independently associated with changes in EDV. In conclusion, recent improvements in AMI management do not abolish LV remodeling, which remains a relatively frequent event after an initial anterior wall AMI.

Editor's Choice-Recent therapeutic trials on fluid removal and vasodilation in acute heart failure.

Recent therapeutic trials regarding the management of acute heart failure (AHF) failed to demonstrate the efficacy of newer therapeutic modalities and agents. Low- versus high-dose and continuous administration of furosemide were shown not to matter. Ultrafiltration was not found to be more efficacious than sophisticated diuretic therapy including dose-adjusted intravenous furosemide and metolazone. Dopamine and nesiritide were not shown to be superior to current therapy. Tezosentan and tovalptan had no effect on mortality. The development of rolofylline was terminated due to adverse effect (seizures). Lastly, preliminary experience with serelaxin indicates a mortality improvement at six months that remains to be confirmed. The disappointing findings of these recent trials may reflect the lack of efficacy of newer therapeutic modalities and agents. Alternatively the disappointing findings of these recent trials may be in part due to methodological issues. The AHF syndrome is complex with many clinical phenotypes. Failure to match clinical phenotypes and therapeutic modalities is likely to be partly responsible for the disappointing findings of recent AHF trials.

Acute mitral regurgitation in Takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TTC) is a well-recognised entity that commonly manifests with chest pain, ST segment abnormalities and transient left ventricular apical ballooning without coronary artery obstructive disease. This syndrome usually portends a favourable outcome. In the rare haemodynamically unstable TTC patients, acute mitral regurgitation (MR) related to systolic anterior motion (SAM) of the mitral valve and left ventricular outflow tract obstruction (LVOTO) is to be considered. Bedside echocardiography is key in recognition of this latter condition as vasodilators, inotropic agents or intra-aortic balloon counter-pulsation worsen the patient's clinical status. We discuss here a case of TTC where nitrate-induced subaortic obstruction and mitral regurgitation led to haemodynamic instability.

Reoperation after the Ross procedure: incidence, management, and survival.

BACKGROUND: The risk of reoperation on the autograft and homograft is the major long-term drawback of the Ross procedure. The incidence and clinical implications of reoperations after the Ross procedure are reported. METHODS: Between March 1992 and February 2010, 336 consecutive patients had a Ross procedure (mean follow-up, 6.2±4.9 years). Autograft implant technique was freestanding root replacement in 269 patients, subcoronary implantation in 52 patients and a modified root replacement with the autograft included in a Valsalva tube graft in 15. RESULTS: Subsequently, 38 patients (11.3%) underwent reoperations, for autograft dilatation in 23 and a significant autograft insufficiency in 9, at 9.6±3.7 years and 2.6±3.9 years, respectively. Aortic and pulmonary infective endocarditis occurred in 3 patients. Three patients underwent a non valve-related cardiac reoperation. Three patients received a transcatheter pulmonary valve implantation after 12.2±1.7 years. At 15 years, freedoms for autograft and homograft explantation (with 95% confidence interval) were 83.3% (77.4%- to 9.2%) and 92.8% (87.6% to 97.9%), respectively. Native aortic valve regurgitation, indexed aortic annulus diameter exceeding 1.35 cm/m2 and autograft diameter were risk factors for dilated autograft reoperation (hazard ratio, 3.23 [95% confidence interval, 1.19 to 8.81], p=0.02; 3.83 [0.9 to 16.33], p=0.07 and 1.2 per mm [1.01 to 1.41], p=0.03), respectively. CONCLUSIONS: Autograft dilatation was the leading cause of reoperation in patients who underwent root replacement. Long-term follow-up is mandatory to determine whether modifications of the operative technique could limit autograft dilatation.