[A critical analysis of ejection fraction]. / La serendipia en torno la fracción de eyección: una revisión de la historia, la casualidad y la cuasi-funcionalidad de una métrica aplaudida.

Ejection fraction (EF) is defined by the ratio of end-systolic volume (ESV) and end-diastolic volume (EDV). The resulting fraction is a dimensionless number whose interpretation is ambiguous and most likely misleading. Despite this limitation, EF is widely accepted as a clinical marker of cardiac function. In this article we analyze the role of ESV, a fundamental variable of ventricular mechanics, compared with the popular EF. Common physiology-based mathematics can explain a simple association between EF and ESV. This concept is illustrated by a detailed analysis of the information obtained from angiocardiography, echocardiography and cardiac magnetic resonance studies. EF versus ESV produces a non-linear curve. For a small ESV, the EF approaches 100%, while for a large ESV, the EF gradually decreases toward zero. This elemental relationship is commonly observed in innervated natural hearts. Thus, the popularity of EF mostly derives from a fortuitous connection with the pivotal variable ESV. Alongside this finding, we unfold historical events that facilitated the emergence of EF as a result of serendipity. Our physiology-based approach denounces the circumstantial theories invoked to justify the importance of EF as an index of cardiac function, which are critically discussed. EF appears to be nothing more than a blessing in disguise. For this reason, we propose the ESV as a more logical metric for the analysis of ventricular function.

Arterial Flow, Pulse Pressure and Pulse Wave Velocity in Men and Women at Various Ages.

The increase in pulse pressure (PP) that occurs with advancing age is predominantly due to reduced arterial distensibility leading to decreased aortic compliance, particularly in the elderly, in whom high blood pressure mainly manifests as isolated systolic hypertension. Since age-related changes in stroke volume are minimal compared with changes in PP, PP is often considered a surrogate measure of arterial stiffness. However, since PP is determined by both cardiac and arterial function, a more precise and reliable means of assessment of arterial stiffness is arterial pulse wave velocity (PWV), a parameter that is only dependent on arterial properties. Arterial stiffness as measured by PWV has been found to be a powerful pressure-related indicator for cardiovascular morbidity and mortality. We analyzed PP and PWV in men and women of various age groups in healthy volunteers as well as cardiac patients with different types of diseases. The findings identified several striking sex-specific differences which demand consideration in guidelines for diagnostic procedures, for epidemiological analysis, and in evaluation of therapeutic interventions.

Heart Function Analysis in Cardiac Patients with Focus on Sex-Specific Aspects.

Cardiac function is best described by investigating the pressure-volume relationships. This information permits description in terms of the ventricular volume regulation graph (VRG), estimation of systolic elastance, evaluation of lusitropic properties, and assessment of ventriculo-arterial coupling. Current techniques yield noninvasive determination of cardiac compartmental volumes, along with systolic/diastolic arterial pressure, while ventricular end-diastolic pressure can be inferred from an echocardiography-based surrogate measure. Ventricular volume is known to vary with age, as well as to be affected by intrinsic cardiac disease and abnormalities of the vascular system. Moreover, 35 years ago it has been shown in healthy adults that left ventricular volume is significantly smaller in women compared to men. This important observation has serious implications for several metrics which are routinely used in clinical practice, e.g., ejection fraction. The remarkable difference between ventricular size in men and women is also a powerful starting point for the study of aging and the investigation of interventions such as exercise. In this review we evaluate sex-specific characteristics of the VRG and the implications for various cardiac patient populations, during basal conditions and intervention such as exercise.

Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.

AIMS: Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. METHODS AND RESULTS: This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. CONCLUSION: The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

Significance of Intermediate Values of Fractional Flow Reserve in Patients With Coronary Artery Disease.

BACKGROUND: The fractional flow reserve (FFR) value of 0.75 has been validated against ischemic testing, whereas the FFR value of 0.80 has been widely accepted to guide clinical decision making. However, revascularization when FFR is 0.76 to 0.80, within the so-called gray zone, is still debatable. METHODS AND RESULTS: From February 1997 to June 2013, all patients with single-segment disease and an FFR value within the gray zone or within the 2 neighboring FFR strata (0.70-0.75 and 0.81-0.85) were included. Study end points consisted of major adverse cardiovascular events (death, myocardial infarction, and any revascularization) up to 5 years. Of 17 380 FFR measurements, 1459 patients were included. Of them, 449 patients were treated with revascularization and 1010 patients were treated with medical therapy. In the gray zone, the major adverse cardiovascular events rate was similar (37 [13.9%] versus 21 [11.2%], respectively; P=0.3) between medical therapy and revascularization, whereas a strong trend toward a higher rate of death or myocardial infarction (25 [9.4] versus 9 [4.8], P=0.06) and overall death (20 [7.5] versus 6 [3.2], P=0.059) was observed in the medical therapy group. Among medical therapy patients, a significant step-up increase in major adverse cardiovascular events rate was observed across the 3 FFR strata, especially with proximal lesion location. In revascularization patients, the major adverse cardiovascular events rate was not different across the 3 FFR strata. CONCLUSIONS: FFR in and around the gray zone bears a major prognostic value, especially in proximal lesions. These data confirm that FFR≤0.80 is valid to guide clinical decision making.

Evolving concepts of angiogram: fractional flow reserve discordances in 4000 coronary stenoses.

AIMS: The present analysis addresses the potential clinical and physiologic significance of discordance in severity of coronary artery disease between the angiogram and fractional flow reserve (FFR) in a large and unselected patient population. METHODS AND RESULTS: Between September 1999 and December 2011, FFR and percent diameter stenosis (DS) as assessed by quantitative coronary angiography were obtained in 2986 patients (n = 4086 coronary stenoses), in whom at least one stenosis was of intermediate angiographic severity. Fractional flow reserve correlated slightly but significantly with DS [-0.38 (95% CI: -0.41; -0.36); P < 0.001]. The sensitivity, specificity, and diagnostic accuracy of a ≥ 50% DS for predicting FFR ≤ 0.80 were 61% (95% CI: 59; 63), 67% (95% CI: 65; 69), and 0.64 (95% CI: 0.56; 0.72), respectively. In different anatomical settings, sensitivity and specificity showed marked variations between 35 to 74% and 58 to 76%, respectively, resulting in a discordance in 35% of all cases for these thresholds. For an angiographic threshold of 70% DS, the diagnostic performance by the Youden's index decreased from 0.28 to 0.11 for the overall population. CONCLUSION: The data confirm that one-third of a large patient population shows discordance between angiogram ≥ 50%DS and FFR ≤ 0.8 thresholds of stenosis severity. Left main stenoses are often underestimated by the classical 50% DS cut-off compared with FFR. This discordance offers physiologic insights for future trials. It is hypothesized that the discordance between angiography and FFR is related to technical limitations, such as imprecise luminal border detection by angiography, as well as to physiologic factors, such as variable minimal microvascular resistance.

ACEF and clinical SYNTAX score in the risk stratification of patients with heavily calcified coronary stenosis undergoing rotational atherectomy with stent implantation.

AIM: To assess ACEF (age, creatinine, and ejection fraction) and Clinical SYNTAX (CSS) score in the risk stratification of patients with heavily calcified stenosis undergoing rotational atherectomy with stent implantation (rota-stenting). METHODS AND RESULTS: ACEF and CSS were calculated in 221 consecutive patients with stable angina undergoing rota-stenting. Mean age of the patients was 74 ± 10 years, left ventricular ejection fraction was 61 ± 18%, and final burr size 1.78 ± 0.24 mm, with 2.6 ± 0.9 burrs used for each patient. Primary end-point was MACE at one-year defined as the composite of cardiac death, myocardial infarction, and target vessel revascularization. Post-hoc analysis was performed by stratifying the clinical outcome according to ACEF and CSS tertiles. At 1 year there was a significantly higher MACE rate in the high tertile of ACEF (24% for ACEFHigh vs. 13% for ACEFMid vs. 9% for ACEFLow; P = 0.017) and CSS (25% for CSSHigh vs. 12% for CSSMid vs. 8% for CSSLow; P = 0.008). The predictive accuracy for both ACEF and CSS was moderate (c-statistics, 0.629 and 0.638, respectively). CONCLUSION: Both ACEF and CSS predict with moderate accuracy MACE at 1-year in patients with heavily calcified coronary stenosis undergoing rotational atherectomy with stent implantation.

Long-term clinical outcome after fractional flow reserve- versus angio-guided percutaneous coronary intervention in patients with intermediate stenosis of coronary artery bypass grafts.

BACKGROUND: Fractional flow reserve (FFR)-guided percutaneous revascularization (percutaneous coronary intervention [PCI]) of intermediate stenosis in native coronary artery is safe and associated with better clinical outcomes as compared with an angiography-guided PCI. It is unknown whether this applies to coronary artery bypass grafts (CABGs). METHODS: We included 223 patients with CABG and with stable or unstable angina and an intermediate stenosis involving an arterial or a venous graft. Patients were divided into 2 groups: FFR guided (n = 65, PCI performed in case of FFR ≤0.80) and angio guided (n = 158, PCI performed based on angiographic evaluation). Primary end point was major adverse cardiac and cerebrovascular event, defined as death, myocardial infarction, target vessel failure, and cerebrovascular accident (CVA). RESULTS: The 2 groups were similar in terms of demographic and clinical characteristics. Percutaneous coronary intervention was performed in 23 patients (35%) of the FFR-guided group and 90 patients (57%) of the angio-guided group (P < .01). In the FFR-guided group, PCI was more often performed in arterial grafts as compared with the angio-guided group (16 [70%] vs 12 [13%], respectively; P < .01). Follow-up was obtained in 96% of patients at a median of 3.8 years (1.6-4.0 years). At multivariate analysis, major adverse cardiac and cerebrovascular event rate was significantly lower in the FFR-guided group as compared with the angio-guided group (18 [28%] vs 77 [51%], hazard ratio 0.33 [0.11-0.96], P = .043]. Procedure costs were overall reduced in the FFR-guided group (€2240 ± €652 vs €2416 ± €522, P = .03). CONCLUSIONS: An FFR-guided PCI of intermediate stenosis in bypass grafts is safe and results in better clinical outcomes as compared with an angio-guided PCI. This clinical benefit is achieved with a significant overall reduction in procedural costs.

Sex-specific Evaluation of Ventricular Ejection Fraction and End-Systolic Volume Applied to Cardiac Resynchronization Therapy.

Cardiac resynchronization therapy (CRT) can decrease the risk of heart failure (HF) events in relatively asymptomatic patients with a reduced ejection fraction (EF) and wide QRS complex. However, individual response to this type of therapy varies widely. Often based on either EF increase or end-systolic volume (ESV) decrease as criterion, a subgroup of super-responders has been described. Therefore, it is important to determine factors that can predict a favorable response and identify those patients who may benefit from CRT. With this goal in mind we explored the possible role of ESV.To improve insight in ventricular pump function we previously introduced the volume regulation graph (VRG), relating ESV to end-diastolic volume (EDV). An individual patient is uniquely defined by the prevailing working point in the volume domain. The traditional metric EF can be graphically derived for each working point. The nonlinear association between EF and ESV is given by EF = 1 + γ {ESV / (δ - ESV)}, with empirical constants γ and δ. The impact of CRT super-responders on EF can be evaluated, taking into account sex-specific ESV values. Based on available regression equations we modeled the impact on EF (as percent points) resulting from CRT-induced fractional ESV changes expressed as % of baseline ESV. Our analysis confirms clinical findings, indicating that CRT super-responders are likely to be women, and clarify why a specific reduction of ESV cannot be directly translated into EF improvement. We propose that the EF as CRT criterion should be abandoned and replaced by sex-specific ESV evaluations.Clinical Relevance- Response to CRT should be evaluated in a sex-specific manner. The smaller heart size in women has implications for the interpretation of percentwise reductions of ESV and their translation into an associated increase of EF.

Ventricular and Atrial Ejection Fractions are Associated with Mean Compartmental Cavity Volume in Cardiac Disease.

Ejection fraction (EF) is considered to provide clinically useful information. Despite its enormous popularity, with more than 75,000 citations in PubMed, only few studies have traced the origin(s) of its foundation. This fact is surprising, as there are perhaps more papers published that criticize EF, than the number of publications that actually provide a solid (mathematical) basis for its alleged applicability. EF depends on two volume determinations, namely end-systolic volume (ESV) and end-diastolic volume (EDV). EF is defined as 1-ESV/EDV, yielding a metric without physical units. Previously we formulated a robust analytical expression for the nonlinear connection between EF and ESV. Here we extend that approach by providing a formula to illustrate that EF is strongly associated with half the sum (HS) of ESV and EDV. HS is not new, but forms a major component in the recently introduced Global Function Index. For 420 heart failure (HF) patients we found for left ventricular angio data: R(ESV, eDv) = 0.92, R(EF, ESV) = -0.90, and R(EF, HS) = -0.65. For echo (33 HF patients stages A, B, C and D): R(EF, HS) = -0.82. For the right atrium (CMRI in 21 acute myocardial infarction patients): R(EF, HS)=-0.65. For the left atrium (N=86) R (EF, hS)=-0.46. ESV indicates the level to which the ventricle is able to squeeze blood out of the cavity via pressure build-up. In contrast, EF refers to relative volume changes, not to the mechanism of pumping action. We conclude that for each cardiac compartment EF borrows its acclaimed attractiveness from the fact that for a wide patient spectrum the ESVand EDV correlate in a fairly linear manner. Attractiveness of EF features a straightforward mathematical derivation, rather than reflecting underlying physiology. Clinical Relevance - Ejection fraction (EF) is found to reflect (mean) ventricular / atrial size, and is primarily associated with end-systolic volume, which variable in turn highly correlates with diastolic volume. As a mathematical construct, EF has little affinity with "function", which is a central concept in physiology.

The Ratio of Diastolic and Systolic Arterial Pressure is Associated with Pulse Pressure.

Pulse pressure (PP) is defined as the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP). The metric PP is not unique, as numerous combinations of SBP and DBP yield the same value for PP. Therefore, we introduced the PP companion (PPC) which is calculated using the Pythagorean theorem. Only the combination of PP and PPC offers unique characterization. Interestingly, PPCwas found to be associated with mean arterial pressure (MAP). Another mathematical construct frequently used in hemodynamic studies refers to the ratio of DBP and SBP, or DBP/SBP, denoted as Prat. As Prat and PP share the same companion (C), we investigated the association between PratC and MAP, as well as the connection between PP and Prat. Various patient cohorts were included: A) 52 heart failure patients (16 women), B) 88 patients (11 women) with acute cardiac syndromes, C) 257 patients (68 men) diagnosed with atherosclerosis or any of various types of autoimmune disease, and D) 106 hypertensives (51 men). Linear regression analysis resulted in the following correlations: A: R (PratC, MAP) = 0.94, R (PP, Prat) = -0.91 B: R (PratC, MAP) = 0.98, R (PP, Prat) = -0.85 C: R (PratC, MAP) = 0.97, R (PP, Prat) = -0.86 D: R (PratC, MAP) = 0.92, R (PP, Prat) = -0.82 We conclude that Prat carries no substantial incremental value beyond PP, while both Prat and PP are incomplete metrics, requiring simultaneous consideration of MAP. Clinical Relevance- Various ratio-based metrics have been introduced in hemodynamic studies without paying attention to missing components or even redundant candidates. Here we present a uniform method to provide comprehensive insight.

Case report on the importance of longitudinal analysis of left ventricular end-systolic volume, rather than ejection fraction, in a heart transplant patient.

BACKGROUND: Sequential determinations of left ventricular (LV) volume constitute a cornerstone in the mechanical performance evaluation of any heart transplant (HTX) patient. A comprehensive analysis of volumetric data offers unique insight into adaptation and pathophysiology. CASE SUMMARY: With a focus on eight sequential biplane angiocardiographic LV end-systolic volume (ESV) determinations, we evaluate the clinical course of a male patient following HTX (female donor) at the age of 61 years. This former smoker had a history of chronic obstructive pulmonary disease, hypertension, and hypercholesterolaemia refractory to treatment, and presented with multivessel coronary artery disease. The later course was complicated by pulmonary hypertension, an abdominal aortic aneurysm, and secondary chronic kidney disease. After an additional episode of pulmonary embolism, the patient died at the age of 79. At one point, the ESV was > 700% higher than the starting value, and actually by far exceeded the relative change of any other volume-based metric evaluated, including ejection fraction (EF). DISCUSSION: The longitudinal study of LV volumetric data in HTX patients offers a unique window to the pathophysiology of remodelling and sex-specific adaptation processes. The present case documents that proper analysis of serial findings form a rich source of clinically relevant information regarding disease progression. End-systolic volume is the primary indicator, in contrast to the popular metric EF. This finding is supported by population-based studies reported in the literature. We conclude that comprehensive analysis of volumetric data, particularly ESV, contributes to personalized medicine and enhances insight into LV (reverse) remodelling, while also informing about prognosis.

Long-term clinical outcome after fractional flow reserve-guided treatment in patients with angiographically equivocal left main coronary artery stenosis.

BACKGROUND: Significant left main coronary artery stenosis is an accepted indication for surgical revascularization. The potential of angiography to evaluate the hemodynamic severity of a stenosis is limited. The aims of the present study were to assess the long-term clinical outcome of patients with an angiographically equivocal left main coronary artery stenosis in whom the revascularization strategy was based on fractional flow reserve (FFR) and to determine the relationship between quantitative coronary angiography and FFR. METHODS AND RESULTS: In 213 patients with an angiographically equivocal left main coronary artery stenosis, FFR measurements and quantitative coronary angiography were performed. When FFR was > or =0.80, patients were treated medically or another stenosis was treated by coronary angioplasty (nonsurgical group; n=138). When FFR was <0.80, coronary artery bypass grafting was performed (surgical group; n=75). The 5-year survival estimates were 89.8% in the nonsurgical group and 85.4% in the surgical group (P=0.48). The 5-year event-free survival estimates were 74.2% and 82.8% in the nonsurgical and surgical groups, respectively (P=0.50). Percent diameter stenosis at quantitative coronary angiography correlated significantly with FFR (r=-0.38, P<0.001), but a very large scatter was observed. In 23% of patients with a diameter stenosis <50%, the left main coronary artery stenosis was hemodynamically significant by FFR. CONCLUSIONS: In patients with equivocal stenosis of the left main coronary artery, angiography alone does not allow appropriate individual decision making about the need for revascularization and often underestimates the functional significance of the stenosis. The favorable outcome of an FFR-guided strategy suggests that FFR should be assessed in such patients before a decision is made "blindly" about the need for revascularization.

Thrombus aspiration in primary percutaneous coronary intervention in high-risk patients with ST-elevation myocardial infarction: a real-world registry.

OBJECTIVES: To evaluate the effect of thrombus aspiration in a real-world all-comer patient population with STEMI undergoing primary PCI. BACKGROUND: Catheter thrombus aspiration in primary PCI was beneficial in randomized clinical trials. METHODS: We enrolled 313 STEMI patients presenting with TIMI Flow Grade 0 or 1 in the infarct related artery at baseline angiogram undergoing primary PCI. PATIENTS were divided in two groups based on whether thrombus aspiration was attempted. This decision was left at operator's discretion. Procedural and long-term clinical outcomes were compared between the two groups. RESULTS: Baseline characteristics were similar between groups: 194 (62%) received thrombus aspiration and 119 underwent conventional PCI. Thrombus aspiration was associated with significantly lower post-PCI TIMI Frame Count values (19 +/- 15 vs. 25 +/- 17; P = 0.002) and higher TIMI Flow Grade 3 (92% vs. 73%; P < 0.001). Postprocedural myocardial perfusion assessed by myocardial blush grade (MBG) was significantly increased in the thrombus aspiration group (MBG 3: 44% vs. 21%; P < 0.001). No significant difference was found between the two groups in clinical outcome at 30 days. At one year, patients treated with thrombus aspiration showed significantly higher overall survival (HR 0.41, 95% CI 0.20-0.81; log-rank P = 0.010) and MACE-free survival (HR 0.49, 95% CI 0.28-0.85; log-rank P = 0.011). CONCLUSIONS: In real-world all-comer STEMI patients with occluded infarct-related artery, thrombus aspiration prior to PCI improves coronary flow, myocardial perfusion, and long-term clinical outcome as compared with PCI in the absence of thrombus aspiration.

Ventricular-arterial uncoupling in heart failure with preserved ejection fraction after myocardial infarction in dogs - invasive versus echocardiographic evaluation.

BACKGROUND: Heart failure with preserved left ventricular ejection fraction and abnormal diastolic function is commonly observed after recovery from an acute myocardial infarction. The aim of this study was to investigate the physiopathology of heart failure with preserved ejection fraction in a model of healed myocardial infarction in dogs. METHODS: Echocardiography, levels of neurohormones and conductance catheter measurements of left ventricular pressure-volume relationships were obtained in 17 beagle dogs 2 months after a coronary artery ligation, and in 6 controls. RESULTS: Healed myocardial infarction was associated with preserved echocardiographic left ventricular ejection fraction (0.57 +/- 0.01, mean +/- SEM) and altered Doppler mitral indices of diastolic function. NT-proBNP was increased, aldosterone was decreased, and norepinephrine was unchanged. Invasive measurements showed a markedly decreased end-systolic elastance (2.1 +/- 0.2 vs 6.1 +/- 0.8, mmHg/ml, p < 0.001) and end-systolic elastance to effective arterial elastance ratio (0.6 +/- 0.1 vs 1.4 +/- 0.2, p < 0.001), with altered active relaxation (dP/dtmin -1992 +/- 71 vs -2821 +/- 305, mmHg/s, p < 0.01) but preserved left ventricular capacitance (70 +/- 6 vs 61 +/- 3, ml at 20 mmHg, p = NS) and stiffness constant. Among echocardiographic variables, the wall motion score index was the most reliable indicator of cardiac contractility while E', E/A and E'/A' were correlated to dP/dtmin. CONCLUSIONS: In the canine model of healed myocardial infarction induced by coronary ligation, heart failure is essentially characterized by an altered contractility with left ventricular-arterial uncoupling despite vascular compensation rather than by abnormal diastolic function.

Cardiopoietic stem cell therapy in ischaemic heart failure: long-term clinical outcomes.

AIMS: This study aims to explore long-term clinical outcomes of cardiopoiesis-guided stem cell therapy for ischaemic heart failure assessed in the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial. METHODS AND RESULTS: CHART-1 is a multinational, randomized, and double-blind trial conducted in 39 centres in heart failure patients (n = 315) on standard-of-care therapy. The 'active' group received cardiopoietic stem cells delivered intramyocardially using a retention-enhanced catheter. The 'control' group underwent patient-level sham procedure. Patients were followed up to 104 weeks. In the entire study population, results of the primary hierarchical composite outcome were maintained neutral at Week 52 [Mann-Whitney estimator 0.52, 95% confidence interval (CI) 0.45-0.59, P = 0.51]. Landmark analyses suggested late clinical benefit in patients with significant left ventricular enlargement receiving adequate dosing. Specifically, beyond 100 days of follow-up, patients with left ventricular end-diastolic volume of 200-370 mL treated with ≤19 injections of cardiopoietic stem cells showed reduced risk of death or cardiovascular hospitalization (hazard ratio 0.38, 95% CI 0.16-0.91, P = 0.031) and cardiovascular death or heart failure hospitalization (hazard ratio 0.28, 95% CI 0.09-0.94, P = 0.040). Cardiopoietic stem cell therapy was well tolerated long term with no difference in safety readouts compared with sham at 2 years. CONCLUSIONS: Longitudinal follow-up documents that cardiopoietic stem cell therapy is overall safe, and post hoc analyses suggest benefit in an ischaemic heart failure subpopulation defined by advanced left ventricular enlargement on tolerable stem cell dosing. The long-term clinical follow-up thus offers guidance for future targeted trials.

Apoptosis predominates in nonmyocytes in heart failure.

The goal of this investigation was to determine the distribution of myocardial apoptosis in myocytes and nonmyocytes in primates and patients with heart failure (HF). Almost all clinical cardiologists and cardiovascular investigators believe that myocyte apoptosis is considered to be a cardinal sign of HF and a major factor in its pathogenesis. However, with the knowledge that 75% of the number of cells in the heart are nonmyocytes, it is important to determine whether the apoptosis in HF is occurring in myocytes or in nonmyocytes. We studied both a nonhuman primate model of chronic HF, induced by rapid pacing 2-6 mo after myocardial infarction (MI), and biopsies from patients with ischemic cardiomyopathy. Dual labeling with a cardiac muscle marker was used to discriminate apoptosis in myocytes versus nonmyocytes. Left ventricular ejection fraction decreased following MI (from 78% to 60%) and further with HF (35%, P < 0.05). As expected, total apoptosis was increased in the myocardium following recovery from MI (0.62 cells/mm(2)) and increased further with the development of HF (1.91 cells/mm(2)). Surprisingly, the majority of apoptotic cells in MI and MI + HF, and in both the adjacent and remote areas, were nonmyocytes. This was also observed in myocardial biopsies from patients with ischemic cardiomyopathy. We found that macrophages contributed the largest fraction of apoptotic nonmyocytes (41% vs. 18% neutrophils, 16% fibroblast, and 25% endothelial and other cells). Although HF in the failing human and monkey heart is characterized by significant apoptosis, in contrast to current concepts, the apoptosis in nonmyocytes was eight- to ninefold greater than in myocytes.

Heart Failure Phenotypes Require Sex-Specific Criteria Which Are Based on Ventricular Dimensions.

Ejection fraction (EF) is often used as a criterion to establish diagnostic phenotypes of heart failure (HF). Because EF is a derived metric based on end-systolic volume (ESV) and end-diastolic volume (EDV), it is more logical to consider ESV or EDV as cut-off marker. We concentrate on the impact of ESV, which has the advantage of being linearly related to EDV and nonlinearly with EF, both with highly significant correlations. In particular we also analyze if HF classification should distinguish between females and males.ESV and EDV were determined by biplane angiography in 197 HF patients (67 women). As body surface indexed (i) ESVi values for adult healthy females are smaller than for males, we employ classes of ESVi (bins of 10 mL/m2) to group preserved and reduced EF's (cut-off at 50%) for HF. Reference values regarding mean and standard deviation for ESVi are based on a control group (N=155, 65 women) without HF. For interpretation of the findings we use the documented universal relationship connecting EF to ESV: EF = 1 + c1 {ESV / (c2 - ESV)}, where c1 and c2 are population-based sex-independent constants. In the reference group ESVi (mL/m2) in women (27.4 ± 27.6) is smaller (P=0.0026) than in their male counterparts (43.6 ± 37.5). Similarly, for HF the ESVi in women (45.7 ± 41.4) is smaller (P=0.0033) than in men (64.2 ± 41.4). This signifies (see formula above) that women have higher values for EF, primarily resulting from smaller ventricular size related to their sex, and not exclusively reflecting disease state. Current phenotype classification based on pooled data for males and females may be inappropriate for either sex.The significantly smaller ESVi observed in women has direct consequences for the traditional classification based on EF cutoff values for HF. Sex-specific criteria (regarding ESVi or EF) for HF phenotypes are warranted, and expectedly have substantial consequences for identification, classification, and management of HF patients.