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.

[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.

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.

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

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.

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.

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.

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.

Sex-Specific Interpretation of Coronary Flow Reserve and Fractional Flow Reserve Metrics, Including Their Companions.

BACKGROUND: Impairment of coronary flow is usually evaluated by considering the ratio of two measurements. Fractional flow reserve (FFR) estimates impact on an epicardial artery by taking mean post-stenotic pressure divided by mean aortic pressure, both obtained during adenosine induced hyperemia. Coronary flow reserve (CFR) compares hyperemic flow or velocity with the baseline situation, also as a ratio. As severity of underlying pathology may differ for men and women, we investigate the impact of these differences on relevant metrics. METHODS: As sex associated differences may cancel out in a ratio, this weakness of a ratio can be compensated by analyzing the intrinsic companion (C) and consider polar coordinates. Thus, besides the familiar ratio based metrics, we also analyze FFRC and CFRC. Outcomes of in silico studies are employed to extrapolate actual patient data and predict consequences. For FFR 129 patients (38 women) were invasively studied using pressure wires. CFR was measured noninvasively for the left anterior descending coronary artery by recording ultrasound based Doppler velocity in 114 individuals (28 women). RESULTS: The FFR can be identified as an indicator of the pressure gradient over the stenosis (R=-0.90), while FFRC differs for men compared to women (P=0.04) and correlates (R=0.93) with post-stenotic driving pressure. CFR shows a difference for men versus women (P=0.04) and is best associated with hyperemic flow (R=0.64), whereas CFRC relates to hyperemia recruited velocity (R=0.97). Simulation studies show that FFR may differ for both sexes when considering elderly. CONCLUSIONS: Analysis of ratios require inclusion of the companion, and sex-specific differences deserve attention.

Fractional Flow Reserve Evaluated as Metric of Coronary Stenosis - A Mathematical Model Study.

Introduction: Coronary arterial stenosis may impair myocardial perfusion with myocardial ischemia and associated morbidity and mortality as result. The myocardial fractional flow reserve (FFR) is clinically used as a stenosis-specific index. Aim: This study aims to identify the relation between the FFR and the degree of coronary arterial stenosis using a simple mathematical model of the coronary circulation. Methods: A mathematical model of the coronary circulation, including an arterial stenosis of variable degree, was developed. The relation between the FFR and the degree of stenosis (defined as the fractional cross sectional area narrowing) was investigated, including the influence of the aortic and venous pressures and the capillary resistance. An additional study concerning 22 patients with coronary artery disease permits comparison of clinical data and in silico findings. Results: The FFR shows an S-shaped relationship with the stenosis index. We found a marked influence of venous and aortic pressure and capillary resistance. The FFR is accompanied by a clinically relevant co-metric (FFR C ), defined by the Pythagorean sum of the two pressures in the definition formula for FFR. In the patient group the FFR C is strongly related to the post-stenotic pressure (R = 0.91). The FFR C requires establishment of a validated cut-off point using future trials. Conclusion: The S-shaped dependence of FFR on the severity of the stenosis makes the FFR a measure of the ordinal scale. The marked influences of the aortic and venous pressures and the capillary resistance on the FFR will be interpreted as significant variations in intra- and inter-individual clinical findings. These fluctuations are partly connected to the neglect of considering the FFR C . At otherwise identical conditions the FFR as measured at baseline differs from the value obtained during hyperemic conditions. This expected observation requires further investigation, as the current hyperemia based evaluation fails to take advantage of available baseline data.

The Pythagorean theorem reveals the inherent companion of cardiac ejection fraction.

BACKGROUND: Quantification of ventricular performance requires a comprehensive metric which is manageable for patient care and clinical trials. Ejection fraction (EF) has been embraced as an attractive candidate. However, being a dimensionless ratio, EF has serious limitations. METHODS: We aim to identify what information is not recognized when limiting the volume-related analysis by exclusively relying on EF. This investigation applies the volume domain concept, relating end-systolic volume (ESV) to end-diastolic volume (EDV). This approach allows graphical identification of the information not covered by EF. Implications for atria, left ventricle (LV) and right ventricle (RV) are investigated in healthy individuals, and cardiac patient groups using various imaging modalities. RESULTS: The Pythagorean theorem indicates that the hypotenuse which relates any {EDV, ESV} combination to EF corresponds with the information not covered by the single metric EF. The impact of the recovered EF companion (EFC) is illustrated in healthy adults (N = 410, LV 2D echocardiography), heart transplant patients (N = 101, LV CT), individuals with heart failure (N = 197, biplane angiocardiography), for the RV with corrected Fallot (N = 124, MRI), diameters for left atrium (N = 49, MRI) and area for right atrium (N = 51, MRI). For any limited EF range we find a spectrum of EFC values, showing that the two metrics contain (partly) independent information, and emphasizing that the sole use of EF only partially conveys the full information available. CONCLUSIONS: The EFC is a neglected companion, containing information which is additive to EF. Analysis based on ESV and EDV is preferred over the use of EF.

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.

Macrophage migration inhibitory factor (MIF) is associated with degree of collateralization in patients with totally occluded coronary arteries.

BACKGROUND: Collaterals in patients with coronary artery disease (CAD) limit myocardial infarction and improve survival. Macrophage migration inhibitory factor (MIF) might play a role in collateral development. We aimed this study to evaluate the association of Macrophage migration Inhibitory Factor (MIF) with the extent of collateralization in patients with coronary occlusion. METHODS AND RESULTS: We consecutively enrolled: a) 40 patients undergoing PCI of a chronic coronary total occlusion (CTO); b) 26 patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI (pPCI) of the infarct-related artery (IRA); c) 12 control patients undergoing angiography without significant coronary artery disease (CTRL). CTO patients were grouped in high (HCG) or low collateralization group (LCG). STEMI patients were grouped in COLL+ or COLL- group depending on the presence of collaterals to the IRA. Blood sampling was performed from the arterial sheath (SYSTEMIC), and distal to the occlusion (LOCAL). SYSTEMIC and LOCAL levels were significantly different between the 3 groups. A progressive increase in MIF ratio (defined as: % (LOCAL-SYSTEMIC)/SYSTEMIC) was observed (CTRL: -0.5[-23;28] vs. CTO: 4[-19;32] vs. STEMI: 55[37;87], p < 0.01). In CTO, MIF ratio was significantly higher in HCG vs. LCG (68 [45;120] vs. 46 [29;66], p = 0.02). In STEMI, MIF ratio was not different between COLL+ and COLL- patients; however, in COLL+, LOCAL was significantly higher as compared with SYSTEMIC (83 ng/ml [63;100] vs. 67 ng/ml [40;79], p = 0.04). CONCLUSIONS: Local MIF is significantly associated with the extent of collateralization in both acute and chronic total coronary occlusions.

Ejection fraction as related to basic components in the left and right ventricular volume domains.

BACKGROUND: Ejection fraction (EF) is commonly applied as a clinically relevant metric to assess ventricular function. The numerical value of EF depends on the interplay between end-systolic volume (ESV) and end-diastolic volume (EDV). Remarkably, the relative impact of the two constitutive components on EF received little attention. METHODS: Three patient groups not using beta-blockers were analyzed for a robust investigation into the relative contribution of ESV and EDV when assessing EF: cardiac patients (N=155) with left ventricular (LV) data obtained by biplane ventriculography, near-normals (N=276) by gated SPECT investigation, and an MRI-based post Fallot repair study including right ventricular (RV) data (N=124), besides LV. We compared various routes to evaluate EF via linear and several types of nonlinear regression with ESV as independent variable. Advanced statistics was applied to evaluate sex-specific differences. RESULTS: In all cases ESV emerges as the dominant component of EF, with less (P<0.0001) impact of EDV. The relationship for EF versus ESV is nonlinear (P<0.0001), and similar for both sexes. A linear approach may be inadequate and generate erroneous statistical outcomes when comparing subgroups of patients. CONCLUSIONS: Values for EF primarily depend on ESV, both for LV and RV. This relationship is essentially nonlinear, and similar for both sexes. A logarithmic approximation is convenient and often acceptable. However, application of linear regression for EF vs ESV may lead to incorrect conclusions, particularly when comparing males and females.

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.

Periprocedural Myocardial Injury and Long-Term Clinical Outcome in Patients Undergoing Percutaneous Coronary Interventions of Coronary Chronic Total Occlusion.

BACKGROUND: Periprocedural myocardial injury (PMI) after percutaneous coronary intervention (PCI) might occur more frequently during challenging procedures such as PCI of chronic coronary total occlusion (CTO). The prognostic implication of PMI in CTO-PCI remains unclear. METHODS: From January 2006 to September 2012, a total of 715 consecutive patients undergoing CTO-PCI were screened at three centers. Only patients with available pre-PCI and post-PCI troponin (cTn) were included (n = 442). PMI was defined as an elevation of cTn >5x the upper reference limit (URL), or a rise of cTn >20% if baseline values were elevated. RESULTS: Patients were grouped into: (1) successful CTO-PCI and no-PMI (Group A; n = 195); (2) successful CTO-PCI with PMI (Group B; n = 133); failed CTO-PCI (Group C; n = 114). Occurrence of major adverse cardiovascular event (MACE) was assessed in 431 patients (97%), at a median follow-up of 25 months, and were significantly lower in patients successfully treated without PMI occurrence, while increased in cases of PMI or failed CTO-PCI (Group A, 9%; Group B, 15%; Group C, 28%; hazard ratio, 1.57 (95% confidence interval, 1.12-2.18); P<.01). At Kaplan-Meier analysis, MACE-free survival was significantly higher in Group A (log-rank, 21.46; P<.001). CONCLUSION: Successful CTO revascularization is still associated with a better long-term clinical outcome vs patients in whom it failed, regardless of the occurrence of PMI.

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.

Hemodynamic determinants and ventriculo-arterial coupling are sex-associated in heart failure patients.

End-systolic volume (ESV) and end-diastolic volume (EDV) are key parameters in the analysis of left ventricular (LV) function, and the study of cardiac remodeling. The volume regulation graph (VRG) relates these fundamental determinants, and permits convenient stratification for clinically relevant covariates. This contribution analyzes sex-associated differences in hemodynamic parameters for 197 heart failure (HF) patients, evaluated by biplane ventriculography, in combination with arterial pressure. We calculated LV parameters such as stroke volume (SV), cardiac output (CO), ESV, EDV, ejection fraction (EF), end-systolic elastance (Emax), besides arterial parameters: effective arterial elastance (Ea), elastance ratio (the coupling index k), peripheral resistance (Rs), pulse pressure (PP), and arterial compliance (C), all normalized for body surface area when appropriate. Average values for heart rate, SV, CO, Ea, C, Rs are similar between the sexes, as are the VRG regression lines. However, ESV and EDV are significantly (P<;0.034 and P<;0.016, respectively) smaller in women (N=67), whereas EF, Emax, mean arterial pressure, PP, and k are higher (P<;0.008 or less). We conclude that the various sex-associated differences observed in these HF patients are striking, and thus require due attention when evaluating the clinical status of HF patients. Formulation of distinct cut-off values for male and female patients with HF seems warranted, when considering specific HF phenotypes.