TMAD enters the toolbox for evaluating selected heart transplant patients.

Adaptation of the heart is often a blessing for the patient, but sometimes a diagnostic challenge for the responsible physician. The clinical difficulty may be enhanced when employing diagnostic tools that are hard to interpret. Ratio-based metrics are notorious in this respect, and particularly risky in the follow-up evaluation of heart transplant patients. However, measures expressed as physical units contribute to a comprehensive clinical evaluation and guide proper patient management.

Statistics at high-altitudes: Relevance for the interpretation of metrics that reveal cardiac morphology and performance.

Survey of four ratio-based metrics, commonly used to evaluate left ventricular performance. The numerator of each ratio is plotted against the corresponding denominator, implying that the slope of the colored line reflects the value of the ratio.9,11 Similar graphs can be constructed for the other cardiac compartments. Data sets obtained at various altitudes and defined with reference to sea level, based on Rao et al.6 Acronyms: E/A unitless ratio of the early (E) and late (A) diastolic wave peak velocities (cm/s); EDD, end-diastolic diameter (mm); EDV, end-diastolic volume (mL); EF, ejection fraction (%); ESD, end-systolic diameter (mm); ESV, end-systolic volume (mL); FS, fractional shortening (%).

Pulse Pressure is Sex-Specifically Associated with the Ratio of Diastolic and Systolic Arterial Pressure in Healthy Children, and Differently During Night Versus Daytime Recordings.

Noninvasive blood pressure recordings typically focus on systolic blood pressure (SBP) and diastolic pressure (DBP). Derived metrics are often analyzed, e.g. pulse pressure (PP), defined as SBP minus DBP. As the metric PP is not unique, we introduced the PP companion (PPC), calculated using the Pythagorean theorem. PPC is associated with mean arterial pressure (MAP). Another mathematical construct frequently used in hemodynamic studies refers to the ratio of DBP and SBP, denoted as Prat. PP and Prat share the same companion (C). The association between PratC and MAP, as well as the connection between PP and Prat has not been studied in healthy children. We analyzed a large set of daytime (DT) and nighttime (NT) data (N=949, age 5 to 16 years, including 485 girls), published in the literature. Average PP increases with age (in 0.5 year increments), while Prat decreases. Prat vs PP yields R2>0.985 for both DT and NT data, when stratified for boys and girls. PPC is significantly lower (P<0.0001) during the night for both sexes. We conclude that Prat carries no substantial incremental value beyond PP, in contrast to PPC which points to DT/NT, age-dependent and sex-specific differences in these children.Clinical Relevance- Various derived metrics based on blood pressure have been introduced in hemodynamic studies, but not all of them are fully independent. The diastolic to systolic pressure ratio in healthy children is inversely associated with pulse pressure, showing partial sex-specific overlap, but substantial daytime versus night differences.

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 Ejection Fraction and Global Strains in Connection with the Volume Regulation Graph.

Ejection fraction (EF) is traditionally considered useful to infer ventricular function. Newer metrics such as global function index (GFI) and various strains add supplemental diagnostic or prognostic value. All these candidates refer to dimensionless ratios, rather than to the characteristics of the underlying components. Therefore, we introduced the volume regulation graph (VRG), relating end-systolic volume (ESV) to end-diastolic volume (EDV). An individual patient is then uniquely defined by the prevailing working point in the volume domain. Alternatively, the combination of EF=(1-ESV/EDV) and any suitable companion (denoted as C) metric (e.g. the Pythagorean mean) specifies this working point.An expression relates EF to global longitudinal (GLS) and circumferential strain (GCS): ESV/EDV = (GLS+1) (GCS+1)2, resembling the empirical regression equation for the VRG. However, the latter has a non-zero intercept (mL). The discrepancy can be solved by the introduction of one or more pertinent companion metrics.We studied 96 patients by cardiac magnetic resonance imaging and calculated EF, EFC, GFI, GLS and GCS. The GFI is inversely related to GLS (R2=0.26). For regression we found: ESV=0.74 EDV-27.0 with R2=0.81 for N=96. Similar results were obtained for echocardiography data (N=25). Graphs relating EF to GLS and GCS indicate that EFC can distinguish patients with nearly identical values for these 3 metrics.Thus, the VRG offers a unifying framework that visualizes the association between ESV and EDV, while documenting iso-EF and iso-EFC trajectories. Newer metrics including GFI, GLS and GCS require consideration of a companion variable such as EFC to permit a comprehensive analysis.Clinical Relevance- The VRG allows insight into ventricular functioning and illustrates the working point concept. Companion metrics (having a physical dimension) should be considered in conjunction with any traditional ratio-based index.

Sex differences in diagnostic modalities of atherosclerosis in the macrocirculation.

Asymptomatic atherosclerosis begins early in life and may progress in a sex-specific manner to become the major cause of cardiovascular morbidity and death. As diagnostic tools to evaluate atherosclerosis in the macrocirculation, we discuss imaging methods (in terms of computed tomography, positron emission tomography, intravascular ultrasound, magnetic resonance imaging, and optical coherence tomography), along with derived scores (Agatston, Gensini, Leaman, Syntax), and also hemodynamic indices of vascular stiffness (including flow-mediated dilation, shear stress, pulse pressure, augmentation index, arterial distensibility), assessment of plaque properties (composition, erosion, rupture), stenosis measures such as fractional flow reserve. Moreover, biomarkers including matrix metalloproteinases, vascular endothelial growth factors and miRNAs, as well as the impact of machine learning support, are described. Special attention is given to age-related aspects and sex-specific characteristics, along with clinical implications. Knowledge gaps are identified and directions for future research formulated.

Sex differences in diagnostic modalities of coronary artery disease: Evidence from coronary microcirculation.

Although atherosclerosis is usually considered a disease of the large arteries, risk factors for atherosclerosis also trigger structural and functional abnormalities at a microvascular level. In cardiac disease, microvascular dysfunction is especially relevant in women, among whom the manifestation of ischemic disease due to impaired coronary microcirculation is more common than in men. This sex-specific clinical phenotype has important clinical implications and, given the higher pre-test probability of coronary microvascular dysfunction in females, different diagnostic modalities should be used in women compared to men. In this review, we summarize invasive and non-invasive diagnostic modalities to assess coronary microvascular function, ranging from catheter-based evaluation of endothelial function to Doppler echocardiography and positron emission tomography. Moreover, we discuss different clinical settings in which microvascular disease plays an important role, underlining the importance of choosing the right diagnostic modality depending on the sex of the patients.

Coronary Flow Velocity Reserve by Echocardiography: Beyond Atherosclerotic Disease.

Coronary flow velocity reserve (CFVR) is defined as the ratio between coronary flow velocity during maximal hyperemia and coronary flow at rest. Gold-standard techniques to measure CFVR are either invasive or require radiation and are therefore inappropriate for large-scale adoption. More than 30 years ago, echocardiography was demonstrated to be a reliable tool to assess CFVR, and its field of application rapidly expanded. Although initially validated to assess the hemodynamic relevance of a coronary stenosis, CFVR by echocardiography was later used to investigate coronary microcirculation. Microvascular dysfunction was detected in many different conditions, ranging from organ transplantation to inflammatory disorders and from metabolic diseases to cardiomyopathies. Moreover, it has been proven that CFVR by echocardiography not only detects coronary microvascular involvement but is also an effective prognostic factor that allows a precise risk stratification of the patients. In this review, we will summarize the many applications of CFVR by echocardiography, focusing on the coronary involvement of systemic diseases.

Case report on right ventricular mural endocarditis, not diagnosed clinically, but histopathologically after cardiac surgery.

Background: Right ventricular mural endocarditis (RVME) is an extremely rare type of infective endocarditis that can occur even in the absence of predisposing factors. The diagnosis is a challenge when no causative pathogen can be detected. Case summary: A previously healthy young man was admitted to a local hospital with a diagnosis of prolonged febrile syndrome and treated for acute sinusitis. As complaints returned, he was hospitalized 3 weeks later, where an echocardiogram demonstrated multiple mobile masses in the right ventricle, and a computed tomography scan revealed extensive pulmonary thromboembolism. During surgery, the endocardial masses were excised, and the pathologist considered an inflammatory myofibroblastic tumour. Despite appropriate medication and initial improvements, the complaints persisted, and 2 weeks after the surgery, the patient returned to the hospital. Imaging studies documented reappearance to the previous findings, whereas blood cultures remained negative. During the second surgery, the new masses resembling vegetations were excised, and histologic analysis indicated infective endocarditis. Adjusted medication was given for 30 days. Just before discharge, no vegetations were seen. At follow-up, 5 years later, he was in a healthy condition. Discussion: Despite careful examinations, initial treatments according to standard protocols were unsuccessful. At final discharge, the patient reported that a tattoo complication prior to the first hospitalization was treated by antibiotics but that he did not complete the course. This omission in the communication further complicated the diagnostic and management processes, leading to surgical interventions that could have been prevented if the neglected antibiotic course was properly disclosed.

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.

Various Approaches to Define the Volume Intercept of the Ventricular End-Systolic Pressure-Volume Relationship: Implications for Statistical Analysis.

Ventricular pump function is often characterized by the (non)linear end-systolic pressure-volume relationship (ESPVR). For each working point on that curve the tangent along with the intercept (Vo) reflect contractile state. Vo on the abscissa is an extrapolated point without physiological meaning, and may be negative. To obtain positive values for the intercept, investigators often choose a non-zero pressure level. Although this preference is mathematically sound, we demonstrate that statistical evaluations may yield different results, depending on the pressure level selected. Published data on 17 cardiac patients representing three diagnostic groups were analyzed, showing dicrotic notch pressure based values -14