Screening of hypercortisolism among patients with hypertension: an Italian nationwide survey.

PURPOSE: Screening of Cushing Syndrome (CS) and Mild Autonomous Cortisol Secretion (MACS) in hypertensive patients is crucial for proper treatment. The aim of the study was to investigate screening and management of hypercortisolism among patients with hypertension in Italy. METHODS: A 10 item-questionnaire was delivered to referral centres of European and Italian Society of Hypertension (ESH and SIIA) in a nationwide survey. Data were analyzed according to type of centre (excellence vs non-excellence), geographical area, and medical specialty. RESULTS: Within 14 Italian regions, 82 centres (30% excellence, 78.790 patients during the last year, average 600 patients/year) participated to the survey. Internal medicine (44%) and cardiology (31%) were the most prevalent medical specialty. CS and MACS were diagnosed in 313 and 490 patients during the previous 5 years. The highest number of diagnoses was reported by internal medicine and excellence centres. Screening for hypercortisolism was reported by 77% in the presence of specific features of CS, 61% in resistant hypertension, and 38% in patients with adrenal mass. Among screening tests, the 24 h urinary free cortisol was the most used (66%), followed by morning cortisol and ACTH (54%), 1 mg-dexamethasone suppression test (49%), adrenal CT or MRI scans (12%), and late night salivary cortisol (11%). Awareness of referral centres with expertise in management of CS was reported by 67% of the participants, which reduced to 44% among non-excellence centres. CONCLUSIONS: Current screening of hypercortisolism among hypertensive patients is unsatisfactory. Strategies tailored to different medical specialties and type of centres should be conceived.

The diagnostic approach and management of hypertension in the emergency department.

Hypertension urgency and emergency represents a challenging condition in which clinicians should determine the assessment and/or treatment of these patients. Whether the elevation of blood pressure (BP) levels is temporary, in need of treatment, or reflects a chronic hypertensive state is not always easy to unravel. Unfortunately, current guidelines provide few recommendations concerning the diagnostic approach and treatment of emergency department patients presenting with severe hypertension. Target organ damage determines: the timeframe in which BP should be lowered, target BP levels as well as the drug of choice to use. It's important to distinguish hypertensive emergency from hypertensive urgency, usually a benign condition that requires more likely an outpatient visit and treatment.

Phenotyping congestion in patients with acutely decompensated heart failure with preserved and reduced ejection fraction: The Decongestion duRing therapY for acute decOmpensated heart failure in HFpEF vs HFrEF- DRY-OFF study.

AIMS: To evaluate pulmonary and intravascular congestion at admission and repeatedly during hospitalization for acute decompensated heart failure (ADHF) in HFrEF and HFpEF patients using lung (LUS) and inferior vena cava (IVC) ultrasound. METHODS AND RESULTS: Three-hundred-fourteen patients (82±9 years; HFpEF =172; HFrEF=142) admitted to Internal Medicine wards for ADHF were enrolled in a multi-center prospective study. At admission HFrEF presented higher indexes of pulmonary and intravascular congestion (LUS-score: 0.9 ±â€¯0.4 vs 0.7 ±â€¯0.4; p<0.01; IVC end-expiratory diameter: 21.6 ±â€¯5.1 mm vs 20±5.5 mm, p<0.01; IVC collapsibility index 24.4 ±â€¯17.4% vs 30.9 ±â€¯21.1% p<0.01) and higher Nt-proBNP values (8010 vs 3900 ng/l; p<0.001). At discharge, HFrEF still presented higher B-scores (0.4 ±â€¯4 vs 0.3 ±â€¯0.4; p = 0.023), while intravascular congestion improved to a greater extent, thus IVC measurements were similar in the two groups. No differences in diuretic doses, urine output, hemoconcentration, worsening renal function were found. At 90-days follow up HF readmission/death did not differ in HFpEF and HFrEF (28% vs 31%, p = 0,48). Residual congestion was associated with HF readmission/death considering the whole population; while intravascular congestion predicted readmission/death in the HFrEF, no association between sonographic indexes and the outcome was found in HFpEF. CONCLUSIONS: Serial assessment of pulmonary and intravascular congestion revealed a higher burden of fluid overload in HFrEF and, conversely, a greater reduction in intravascular venous congestion with diuretic treatment. Although other factors beyond EF could play a role in congestion/decongestion patterns, our data may be relevant for further phenotyping HF patients, considering the importance of decongestion optimization in the clinical approach.

Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience of the URRAH (Uric Acid Right for Heart Health) Project.

The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

Diagnosis and treatment of hypertensive emergencies and urgencies among Italian emergency and intensive care departments. Results from an Italian survey: Progetto GEAR (Gestione dell'Emergenza e urgenza in ARea critica).

Hypertensive emergencies (HE) and urgencies (HU) are frequent causes of patients referral to Emergency Department (ED) and the approach may be different according to local clinical practice. Our aim was to explore awareness, management, treatment and counselling after discharge of HE and HU in Italy, by mean of an on-line survey. The young investigator research group of the Italian Society of Hypertension developed a 23-item questionnaire spread by e-mail invitation to the members of Italian Scientific societies in the field of Hypertension. 665 questionnaires were collected from EDs, Emergency and Urgency Medicine, Cardiology or Coronary Units, Internal Medicines, Intensive care, Stroke units. Symptoms considered suspicious of acute organ damage were: chest pain (89.0%), visual disturbances (89.8%), dyspnoea (82.7%), headache (82.1%), dizziness (52.0%), conjunctival haemorrhages (41.5%), tinnitus (38.2%) and epistaxis (34.4%). Exams more frequent prescribed were: electrocardiogram (97.2%), serum creatinine (91.4%), markers of cardiomyocyte necrosis (66.2%), echocardiography (65.1%). The use of intravenous or oral medications to treat HEs was 94.7% and 3.5%, while for HUs 24.4% and 70.8% respectively. Of note, a surprisingly high percentage of physicians (22 % overall, 24.5% in North Italy) used to prescribe sublingual nifedipine. After discharge, home blood pressure monitoring and general practitioner re-evaluation were more frequently suggested, while ambulatory blood pressure monitoring and hypertension specialist examination were less prescribed. The differences observed across the different macro-areas, regarded prescription of diagnostic test and drug administration. This survey depicts a complex situation of shades and lights in the real-life management of HE and HU in Italy.

Ocular fundus photography with a smartphone device in acute hypertension.

BACKGROUND: The ocular fundus examination is infrequently and poorly performed in the emergency department (ED) clinical settings, placing patients at risk for missed diagnosis of hypertensive emergencies. The aim of this study was to investigate the feasibility of the ocular fundus photography with a smartphone small optical device in an ED setting and to compare it with a traditional ocular fundus examination. METHODS: The study included 52 consecutive patients (mean age 69 ±â€Š16 years, 50% women) presenting to a hospital ED with an acute increase in blood pressure (SBP > 180 and/or DBP > 100 mmHg). When admitted to the ED all patients had mydriatic ocular fundus examination obtained by a medical student (observer 1) using both a traditional ophthalmoscope and a commercially available ocular fundus smartphone device (D-Eye, Si14 S.p.A., Padova, Italy), to assess the presence of grade III and IV Keith Wegener retinopathy. All ocular fundus images and videos recorded with the D-Eye system were analyzed by two independent expert (ophthalmologist - observer 2) and inexpert (medical student - observer 1) observers. A quantitative score of hemorrages, exudates and/or papillary edema was used (0 absent, 1 early, 2 moderate, 3 severe and 4 very severe). The Cohen K coefficient was used to assess the interobserver concordance index. RESULTS: The mean duration of ocular fundus examination was 130 ±â€Š39 and 74 ±â€Š31 s for traditional ophthalmoscopy and for smartphone D-Eye, respectively. No relevant abnormalities of the ocular fundus were detected by traditional ophthalmoscopy, performed by observer 1, whereas a significant number of abnormal ocular fundus findings were detected by the use of the D-Eye device in 17 and 19 patients by observer 1 and observer 2, respectively. The K coefficient value ranged from 0.66 to 0.77 (good concordance) for the assessment of hemorrhages and exudates, and from 0.89 to 0.90 (optimal concordance) for the evaluation of presence and severity of papilledema. CONCLUSION: Our results show that a new small smartphone device (D-Eye) may be feasible in an ED setting for the fundoscopic examination, detecting a significant number of abnormal ocular fundus. The reliability of relevant ocular fundus abnormalities seems to be superior in respect to traditional retinal fundoscopy.

Serum uric acid and its relationship with metabolic syndrome and cardiovascular risk profile in patients with hypertension: insights from the I-DEMAND study.

BACKGROUND AND AIMS: The independent role of serum uric acid (SUA) as a marker of cardio-renal risk is debated. The aim of this study was to assess the relationship between SUA, metabolic syndrome (MS), and other cardiovascular (CV) risk factors in an Italian population of hypertensive patients with a high prevalence of diabetes. METHODS AND RESULTS: A total of 2429 patients (mean age 62 ± 11 years) among those enrolled in the I-DEMAND study were stratified on the basis of SUA gender specific quartiles. MS was defined according to the NCEP-ATP III criteria, chronic kidney disease (CKD) as an estimated GFR (CKD-Epi) <60 ml/min/1.73 m(2) or as the presence of microalbuminuria (albumin-to-creatinine ratio ≥2.5 mg/mmol in men and ≥3.5 mg/mmol in women). The prevalence of MS, CKD, and positive history for CV events was 72%, 43%, and 20%, respectively. SUA levels correlated with the presence of MS, its components, signs of renal damage and worse CV risk profile. Multivariate logistic regression analysis revealed that SUA was associated with a positive history of CV events and high Framingham risk score even after adjusting for MS and its components (OR 1.10, 95% CI 1.03-1.18; P = 0.0060; OR 1.28, 95% CI 1.15-1.42; P < 0.0001). These associations were stronger in patients without diabetes and with normal renal function. CONCLUSIONS: Mild hyperuricemia is a strong, independent marker of MS and high cardio-renal risk profile in hypertensive patients under specialist care. Intervention trials are needed to investigate whether the reduction of SUA levels favorably impacts outcome in patients at high CV risk.

Results from a pilot study on amiodarone administration in monogenic frontotemporal dementia with granulin mutation.

Frontotemporal dementia (FTD) is one of the most important neurodegenerative conditions and Granulin (GRN) is one of the major genes associated to the disease. FTD-GRN patients are still orphan for any evidence-based target-therapy approach. Interestingly, it has been recently found that alkalizing agents rescued haploinsufficiency in cellular models expressing FTD-GRN mutations. We set up a pilot phase II clinical trial in five FTD patients with GRN Thr272s(g.1977_1980delCACT) mutation, to determine if amiodarone (200 mg/day) may (1) reverse progranulin deficiency and (2) delay disease progression. Each patient was scheduled for 7 study visits over 12 months period. We assessed GRN levels at baseline and after amiodarone administration during the treatment course. Somatic and neurologic examinations, along with cognitive and behavioral assessment were recorded as well. No significant effect on peripheral GRN levels was observed. In treated FTD, disease course did not differ when compared with a group of untreated FTD-GRN patients. This is the first trial targeting progranulin rescue in FTD-GRN patients using amiodarone. Despite the negative findings, it may be interesting to extend this attempt to a larger sample of subjects and to other alkalizing agents to restore granulin haploinsufficiency.

Management of atrial fibrillation in the Emergency Department: current approach and future expectations.

Atrial fibrillation (AF) is the most common cardiac dysrhythmia and occurs in 3.3%-10% of emergency admissions. It is frequently quoted for people over the age of 75, but the cases of AF in young subjects without structural heart disease are also increasing, therefore, leading to the evaluation of "lonely atrial fibrillation" as a new challenge for the clinician. The first diagnosis and treatment often occur in the emergency room and the emergency physician has therefore to evaluate the initial step towards the therapeutic decisions. Although international standard guidelines are available, AF treatment in the Emergency Department (ED) is still heterogeneous in terms of the management strategy chosen. There are two main strategies for the management of AF: rate and rhythm control. Moreover, antithrombotic treatment is pivotal in AF to prevent cardioembolic stroke and it is considered a primary objective after an accurate assessment of antithrombotic treatment risks and benefits. The introduction of innovative echocardiographic approach, directly in ED, seems to improve the management and risk stratification of patients with AF. This review aims to provide an overview about the current approach and the future expectations in the management of AF in ED. This manuscript represents a synopsis of the lectures on AF management in the ED of the Third Italian GREAT Network Congress, that was hold in Rome, 15-19 October 2012. We decided to use only the most relevant references for each contribution as suggested by each participant at this review.

Prospective appraisal of the prevalence of primary aldosteronism in hypertensive patients presenting with atrial flutter or fibrillation (PAPPHY Study): rationale and study design.

Primary aldosteronism (PA) is the most common endocrine form of hypertension and may carry an increased risk of atrial flutter or fibrillation (AFF). The primary goal of this multicentre cohort study is thus to prospectively establish the prevalence of PA in consecutive hypertensive patients referred for lone (non-valvular), paroxysmal or permanent AFF. Secondary objectives are to determine: (1) the predictors of AFF in patients with PA; (2) the rate of AFF recurrence at follow-up after specific treatment in the patients with PA; (3) the effect of AFF that can increase atrial natriuretic peptide via the atrial stretch and thereby blunt aldosterone secretion, on the aldosterone-to-renin ratio (ARR), and thus the case detection of PA; (4) the diagnostic accuracy of ARR based on plasma renin activity or on the measurement of active renin (DRA) for diagnosing PA in AFF patients. Case detection and subtyping of PA will be performed according to established criteria, including the 'four corners criteria' for diagnosing aldosterone-producing adenoma. Pharmacologic or direct current cardioversion will be undertaken whenever indicated following current guidelines. The hormonal values and ARR will be compared within patient between AFF and sinus rhythm. Organ damage, cardiovascular events and recurrence of AFF will also be assessed during follow-up in patients with PA.

Pulse wave velocity and cardiovascular risk stratification in a general population: the Vobarno study.

BACKGROUND: Hypertension guidelines underline the importance of quantification of total cardiovascular risk; an extensive evaluation of target organ damage (TOD) may increase the number of patients classified at high-added cardiovascular risk. OBJECTIVE: To assess the effect of the evaluation of different forms of TOD, in addition to 'routine' workup, on cardiovascular risk stratification in a general population sample in Northern Italy. METHODS: In 385 patients (age 57 +/- 10 years, 44% men, 64% hypertensives, 32% treated), left ventricular and carotid artery structure and carotid-femoral pulse wave velocity (PWV) were measured. All patients underwent laboratory examinations. Patients were divided into risk categories according to European Society of Hypertension/European Society of Cardiology guidelines before and after TOD evaluation. RESULTS: After routine workup, patients were classified as follows: 6% at average cardiovascular risk, 35% at low cardiovascular risk, 25% at moderate cardiovascular risk, 33% at high cardiovascular risk and 1% at very high cardiovascular risk. The proportion of patients at low or moderate cardiovascular risk reclassified at high cardiovascular risk were 5, 14, 30 and 14% after echocardiography, measurement of albuminuria and estimated glomerular filtration rate, carotid ultrasound and PWV, respectively (chi P < 0.001 for all vs. routine). Assessment of PWV in addition to echocardiography led to an increase of the proportion of patients at high risk (from 5 to 15%, P < 0.001), as for PWV in addition to albuminuria, estimated glomerular filtration rate or both (from 14 to 31%, P < 0.01), but did not affect risk stratification in addition to carotid ultrasound (from 30 to 34%, P = NS). CONCLUSION: Our data suggest that measurement of PWV may significantly change cardiovascular risk stratification in addition to echocardiography and to detection of albuminuria and/or of a reduction of estimated glomerular filtration rate, but not after carotid ultrasound. Our results confirm that evaluation of different forms of TOD is useful for a more accurate assessment of global cardiovascular risk.

Echocardiography in clinical practice: the burden of arterial hypertension. A multicenter Italian survey.

Little information is available about the burden of hypertension on echo-lab activity in current practice. The aim of the present nation-wide survey in outpatient echo-labs was to investigate the prevalence rates of (1) echo examinations performed for the evaluation of hypertensive cardiac damage; (2) reports providing quantitative data on left ventricular (LV) structure and geometry; (3) LV hypertrophy (LVH) in hypertensives referred to echo labs. The study was carried out in 14 outpatient echo-labs across Italy. Prescriptions written by general practitioners were used to identify the indications for the examinations. Estimates of LVH were derived from original echo reports or were calculated from LV primary measures, when available, with Devereux's formula in a post-analysis. Echo examination was performed in 2449 subjects (1245 men and 1204 women); hypertension was the indication for echo in 745 (30.4%) cases. In this subgroup, LV mass (LVM), LVM indexed to body surface area, LVM indexed to height(2.7) and relative wall thickness ratio were reported in 58, 59, 54 and 52%, respectively. LVH was present in 53% of untreated hypertensives and, among treated patients, in 45 and 65% of those with and without blood pressure control, respectively. Our findings show that (1) hypertension accounts for approximately one-third of echo examinations performed in clinical practice; (2) a large fraction of echo reports do not provide quantitative data on LVM and LV geometry, (3) LVH is highly prevalent in hypertensives referred to echo labs for assessment of cardiac damage.

Effects of antihypertensive treatment on ultrasound measures of myocardial fibrosis in hypertensive patients with left ventricular hypertrophy: results of a randomized trial comparing the angiotensin receptor antagonist, candesartan and the angiotensin-converting enzyme inhibitor, enalapril.

OBJECTIVE: To compare the effects of the angiotensin II receptor antagonist candesartan with the angiotensin-converting enzyme inhibitor enalapril on myocardial fibrosis evaluated by echoreflectivity analysis. METHODS: Hypertensive patients (n = 196) with echocardigraphically documented left ventricular hypertrophy were randomized to candesartan 8-16 mg/day (n = 91) or enalapril 10-20 mg/day (n = 105) with possible addition of hydrochlorothiazide (12.5-25 mg/day) for 48 weeks. Echoreflectivity analysis was performed on ultrasound two-dimensional tracings of the midapex septum with a specifically designed and validated software. Colour histograms were obtained; the primary outcome variable was the treatment-related change in histogram width (broadband), previously shown to correlate with collagen volume on endomyocardial biopsy; changes in mean colour scale were secondary outcome variable. RESULTS: Echoreflectivity analysis was feasible in 84 patients (48 candesartan, 36 enalapril). Broadband decreased significantly in the candesartan (-8.0 colour levels) and in the enalapril group (-12.9 colour levels) with no significant difference between treatments (P = 0.409); no significant changes occurred in mean colour scale. Patients under monotherapy (n = 46) showed similar trends as the larger intention to treat cohort, without significant difference between treatments. CONCLUSION: In hypertensive patients with left ventricular hypertrophy, both candesartan and enalapril induce a moderate but statistically significant reduction in an echoreflectivity index of myocardial fibrosis.

Prognostic role of flow-mediated dilatation of the brachial artery in hypertensive patients.

BACKGROUND: The prognostic role of endothelial dysfunction, as evaluated by flow-mediated vasodilatation of the brachial artery, has been demonstrated in patients at very high risk. We aimed to investigate whether flow-mediated vasodilatation predicts cardiovascular events in uncomplicated hypertensive patients. METHODS AND RESULTS: A total of 172 prospectively identified uncomplicated hypertensive patients (age 56 +/- 8 years, 41% women, 48 with diabetes mellitus type 2) were studied. At baseline all patients were untreated and underwent baseline standard laboratory examination. A standard echocardiogram was performed for the evaluation of left ventricular anatomy and function and patients with systolic dysfunction or left ventricular wall motion abnormalities were excluded. Endothelial function was measured as flow-mediated vasodilatation of the brachial artery using high-resolution ultrasound. Patients were followed for 95 +/- 37 months (range 2-136 months). A first nonfatal or fatal cardiovascular event occurred in 32 patients. The incidence of cardiovascular events was 1.4 and 3.1 per 100 patient-years in patients with a flow-mediated vasodilatation below and above the median value (4.7%), respectively (P < 0.005 by the log-rank test). In Cox analysis, controlling for age, sex, glycemia, cholesterol, smoking, BMI, systolic and diastolic blood pressure at baseline and left ventricular mass index, a low flow-mediated vasodilatation conferred an increased risk of cardiovascular events (odds ratio 2.67, 95% confidence interval 1.17 to 6.1, P = 0.02). CONCLUSION: The presence of endothelial dysfunction, as evaluated by flow-mediated vasodilatation of the brachial artery, identifies hypertensive patients at increased risk of nonfatal and fatal cardiovascular events.

Macro and microvasculature in hypertension: therapeutic aspects.

Macrovasculature, microvasculature and the heart determine the structure and function of the circulatory system. Due to the viscoelastic properties of large arteries, the pulsatile pressure and flow that result from intermittent ventricular ejection is smoothed out, so that microvasculature mediates the delivery of nutrients and oxygen to tissues steadily. The disruption of this function, which occurs when microvascular structure develops in response to hypertension, leads to end-organ damage. Microvascular structure is not only the site of vascular resistance, but also the origin of most of the wave reflections generating increased central systolic blood pressure (SBP) in the elderly. Nowadays many data of the literature suggest that hypertension-related damage to the micro and macrovascular system may be manageable through pharmacological agents. Among them, beta-blocking agents and diuretics poorly modify microvascular structure, whereas angiotensin and calcium entry blockade has an opposite effect, thereby reducing central wave reflections and, finally, causing a selective SBP reduction.

Maternal cardiovascular function in pregnancies complicated by intrauterine growth restriction.

OBJECTIVE: To investigate maternal cardiovascular function in pregnancies complicated by intrauterine growth restriction (IUGR). METHODS: Maternal echocardiography and ambulatory blood pressure monitoring were performed in pregnancies complicated by IUGR (n = 12) and controls (n = 12), all of whom were normotensive at enrollment. RESULTS: Compared to controls, maternal blood pressure (P = 0.016) and total vascular resistance (P = 0.008) were higher in IUGR pregnancies. Heart rate was lower (P = 0.003), as was systolic function expressed by midwall fractional shortening (P = 0.04). No significant differences between the two groups were observed for left atrial or left ventricular dimensions, nor for left ventricular geometry. Assessment of diastolic function by means of transmitral Doppler flow measurements revealed a significantly longer isovolumetric relaxation time in pregnancies with IUGR (P = 0.006). CONCLUSIONS: In normotensive pregnancies complicated by IUGR, as compared to controls, there is decreased diastolic and systolic maternal cardiac function, and a higher blood pressure.

Inappropriate left ventricular mass: Reliability and limitations of echocardiographic measurement for risk stratification and follow-up in single patients.

BACKGROUND: The appropriateness of left ventricular (LV) mass to cardiac workload may be calculated by the ratio of observed LV mass to the value predicted for an individual's sex, height, and stroke work at rest. OBJECTIVE: To investigate test-retest reproducibility of observed/predicted LV mass in a single patient. DESIGN AND METHODS: We measured intraclass correlation and interval of agreement between two M-mode tracings, recorded both at the same session and 3-10 days apart in 200 participants (45 +/- 13 years, body mass index 25 +/- 4 kg/m; 99 hypertensive and 101 normotensive; 50% of each group were women) in 16 centres in Italy. Tracings were read by two observers in each centre. RESULTS: The values of observed/predicted LV mass value ranged from 40.78 to 215.50%. On the same day, the within-observer 90% interval of agreement between tracings 1 and 2 was -23 to +20%. For day-to-day test-retest within-observer variability (average three cycles), the 90% interval of agreement of the observed/predicted LV mass was -30 to +32%. The 90% interval of agreement of test-retest between-observer variability was -25 to +25%. The categorical consistency of retest in the identification of subjects with appropriate LV mass, classified in the first study (i.e. > 73% and < 128%), was 90% (k = 0.87). CONCLUSION: Measurement of the appropriateness of LV mass in single patients allows acceptable risk stratification, with a coefficient of consistency similar to that reported for LV mass. The probability of a true change (90% chance) in observed/predicted LV mass over time is maximized for a single-reader difference greater than 22%, although lesser differences might also have clinical relevance.