Design and baseline characteristics of the Finerenone, in addition to standard of care, on the progression of kidney disease in patients with Non-Diabetic Chronic Kidney Disease (FIND-CKD) randomized trial.

BACKGROUND AND HYPOTHESIS: Finerenone, a non-steroidal mineralocorticoid receptor antagonist, improved kidney, and cardiovascular outcomes in patients with CKD and T2D in two Phase 3 outcome trials. The FIND-CKD study investigates the effect of finerenone in adults with CKD without diabetes. METHODS: FIND-CKD (NCT05047263 and EU CT 2023-506897-11-00) is a randomized, double-blind, placebo-controlled Phase 3 trial in patients with CKD of non-diabetic aetiology. Adults with a urinary albumin-creatinine ratio (UACR) of ≥ 200 to ≤3500 mg/g and eGFR ≥ 25 to <90 mL/min/1.73 m2 receiving a maximum tolerated dose of a renin-angiotensin-system (RAS) inhibitor were randomized 1:1 to once daily placebo or finerenone 10 or 20 mg depending on eGFR above or below 60 mL/min/1.73 m2. The primary efficacy outcome is total eGFR slope, defined as the mean annual rate of change in eGFR from baseline to Month 32. Secondary efficacy outcomes include a combined cardiorenal composite outcome comprising time to kidney failure, sustained ≥57% decrease in eGFR, hospitalization for heart failure, or cardiovascular death, as well as separate kidney and cardiovascular composite outcomes. Adverse events are recorded to assess tolerability and safety. RESULTS: Across 24 countries, 3231 patients were screened and 1584 were randomized to study treatment. The most common causes of CKD were chronic glomerulonephritis (57.0%) and hypertensive/ischaemic nephropathy (29.0%). Immunoglobulin A nephropathy was the most common glomerulonephritis (26.3% of the total population). At baseline, mean eGFR and median UACR were 46.7 mL/min/1.73 m2 and 818.9 mg/g, respectively. Diuretics were used by 282 participants (17.8%), statins by 851 (53.7%), and calcium channel blockers by 794 (50.1%). SGLT2 inhibitors were used in 16.9% of patients; these individuals had a similar mean eGFR (45.6 vs 46.8 mL/min/1.73 m2) and slightly higher median UACR (871.9 vs 808.3 mg/g) compared to those not using SGLT2 inhibitors at baseline. CONCLUSIONS: FIND-CKD is the first Phase 3 trial of finerenone in patients with CKD of non-diabetic aetiology.

Peak CK-MB has a strong association with chronic scar size and wall motion abnormalities after revascularized non-transmural myocardial infarction - a prospective CMR study.

BACKGROUND: Large myocardial infarction (MI) is associated with adverse left ventricular (LV) remodeling (LVR). We studied the nature of LVR, with specific attention to non-transmural MIs, and the association of peak CK-MB with recovery and chronic phase scar size and LVR. METHODS: Altogether 41 patients underwent prospectively repeated cardiovascular magnetic resonance at a median of 22 (interquartile range 9-29) days and 10 (8-16) months after the first revascularized MI. Transmural MI was defined as ≥75% enhancement in at least one myocardial segment. RESULTS: Peak CK-MB was 86 (40-216) µg/L in median, while recovery and chronic phase scar size were 13 (3-23) % and 8 (2-19) %. Altogether 33 patients (81%) had a non-transmural MI. Peak CK-MB had a strong correlation with recovery and chronic scar size (r ≥ 0.80 for all, r ≥ 0.74 for non-transmural MIs; p < 0.001). Peak CK-MB, recovery scar size, and chronic scar size, were all strongly correlated with chronic wall motion abnormality index (WMAi) (r ≥ 0.75 for all, r ≥ 0.73 for non-transmural MIs; p < 0.001). There was proportional scar size and LV mass resorption of 26% (0-50%) and 6% (- 2-14%) in median. Young age (< 60 years, median) was associated with greater LV mass resorption (median 9%vs.1%, p = 0.007). CONCLUSIONS: Peak CK-MB has a strong association with chronic scar size and wall motion abnormalities after revascularized non-transmural MI. Considerable infarct resorption happens after the first-month recovery phase. LV mass resorption is related to age, being more common in younger patients.

Assessment of myocardial infarct size with body surface potential mapping: validation against contrast-enhanced cardiac magnetic resonance imaging.

BACKGROUND: Assessment of myocardial infarct (MI) size is important for therapeutic and prognostic reasons. We used body surface potential mapping (BSPM) to evaluate whether single-lead electrocardiographic variables can assess MI size. METHODS: We performed BSPM with 120 leads covering the front and back chest (plus limb leads) on 57 patients at different phases of MI: acutely, during healing, and in the chronic phase. Final MI size was determined by contrast-enhanced cardiac magnetic resonance imaging (DE-CMR) and correlated with various computed depolarization- and repolarization-phase BSPM variables. We also calculated correlations between BSPM variables and enzymatic MI size (peak CK-MBm). RESULTS: BSPM variables reflecting the Q- and R wave showed strong correlations with MI size at all stages of MI. R width performed the best, showing its strongest correlation with MI size on the upper right back, there representing the width of the "reciprocal Q wave" (r = 0.64-0.71 for DE-CMR, r = 0.57-0.64 for CK-MBm, P < 0.0001). Repolarization-phase variables showed only weak correlations with MI size in the acute phase, but these correlations improved during MI healing. T-wave variables and the QRSSTT integral showed their best correlations with DE-CMR defined MI size on the precordial area, at best r = -0.57, P < 0.0001 in the chronic phase. The best performing BSPM variables could differentiate between large and small infarcts at all stages of MI. CONCLUSIONS: Computed, single-lead electrocardiographic variables can estimate the final infarct size at all stages of MI, and differentiate large infarcts from small.

Predicting recovery of myocardial function by electrocardiography after acute infarction.

BACKGROUND: In acute ischemic left ventricular (LV) dysfunction, distinguishing viable myocardium is clinically important. METHODS: Body surface potential mapping (Electrocardiography [ECG] with 123 leads), was recorded in 62 patients with acute coronary syndrome (ACS). ECG variables were computed from de- and repolarization phases. LV segmental wall motion was assessed by echocardiography acutely and after 1 year. RESULTS: The number of dysfunctional segments (DFS) diminished during follow-up in 37 patients (recovery group) and remained the same or increased in 25 patients (nonrecovery group). Acutely, DFS was 5.7 ± 2.1 versus 4.4 ± 2.4 (P = 0.02), and peak CK-MBm 141 ± 157 versus 156 ± 167 µg/L (P = 0.78) in the recovery versus nonrecovery group. At follow-up, DFS was 1.9 ± 1.7 versus 6.5 ± 2.6 (P < 0.001). The best ECG variable to predict decrease in DFS depended on the region of acute LV dysfunction: The best variable in the left anterior descending region was the integral of the first QRS integral (area under the curve [AUC] 0.82, P = 0.002); in the right coronary artery region, this was the integral of the ST segment (AUC 0.98, P = 0.003); and in the left circumflex region, the area including the ST segment and the T wave (AUC 0.97, P = 0.006). CONCLUSIONS: In ACS patients, computed ECG variables predict recovery of LV function from ischemic myocardial injury, even in the presence of comparable CK-MBm release and LV dysfunction.

Single-lead electrocardiographic variables in the detection of prior myocardial infarction with respect to Q-wave status and infarct age.

OBJECTIVES: Conventionally, the detection of prior myocardial infarction (MI) is based on QRS abnormalities, which may ignore non-Q-wave MI (NQMI). We aimed at finding automatically applicable quantitative ECG variables for diagnosing prior MI. METHODS: Body surface potential mapping (BSPM) was registered and automatically analyzed in 144 patients with prior MI and in 75 healthy controls. The MI was defined according to its age as recent or old, and Q-wave status as Q-wave MI (QMI) or NQMI. RESULTS: The QRSSTT integral, the STT integral and the T-wave apex amplitude applied in single, selected leads were found to be the optimal parameters in the detection of prior MI. The areas under the receiver-operating characteristic curves (AUC) were 89% for each, and detection was equal in old and recent MI (AUCs from 87 to 90%), and in QMI and NQMI (AUCs from 88 to 90%). CONCLUSIONS: The quantitative, automatically applicable single-lead variables comprising ventricular repolarization was effective in detecting prior MI, irrespective of the time elapsed from MI or the Q-wave status. These variables could be suitable for population studies and health screening purposes and are applicable to automatic ECG diagnostics of prior MI.

Tissue Doppler strain-mapping in the assessment of the extent of chronic myocardial infarction: validation using magnetic resonance imaging.

AIMS: The distribution of myocardial strain values can be visualized by colour-coded strain images. We examined for the first time if this strain-mapping function can be used to study the extent of prior myocardial infarction. METHODS AND RESULTS: Echocardiography and cardiac magnetic resonance imaging with delayed contrast enhancement were performed in 26 patients with chronic myocardial infarction. Two-dimensional strain images of the left ventricle were obtained in all standard apical views. Myocardial segments (n = 416) were assigned a score ranging from one to four based on the strain-coded colour of the segment, with higher scores representing worse myocardial function. Strain-mapping scores and quantitative strain values averaged, respectively, 1.3 +/- 0.6 and -16.4 +/- 7.6% in segments without infarction, 1.7 +/- 1.0 and -15.0 +/- 8.6% in non-transmural infarctions, and 2.8 +/- 1.2 and -6.5 +/- 8.6% in transmural infarctions. Strain-mapping had a sensitivity of 60% and a specificity of 95% in detecting segments with transmural myocardial infarction. Corresponding values for echocardiographic wall motion analysis were 50 and 96%. Strain-mapping was possible in 80% of the segments and inter-observer agreement was substantial (kappa = 0.63). CONCLUSION: Strain-mapping is a clinically applicable method for the assessment of regional myocardial function in post-myocardial infarction patients. Strain-mapping has reasonable feasibility and is more sensitive in detecting infarction damage than routine wall motion analysis.

Low MMP-8/TIMP-1 reflects left ventricle impairment in takotsubo cardiomyopathy and high TIMP-1 may help to differentiate it from acute coronary syndrome.

BACKGROUND: Matrix metalloproteinase 8 (MMP-8) is the most potent type-I collagen protease. Such collagen mainly constitutes the transient fibrosis in takotsubo cardiomyopathy (TTC) endomyocardial biopsies. High MMP-8 and tissue-inhibitor of matrix metalloproteinase-1 (TIMP-1) levels are implicated in acute coronary syndrome (ACS). We compared MMP-8 and TIMP-1 levels in consecutive TTC and ACS patients, and their association to TTC severity. METHODS AND RESULTS: In 45 acute serum samples of TTC, 2072 ACS and 1000 controls, TIMP-1 differed between ACS 146.7ng/mL (115.0-186.3) (median (interquartile range)), TTC 115.7 (94.3-137.7) and controls 80.9 (73.2-90.4), (p<0.0001). MMP-8 levels were similar between ACS and TTC. In receiver-operating characteristics analysis, TIMP-1 differentiated TTC from ACS with an area under the curve (AUC) of 0.679 (p<0.0001) surpassing troponin T (TnT) at 0.522 (p = 0.66). Compared to other differing factors (age, sex, smoking), TIMP-1 improved diagnostic specificity and sensitivity from AUC of 0.821 to 0.844 (p = 0.007). The MMP8/TIMP-1 molar ratio differentiated normal ejection fraction (EF) at 0.27 (0.13-0.51) from decreased EF<50% at 0.08 (0.05-0.20), (p = 0.04) in TTC, but not in ACS. CONCLUSIONS: Even with other differing factors considered, TIMP-1 differentiated TTC from ACS better than TnT. In TTC, the low MMP-8/TIMP-1 molar ratio may reflect decreased proteolysis and increased transient fibrosis, perhaps in part explaining the left-ventricle impairment.

Noninvasive analysis of coronary artery disease with combination of MDCT and functional MRI.

RATIONALE AND OBJECTIVES: We evaluated the diagnostic accuracy of an eight-row multidetector computed tomography coronary angiography (MDCT-CA) in detecting high-grade (>50%) stenoses in the three main coronary arteries in patients with coronary artery disease (CAD). Side branches were excluded. We correlated magnetic resonance imaging (MRI) findings of the myocardium with MDCT-CA of the coronary arteries. MATERIALS AND METHODS: Fourteen CAD patients underwent conventional coronary angiography (CCA), MDCT-CA, and MRI. We determined the calcium burden with non-enhanced MDCT scan. Then MDCT-CA was performed after intravenous contrast injection during a single breathhold. The left ventricular (LV) MR cine imaging was assessed at rest and perfusion defects were observed during pharmacologic stress after contrast administration. Delayed contrast-enhanced MRI was performed to picture infarctions. RESULTS: MDCT-CA had sensitivity 82%, specificity 94%, positive predictive value 79%, and negative predictive value 95% of stenoses of more than 50% in the main coronary arteries when compared with CCA. LV wall dysfunction, perfusion defects, and infarctions were detected in 50%-78% of sectors assigned to calcifications or stenoses, but also in sectors supplied by normally perfused coronary arteries. CONCLUSIONS: CCA and MDCT-CA revealed comparable results in evaluating stenotic lesions above 50% in the main subepicardial coronary branches. There were no significant correlations between the degree of stenosis or calcification at MDCT-CA and the MR findings, but the combined information of MDCT-CA and MRI showed the variability of myocardial changes in regions perfused by significantly stenosed, calcified, and normal main coronary arteries.

Practical implications of novel serum ELISA-assay for matrix metalloproteinase-8 in acute cardiac diagnostics.

Matrix metalloproteinases (MMPs) play a major role in inflammatory processes as they degrade extracellular proteins and modify immune responses. Inflammation is the driving factor in atherogenesis and MMPs, particularly MMP-8, has been linked to atherosclerotic plaque progression. MMP-8 is shown to be strongly associated with cardiovascular diseases (CVDs) and its complications thus providing a potential marker to identify patients at risk. Previously, laborious and expensive immunofluorometric assay (IFMA) was needed to reliably detect MMP-8 levels in serum. In this study, we compared a novel in-house ELISA-assay, dentoELISA, to the standard IFMA in determination of serum MMP-8 concentrations. As a cheaper and non-laborious assay, ELISA proved to be diagnostically as sensitive and specific as the IFMA. ROC statistics showed highly similar areas under the curve for both assays (0.779 versus 0.781). Furthermore, the concentrations measured by ELISA correlated significantly with concentrations determined with IFMA (r = 0.881, P < 0.001). In our study population, MMP-8 levels were significantly higher in the acute coronary syndrome patients (n = 2071) in comparison to reference population without significant coronary artery disease (n = 653). With this background, MMP-8-ELISA could provide interesting new approaches to novel CVD diagnostics.

Localization of prior myocardial infarction by repolarization variables.

BACKGROUND: To find quantitative, automatically applicable electrocardiographic (ECG) variables for detecting prior myocardial infarction (MI) in different myocardial regions. METHODS: Observational study. Body surface potential mapping (BSPM) was recorded at rest, and automatically analyzed with regard to ECG parameters, blinded to the clinical characteristics of the study subjects, 144 patients with prior MI and 75 healthy controls. MI location was determined by cine angiography or echocardiography as anterior (66 patients), inferoposterior (89 patients), and lateral (15 patients). Patients' 12-lead ECG was interpreted according to Minnesota code (Q-wave MI in 97 patients). The QRSSTT, QRS, and STT integrals, and the T-apex amplitude in detecting prior anterior and inferoposterior MI were analyzed. RESULTS: The T-apex amplitude, QRSSTT integral, and STT integral were functional in detecting MI in all tested locations on a single-lead basis, with areas under receiver operating characteristic curves (AUC) of over 90% (p<0.001) in optimal sites. In the best leads AUC for the QRSSTT integral in anterior MI was 93% (CI 87-99%) and for the inferoposterior MI 92% (CI 88-97%). These repolarization variables outperformed the Minnesota code in all tested MI locations. They were also able to distinguish between anterior and inferoposterior MI with an AUC of >85% (p<0.001). CONCLUSIONS: Quantitative, automatically applicable single-lead repolarization variables detect prior MI irrespective of its location. They may simplify the screening for and localization of old infarctions as compared to the conventional ECG methods.

Magnetocardiographic assessment of healed myocardial infarction.

BACKGROUND: We evaluated the capability of multichannel magnetocardiography (MCG) to detect healed myocardial infarction (MI). METHODS: Multichannel MCG over frontal chest was recorded at rest in 21 patients with healed MI, detected by cine- and contrast-enhanced magnetic resonance imaging, and in 26 healthy controls. Of the 21 MI patients, 11 had non-Q wave and 10 Q wave MIs. QRS, ST-segment, T wave and ST-T wave integrals, ST-segment and T wave amplitudes, and QRS and ST-T wave magnetic field map orientations were measured. RESULTS: The MCG repolarization indexes, such as ST segment and ST-T wave integrals, separated the MI group from the controls (ST-T wave integral -1.4 +/- 5.3 vs 1.5 +/- 4.7 pTs, P = 0.034). The abnormalities were more distinct in the Q wave-MI than in the non-Q wave MI subgroup. In the latter, however, a trend similar to the Q wave MI group was found. The relation of QRS area to ST segment and T wave integral improved the detection of healed MIs compared to the ST-T wave indexes alone (QRS-ST-T discordance 14 +/- 10 vs 5.0 +/- 7.1 pTs, P = 0.003). When comparing the MI group to the controls, the orientation of the magnetic field maps differed in the ST-T wave maps (163 +/- 119 degrees vs 58 +/- 17 degrees, P < 0.001) but not in the QRS maps (111 +/- 95 degrees vs 106 +/-93 degrees, P = 0.646). CONCLUSIONS: The MCG repolarization variables can detect healed MI. These ST-T wave abnormalities are more pronounced in patients with Q wave MI than in patients with non-Q wave MIs. Relating the signals of depolarization and repolarization phases improves the detection of healed MI. Repolarization abnormalities are common in healed MI and thus should not always be interpreted as present ongoing ischemia.

Spatial repolarization abnormalities in old myocardial infarction.

Conventional electrocardiogram criteria for myocardial infarction (MI) rely on QRS features, but ST-T segment is also affected. We recorded body surface potential mapping in 24 patients with prior MI and in 24 controls. T-wave maximum amplitude and QRS and ST-T integrals were automatically determined. Old MI was verified by magnetic resonance imaging. ST-T integral and T-wave maximum amplitude outperformed QRS integral in detecting MI, with area under receiver operating characteristic curve of 94%, 95%, and 83%, respectively. ST-T integral performed better in non-Q-wave than Q-wave MI, with area under receiver operating characteristic curve of 97% and 92%, respectively. QRS integral correlated negatively with ST-T integral in patients with MI (r = -0.58, P < .001) and positively in controls (r = 0.45, P < .001). In conclusion, ST-T integral proved equal to QRS integral in old MI detection. Inclusion of ventricular repolarization phase and development of electrocardiographic analysis over larger chest area may improve the QRS-based diagnosis of old myocardial infarction.

Serum IgG2 concentration is associated with Gm-allotypes of IgG2 but not with the R131H polymorphism of human Fc-gamma receptor type IIa.

Serum concentrations of immunoglobulins IgG, IgG1, and IgG2 were determined in 62 Finnish subjects who were also typed for Gm(n) allele of IgG2 and R131 and H131 alleles of the Fcy receptor IIa. Statistically significant G2m-allotype-associated differences in serum concentrations of IgG2 were found; the mean concentration of IgG2 was high in Gm(n)-positive homozygotes (3.9 g/liter) and low in Gm(n)-negative individuals (2.6 g/liter; P = 0.0036), which is in accordance with previous reports. Contrary to an earlier report, no statistically significant R131/ H131-allotype-associated differences were found in serum concentrations of IgG2, not even in the case where the IgG2 concentration was calculated relative to the IgGI or IgG concentration (IgG2/IgG1 or IgG2/IgG). The gene frequencies of R131 and H131 alleles were 0.516 and 0.484, respectively, which did not differ significantly from those reported earlier for Finnish or other Caucasian populations.

Temporal analysis of the depolarization wave of healed myocardial infarction in body surface potential mapping.

BACKGROUND: We studied the ability of different time segments of the depolarization wave recorded with body surface potential mapping (BSPM) to detect and localize myocardial infarction (MI). METHODS: BSPM was recorded in 24 patients with remote MI and in 24 healthy controls. Cine and contrast-enhanced magnetic resonance imaging (MRI) was used as a reference method. Patients were grouped according to anatomical location of their MI. The QRS complex was divided into six temporally equal segments, for which time integrals were calculated. RESULTS: The time segments of the QRS complex showed different MI detection capability depending on MI location. For anterior infarction the second segment of the QRS complex was the best in MI detection and the optimal area was on the right inferior quadrant of the thorax (time integral average -1.5 +/- 1.8 mVms patients, 1.0 +/- 1.6 mVms controls, P = 0.002). For lateral infarction the first segment of the QRS complex performed best and the optimal area for MI detection was the left fourth intercostal area (time integral average 1.8 +/- 1.0 mVms patients, 0.7 +/- 0.5 mVms controls, P = 0.024). For inferior and posterior MI the mid-phases of the QRS complex were the best and the optimal area was the mid-inferior area of the thorax (time integral average -6.2 +/- 8.3 mVms patients, 3.3 +/- 4.3 mVms controls, P = 0.002; -9.1 +/- 6.1 mVms patients, 0.6 +/- 7.1 mVms controls, P = 0.001, respectively). CONCLUSIONS: Time segment analysis of the depolarization wave offers potential for improving the detection and localization of healed MI.