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To identify anatomical and morphological plaque features predictors of PCI and create a multiparametric score to increase the predictive yield. Moreover, we assessed the incremental predictive value of FFR CT (Fractional Flow Reserve derived from CCTA) trans -lesion gradient (ΔFFR CT) when integrated into the score. Observational cohort study including patients undergoing CCTA for suspected coronary artery disease, with FFR CT available, referred to invasive coronary angiogram and assessment of fractional flow reserve. Plaque analysis was performed using validated semi-automated software. Logistic regression was performed to identify anatomical and morphological plaque features predictive of PCI. Optimal thresholds were defined by area under the receiver-operating characteristics curve (AUC) analysis. A scoring system was developed in a derivation cohort (70 ​% of the study population) and tested in a validation cohort (30 ​% of patients). The overall study population included 340 patients (455 vessels), among which 238 patients (320 vessels) were included in the derivation cohort. At multivariate logistic regression analysis, absence of left main disease, diameter stenosis (DS), non-calcified plaque (NCP) volume, and percent atheroma volume (PAV) were independent predictors of PCI. Optimal thresholds were: DS ​≥ ​50 ​%, volume of NCP>113 ​mm3 and PAV>17 ​%. A weighted score (CT-PCI Score) ranging from 0 to 11 was obtained. The AUC of the score was 0.80 (95%CI 0.74–0.86). The integration of ΔFFR CT in the CT-PCI score led to a mild albeit not significant increase in the AUC (0.82, 95%CI 0.77–0.87, p ​= ​0.328). Plaque anatomy and morphology derived from CCTA could aid in identifying patients amenable to PCI. Derivation of the "CT-PCI score". At the top, each variable included in the score with the relative score assigned is described. At the bottom, the ROC curve of the score to predict PCI is reported. [Display omitted] Coronary CT Angiography (CCTA) has become an established tool in the diagnostic work-up of patients with a low-to-intermediate likelihood of coronary artery disease (CAD), allowing the evaluation of anatomical, morphological, and functional plaque features. CCTA could aid decision-making for treatment strategy. We derived a CCTA score (CT-PCI score) based on plaque anatomy and morphology able to predict PCI referral in a cohort of patients undergoing CCTA for suspected CAD, with FFR CT available, referred to invasive coronary angiography and physiological assessment. The AUC of the score was 0.80 (95%CI 0.74–0.86), sensitivity ​= ​68.0 ​%, specificity ​= ​84.0 ​%, accuracy ​= ​80.0 ​%. The integration of ΔFFR CT in the CT-PCI score led to a mild albeit not significant increase in the accuracy. [ABSTRACT FROM AUTHOR]

Coronary flow reserve (CFR) and microvascular resistance reserve (MRR) can, in principle, be derived by any method assessing coronary flow. The aim of this study was to compare CFR and MRR as derived by continuous (CFR cont and MRR cont) and bolus thermodilution (CFR bolus and MRR bolus). A total of 175 patients with chest pain and nonobstructive coronary artery disease were studied. Bolus and continuous thermodilution measurements were performed in the left anterior descending coronary artery. MRR was calculated as the ratio of CFR to fractional flow reserve and corrected for changes in systemic pressure. In 102 patients, bolus and continuous thermodilution measurements were performed in duplicate to assess test-retest reliability. Mean CFR bolus was higher than CFR cont (3.47 ± 1.42 and 2.67 ± 0.81 [ P < 0.001], mean difference 0.80, upper limit of agreement 3.92, lower limit of agreement −2.32). Mean MRR bolus was also higher than MRR cont (4.40 ± 1.99 and 3.22 ± 1.02 [ P < 0.001], mean difference 1.2, upper limit of agreement 5.08, lower limit of agreement −2.71). The correlation between CFR and MRR values obtained using both methods was significant but weak (CFR, r = 0.28 [95% CI: 0.14-0.41]; MRR, r = 0.26 [95% CI: 0.16-0.39]; P < 0.001 for both). The precision of both CFR and MRR was higher when assessed using continuous thermodilution compared with bolus thermodilution (repeatability coefficients of 0.89 and 2.79 for CFR cont and CFR bolus , respectively, and 1.01 and 3.05 for MRR cont and MRR bolus , respectively). Compared with bolus thermodilution, continuous thermodilution yields lower values of CFR and MRR accompanied by an almost 3-fold reduction of the variability in the measured results. [Display omitted] [ABSTRACT FROM AUTHOR]

To investigate the learning curve and the minimum number of cases required for a cardiologist in training to acquire the skills to an accurate pre-TAVI cardiac CT (CCT) analysis using a semi-automatic software. In this prospective, observational study, 40 CCTs of patients scheduled for TAVI were independently evaluated twice by 5 readers (80 readings each, 400 in total): a certified TAVI-CT specialist served as the reference reader (RR) and 4 cardiology fellows (2 interventional and 2 non-invasive cardiac imaging) as readers. The primary outcome was the minimum number of cases required to achieve an accuracy in imaging interpretation ≥80%, defined as the agreement between each reader and the RR in both balloon and self-expandable valve size choice. The secondary outcomes were the intra- and inter-observer variability. After 50 readings (25 cases repeated twice) cardiology fellows were able to select the appropriate valve size with ≥ 80% of accuracy compared to the RR, independently of valve calcification, image quality and slice thickness. Learning curves of both interventional and non-invasive cardiac imaging fellows showed a similar trend. Cardiology fellows achieved a very high intra- and inter-observer reliability for both perimeter and area assessment, with an intraclass correlation coefficient (ICC) ranging from 0.96 to 0.99. Despite the individual differences, cardiology fellows required 50 readings (25 cases repeated twice) to get adequately skilled in the pre-TAVI CCT interpretation. These results provide valuable information for developing adequate training sessions and education protocols for both companies and cardiologists involved. We prospectively investigated the learning curve for a cardiologist in training to acquire the skills to an accurate pre-TAVI cardiac-CT (CCT) analysis, using a semi-automatic software. Forty CCTs of patients scheduled for TAVI were evaluated twice by 5 readers (80 readings each, 400 in total): a certified TAVI-CT specialist served as reference reader (RR) and 4 cardiology fellows as readers. After 50 readings (25 cases repeated twice) cardiology fellows were able to select the appropriate valve size with ≥80% of accuracy compared to RR. These results provide valuable information for developing adequate training sessions for companies and cardiologists involved. [Display omitted] [ABSTRACT FROM AUTHOR]

Acute decompensated heart failure (ADHF) is a major cause of hospitalizations in older adults, leading to high mortality, morbidity, and healthcare costs. To address the persistent poor outcomes in ADHF, novel device-based approaches targeting specific pathophysiological mechanisms are urgently needed. The recently introduced DRI 2 P 2 S classification categorizes these innovative therapies based on their mechanisms. Devices include dilators (increasing venous capacitance), removers (directly removing sodium and water), inotropes (enhancing left ventricular contractility), interstitials (accelerating lymph removal), pushers (increasing renal arterial pressure), pullers (decreasing renal venous pressure), and selective drippers (selective intrarenal drug infusion). Some are tailored for chronic HF, while others focus on the acute setting. Most devices are in early development, necessitating further research to understand mechanisms, assess clinical effectiveness, and ensure safety before routine use in ADHF management. Exploring these innovative device-based strategies may lead to improved outcomes and revolutionize HF treatment in the future. [ABSTRACT FROM AUTHOR]

Diuretic resistance in acute heart failure is a common clinical problem, and it is associated with adverse outcomes. Effective therapies are still lacking. The Doraya catheter, a temporary intravenous flow regulator placed in the inferior vena cava below the level of the renal veins, is a novel device designed to target renal and cardiac congestion, thereby improving diuretic response. A first-in-man clinical study is currently ongoing. [ABSTRACT FROM AUTHOR]

Objectives This study sought to assess the impact of a wide range of mean right atrial pressure (P ra ) on fractional flow reserve (FFR) measurements. Background FFR invasively assesses the ischemic potential of coronary stenoses. FFR is calculated as the ratio of mean distal coronary pressure (P d ) to mean aortic pressure (P a ) during maximal hyperemia. The P ra is considered to have little impact if it is within normal range, so it is neglected in the formula. Methods In 1,676 stenoses of 1,235 patients undergoing left-right heart catheterization for ischemic (642 [52%]) or valvular heart disease (593 [48%]), the authors compared the FFR values calculated without accounting for P ra (FFR= P d /P a ) to the corresponding myocardial fractional flow reserve (FFR myo ) values accounting for P ra (FFR myo = P d − P ra /P a − P ra ). Results The median P ra was 7 (interquartile range [IQR]: 5 to 10) mm Hg with a maximum of 27 mm Hg. The correlation and agreement between FFR and FFR myo was excellent (R 2 = 0.987; slope 1.096 ± 0.003). The median FFR (0.85; IQR: 0.78 to 0.91) was slightly but statistically significantly higher than the median FFR myo (0.83; IQR: 0.76 to 0.90; p < 0.001) with a median difference of 0.01 (IQR: 0.01 to 0.02). Values of FFR above the cutoff of 0.80 provided an FFR myo ≤0.80 in 110 (9%) stenoses. No FFR value above 0.80 provided an FFR myo ≤0.75. Conclusions The difference between FFR and FFR myo was minimal even in patients with markedly increased P ra . FFR values above the gray zone (i.e., >0.80) did not yield values below the gray zone (i.e., ≤0.75) in any case, which suggests that the impact of right atrial pressure on FFR measurement is indeed negligible. [ABSTRACT FROM AUTHOR]

Background The presence of ergoreflex activity and its current relationship to hyperventilation and prognosis in cardiac patients is unclear. Therefore, we evaluated ergoreflex activity in cardiac patients with and without heart failure (CHF) as well as in healthy subjects, and we examined how ergoreceptor activity was related to a mortality risk score in CHF (MAGGIC). Methods and Results Twenty-five healthy subjects and 76 patients were included, among whom were 25 with ischemic heart disease (IHD), 24 with stable CHF, and 27 with unstable CHF. Ergoreflex activity was measured with a dynamic handgrip exercise, followed by post-handgrip regional circulatory occlusion (PH-RCO). Ergoreflex activity contributed significantly to ventilation (median [interquartile range] %V) in unstable CHF (81 [73-91] %V without PH-RCO, 92 [82–107] %V with PH-RCO, and 11 [6–20] difference in %V; P < .001) and was positively correlated with the MAGGIC risk score (Spearman ρ = 0.431; P = .002). No ergoreflex activity was observed in healthy subjects (−4 [−10 to 5] difference in %V), IHD (0 [−8 to 3] Diff in %V) and stable CHF (−3 [−11 to 6] difference in %V). Conclusions Ergoreflex activity contributes to hyperventilation, but only in CHF patients with persistent symptoms, and is closely related to the MAGGIC risk score. Ergoreflex activity was not present in patients with IHD or stable CHF, suggesting other reasons for the increased ventilatory drive in those patients. [ABSTRACT FROM AUTHOR]

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

Objectives: This study sought to evaluate the long-term clinical outcome of patients with an angiographically intermediate left anterior descending coronary artery (LAD) stenosis in whom the revascularization strategy was based on fractional flow reserve (FFR). Background: When revascularization is based mainly on angiographic guidance, a number of hemodynamically nonsignificant stenoses will be revascularized. Methods: In 730 patients with a 30% to 70% isolated stenosis in the proximal LAD and no significant valvular disease, FFR measurements were obtained to guide treatment strategy. When FFR was ≥0.80, the patients (n = 564) were treated medically (medical group); when FFR was <0.80, the patients (n = 166) underwent a revascularization procedure (revascularization group; 13% coronary artery bypass graft surgery and 87% percutaneous coronary intervention). A 100% long-term clinical follow-up (median follow-up: 40 months) was obtained. The 5-year survival of the medical group was compared with that of a reference population. For each patient, 4 controls were selected from an age- and sex-matched control population. Results: The 5-year survival estimate was 92.9% in the medical group versus 89.6% in the controls (p = 0.74). The mean diameter stenosis was significantly smaller in the medical than in the revascularization group (39 ± 14% vs. 54 ± 13%, p < 0.0001), but there was a large overlap between both groups. The 5-year event-free survival estimates (death, myocardial infarction, and target vessel revascularization) were 89.7% and 68.5%, respectively (p < 0.0001). Conclusions: Medical treatment of patients with a hemodynamically nonsignificant stenosis (FFR ≥0.80) in the proximal LAD is associated with an excellent long-term clinical outcome with survival at 5 years similar to an age- and sex-matched control population. [Copyright &y& Elsevier]

Background: DES is superior to BMS in reducing restenosis and repeat revascularization. Available data are less convincing in small vessel disease. Aim of our study is to assess long-term clinical outcome of drug-eluting stents (DES) vs. bare-metal stents (BMS) in small coronary vessel disease. Methods: Procedural and long-term clinical outcomes were assessed in consecutive patients (pts) treated with stenting of native small coronary arteries (reference vessel diameter and implanted stent < 3mm). Results: Pts enrolled were 645: DES group (n = 277) presented more frequently diabetes (173 [62%] vs. 32 [9%], P < .0001), higher body mass index (27 ± 5 vs. 26 ± 4, P = .01) and with previous PCI (115 [42%] vs. 118 [32%], P = .01) as compared to BMS group (n=368). DES group presented more frequently with unstable angina (46 [17%] vs. 38 [10%], P = .02); BMS group presented more frequently with myocardial infarction (103 [28] vs. 43 [15], P = .0002). Reference vessel (2.27 ± 0.36 vs. 2.24 ± 0.36, P = .29), minimal lumen (0.81 ± 0.32 vs. 0.80 ± 0.31, P = .84) and stent diameter (2.59 ± 0.17 vs. 2.60 ± 0.15, P = .69) did not differ between the 2 groups. Lesion length was significantly higher in DES group (15.85 ± 6.81 vs. 13.66 ± 7.18, P = .01). At a median clinical follow-up of 3.0 years (IQR range 2.2-4.6), pts with DES showed significantly lower major adverse cardiac events (MACE, HR 0.51, 95%CI 0.33-0.78) and target vessel revascularization (TVR, HR 0.44, 95%CI 0.25-0.78). No differences were observed between the two groups as to death, myocardial infarction and stent thrombosis. Conclusions: In small vessel disease, DES was more frequently implanted in pts at higher risk of restenosis, though it demonstrated to be more effective than BMS in reducing MACE and TVR at long-term follow-up. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to define the additional effective radiation dose, procedural time, and contrast medium needed to obtain fractional flow reserve (FFR) measurements after a diagnostic coronary angiogram. Background: The FFR measurements performed at the end of a diagnostic angiogram allow the obtaining of functional information that complements the anatomic findings. Methods: In 200 patients (mean age 66 ± 10 years) undergoing diagnostic coronary angiography, FFR was measured in at least 1 intermediate coronary artery stenosis. Hyperemia was achieved by intracoronary (n = 180) or intravenous (n = 20) adenosine. The radiation dose (mSv), procedural time (min), and contrast medium (ml) needed for diagnostic angiography and FFR were recorded. Results: A total of 296 stenoses (1.5 ± 0.7 stenoses per patient) were assessed. The additional mean radiation dose, procedural time, and contrast medium needed to obtain FFR expressed as a percentage of the entire procedure were 30 ± 16% (median 4 mSv, range 2.4 to 6.7 mSv), 26 ± 13% (median 9 min, range 7 to 13 min), and 31 ± 16% (median 50 ml, range 30 to 90 ml), respectively. The radiation dose and contrast medium during FFR were similar after intravenous and intracoronary adenosine, though the procedural time was slightly longer with intravenous adenosine (median 11 min, range 10 to 17 min, p = 0.04) than with intracoronary adenosine (median 9 min, range 7 to 13 min). When FFR was measured in 3 or more lesions, radiation dose, procedural time, and contrast medium increased. Conclusions: The additional radiation dose, procedural time, and contrast medium to obtain FFR measurement are low as compared to other cardiovascular imaging modalities. Therefore, the combination of diagnostic angiography and FFR measurements is warranted to provide simultaneously anatomic and functional information in patients with coronary artery disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: Congestive heart failure (CHF) is associated with a blunted force-frequency relation (FFR) and myocardial contractile reserve (MCR) partially from a downregulation of β1-adrenoreceptors (β1-AR). We investigated whether acute and chronic cardiac resynchronization therapy (CRT) was capable of reversing the blunted FFR and MCR and if this was associated with upregulation of β1-AR. Methods and Results: Left ventricle dP/dtmax was invasively measured in 10 CHF patients (New York Heart Association class ≥3; ejection fraction <25%) during incremental dual chamber (DDD)-CRT pacing at 70, 90, 110, and 130 beats/min, with and without continuous infusion of intravenous dobutamine, immediately after CRT implantation (BL) and 4 months later (FU). In a subgroup of 5 patients, serial left ventricle β1 and β2-AR gene expression was measured using reverse transcriptase-polymerase chain reaction. Four months after the initiation of resynchronization therapy, DDD-CRT pacing results in a significant upward shift of the heart rate versus LV dP/dtmax relationship (P < .01) with force frequency amplification as evidenced by the steeper slope of the force frequency response (P = .04). Infusion of dobutamine recruits myocardial contractile reserve and increases the heart rate versus LV dP/dtmax relationship at BL and at FU (both P < .05). However, only at follow-up was an additional force frequency amplification noticed (P < .05) during dobutamine infusion. This observation was paralleled by a significant upregulation of β1-AR gene expression (P = .02). Conclusions: Chronic CRT is associated with a partial restoration of the FFR and with a recruitment in myocardial contractile reserve, which is paralleled by upregulation of β1-AR. [Copyright &y& Elsevier]

Abstract: Background: Pulsed-wave tissue Doppler imaging (TDI) was shown to predict short-term left ventricular functional recovery after cardiac resynchronization therapy (CRT). However, few data are available regarding the baseline cardiac asynchrony and clinical outcome after CRT. Therefore, we aimed to investigate the prognostic value of pre-CRT cardiac asynchrony on clinical outcome after CRT. Methods: The study population consisted of 48 consecutive patients with moderate to severe heart failure and a wide QRS complex undergoing implantation of biventricular pacemaker. Cardiac asynchrony was assessed at pulsed-wave TDI from measurements of regional electromechanical coupling times in basal segments of both ventricles (Sum asynchrony). Clinical end-points were cardiac mortality and hospitalization for worsening heart failure. Results: During a follow-up period of 970±319 days, clinical end-point (9 deaths, 15 hospitalizations) occurred in 24 patients (clinical nonresponders). At baseline, responders showed higher asynchrony than nonresponders (153±57 ms vs. 103±58 ms, p <0.01). Sum asynchrony of >98 ms showed the highest accuracy (AUC=0.80, sensitivity 92%, specificity 67%) to identify responders. In contrast, baseline NYHA class, conventional echo-Doppler indices and QRS complex duration were similar in both groups. Eight end-point events (3 deaths) occurred in 30 patients with significant Sum asynchrony (>98 ms) as compared to 16 events (6 deaths) in 18 patients with smaller Sum asynchrony (27% vs. 89%; HR 0.14; 95% CI 0.04 to 0.46; p <0.001). Favorable clinical outcome was associated with larger left ventricular functional recovery at 2 years follow-up (p <0.001). Conclusions: TDI-derived index of baseline intra- and interventricular asynchrony appears to predict long-term clinical outcome after CRT. [Copyright &y& Elsevier]

Objectives: We studied whether functional improvement after cardiac resynchronization therapy (CRT) is associated with reversal of the heart failure (HF) gene program. Background: Cardiac resynchronization therapy improves exercise tolerance and survival in patients with advanced congestive HF and dyssynchrony. Methods: Twenty-four patients referred for CRT underwent left ventricular (LV) endomyocardial biopsies immediately before CRT implantation (baseline). In addition, 17 of them underwent LV endomyocardial biopsy procurement 4 months later (follow-up). In 6 control patients with normal LV function, LV biopsies were obtained at the time of coronary artery bypass grafting. The LV messenger ribonucleic acid (mRNA) levels of contractile and calcium regulatory genes were measured by quantitative real time polymerase chain reaction and normalized for glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The HF patients showing an improvement in New York Heart Association (NYHA) functional class by >1 score and a relative increase in LV ejection fraction ≥25% at 4 months after CRT were considered as responders. Results: The HF patients were characterized by lower LV mRNA levels of α-myosin heavy chain (α-MHC), β-myosin heavy chain (β-MHC), sarcoplasmic reticulum calcium ATPase 2α (SERCA), phospholamban (PLN), and higher brain natriuretic peptide (BNP) mRNA levels as compared with control subjects. Responders to CRT (n = 11) showed an increase in LVEF (p < 0.001), a decrease in left ventricular end-diastolic diameter (p = 0.003), and NYHA functional class (p = 0.002), and a reduction in N-terminal proBNP levels (p = 0.032) as compared with baseline. This was associated with an increase in mRNA levels of α-MHC (p = 0.035), SERCA (p = 0.032), a decrease in BNP mRNA levels (p = 0.002), and an increase in the ratio of α-/β-MHC (p = 0.018) and SERCA/PLN (p = 0.012). No significant changes in molecular profile were observed in nonresponders. Conclusions: In HF patients with electromechanical cardiac dyssynchrony, functional improvement related to CRT is associated with favorable changes in established molecular markers of HF, including genes that regulate contractile function and pathologic hypertrophy. [Copyright &y& Elsevier]

Background: Heart failure is associated with a reduction in left ventricular (LV) contractility as evidenced by a blunted force-frequency response (FFR) and downregulation of contractility regulating genes.Objective: This study sought to investigate whether cardiac resynchronization therapy (CRT) is capable of reversing the blunted FFR and the downregulation of contractility regulating genes.Methods: Twenty heart failure patients underwent echocardiographic examination during incremental AAI and DDD-CRT pacing at 70, 90, and 110 beats/min, immediately after and 4 months after CRT implantation. The FFR was determined from the ratio of the LV systolic pressure/end systolic volume index at given heart rate. In a subgroup of 6 patients with idiopathic dilated cardiomyopathy, serial LV dP/dtmax was invasively measured during both pacing modes and serial LV endomyocardial biopsies were taken to measure sarcoplasmatic reticulum calcium ATPase 2alpha (SERCA2alpha), phospholamban (PLN), sarcolemmal sodium calcium exchanger (NCX), beta1-adrenoreceptor (beta1-AR), and apelin (APL) gene expression using reverse-transcriptase polymerase chain reaction.Results: Acutely, DDD-CRT pacing was associated with a decrease in dyssynchrony (P <.01) and increase in diastolic filling time (P <.01) at all heart rates paralleled by an upward shift of the FFR (P <.01) without force-frequency amplification. A greater upward shift of the FFR was noticed during DDD-CRT as compared with AAI (P <.01) after 4 months. In addition, CRT was associated with a significant force-frequency amplification at follow-up as evidenced from the steeper slope of the FFR relationship (P = .039). This was associated with a significant upregulation of SERCA2alpha P = .01), PLN (P = .01), their ratio (P = .01), ratio of SERCA/NCX (P = .02), beta1-AR (P = .03), and APL (P = .01) mRNA levels.Conclusion: CRT is associated with an acute upward shift in the FFR without force-frequency amplification related to restored synchronicity and increased filling time of the LV. Only chronic CRT is associated with force-frequency amplification in parallel to upregulation of contractility regulating genes. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to quantify the changes in cardiopulmonary function after minimally invasive video-assisted mitral valve repair for organic mitral regurgitation (MR) in asymptomatic or minimally symptomatic patients. Methods: Twenty-six patients (age 54 ± 11 years) with severe organic MR (regurgitant volume of 94 ± 37 mL, effective regurgitant orifice [ERO] of 0.73 ± 0.35 cm2) and mild or no symptoms (New York Heart Association class 1.2 ± 0.4) underwent exercise echocardiography and cardiopulmonary exercise testing 1 week before and 4 months after uncomplicated video-assisted mitral valve repair. Results: During exercise, left ventricular ejection fraction increased from 68% ± 7% to 74% ± 6% (P < .0001), but ERO did not change significantly. Four months after video-assisted mitral valve repair, a significant improvement was observed in peak oxygen uptake (Vo 2max from 23 ± 6 to 25 ± 7 mL · kg−1 · min−1, P < .001), peak oxygen pulse (11 ± 3 to 12 ± 4 mL per beat, P < .005) as well as in maximal workload (from 143 ± 49 to 159 ± 55 W, P < .0001). When only patients without any symptoms (New York Heart Association class I, n = 20) were considered, these changes were even more pronounced (Vo 2max from 24 ± 7 to 27 ± 7 mL · kg−1 · min−1, P < .001). Post-operative changes in Vo 2max correlated with preoperative exercise-induced contractile reserve (r = 0.72, P < .0001), preoperative ERO (r = 0.49, P < .05), and preoperative ejection fraction at rest (r = 0.42, P < .05). Conclusion: In patients with severe organic MR but mild or no symptoms, cardiopulmonary performance improves after successful minimally invasive video-assisted mitral valve repair. Improvement is directly related to preoperative left ventricular function and contractile reserve. [Copyright &y& Elsevier]

Background: Cardiac dyssynchrony is frequent in advanced heart failure, and cardiac resynchronization therapy (CRT) may offer an alternative to heart transplantation. We aimed to investigate the impact of CRT on freedom from Tx and death in transplant candidates with end-stage heart failure. Methods: Over a period of 2 years, 46 consecutive patients with refractory congestive heart failure due to dilated cardiomyopathy were referred for heart transplant evaluation. Patients with cardiac dyssynchrony >107 milliseconds according to tissue Doppler imaging (TDI) or QRS duration >150 milliseconds were treated with CRT (CRT group, n = 24), whereas patients without dyssynchrony were not treated (non-CRT group, n = 22). Results: At baseline, both groups showed similar hemodynamic and functional parameters, including ejection fraction (19 ± 10% vs 21 ± 12%, not statistically significant [NS]) and Vo 2max (11.9 ± 2.0 vs 12.0 ± 1.8 ml/kg/min, NS). After a follow-up of 488 ± 346 days, cumulative survival with freedom from transplantation and death was higher in CRT vs non-CRT patients (92% vs 39%; p < 0.001). CRT patients showed a decrease in New York Heart Association (NYHA) class from 3.2 ± 1.1 to 2.2 ± 0.9 (p = 0.003) and an increase in Vo 2max from 11.9 ± 2.0 to 13.1 ± 1.8 ml/kg/min (p = 0.02), and 71% (17 of 24) of these patients were successfully removed from the waiting list. Conclusions: In heart transplant candidates with significant dyssynchrony, CRT delays heart transplantation and improves NYHA class and exercise capacity. For these patients, CRT should be considered before heart transplantation. [Copyright &y& Elsevier]

Background: The aim of cardiac resynchronization therapy is correction of left ventricular (LV) dyssynchrony. However, little is known about the optimal timing of LV and right ventricular (RV) stimulation.Objectives: The purpose of this study was to evaluate the acute hemodynamic effects of biventricular pacing, using a range of interventricular delays in patients with advanced heart failure.Methods: Twenty patients with dilated ischemic (n = 12) and idiopathic (n = 8) cardiomyopathy (age 66 +/- 6 years, New York Heart Association class III-IV, LV end-diastolic diameter >55 mm, ejection fraction 22% +/- 18%, and QRS 200 +/- 32 ms) were implanted with a biventricular resynchronization device with sequential RV and LV timing (VV) capabilities. Tissue Doppler echocardiographic parameters were measured during sinus rhythm before implantation and following an optimal AV interval with both simultaneous and sequential biventricular pacing. The interventricular interval was modified by advancing the LV stimulus (LV first) or RV stimulus (RV first) up to 60 ms. For each stimulation protocol, standard echocardiographic Doppler and tissue Doppler imaging (TDI) echo were used to measure the LV outflow tract velocity-time integral, LV filling time, intraventricular delay, and interventricular delay.Results: The highest velocity-time integral was found in 12 patients with LV first stimulation, 5 patients with RV first stimulation, and 3 patients with simultaneous biventricular activation. Compared with simultaneous biventricular pacing, the optimized sequential biventricular pacing significantly increased the velocity-time integral (P <.001) and LV filling time (P = .001) and decreased interventricular delay (P = .013) and intraventricular delay (P = .010). The optimal VV interval could not be predicted by any clinical nor echocardiographic parameter. At 6-month follow-up, the incidence of nonresponders was 10%.Conclusion: Optimal timing of the interventricular interval results in prolongation of the LV filling time, reduction of interventricular asynchrony, and an increase in stroke volume. In patients with advanced heart failure undergoing cardiac resynchronization therapy, LV hemodynamics may be further improved by optimizing LV-RV delay. [ABSTRACT FROM AUTHOR]

Objectives: We postulated that both diastolic and systolic load modulate B-type natriuretic peptide (BNP) production in human pressure overload hypertrophy/failure. Background: In isolated myocytes, diastolic stretch induces BNP messenger ribonucleic acid expression. However, the mechanism of the BNP release in human hypertrophy remains controversial. Methods: In 40 patients with symptomatic aortic stenosis (AS), left ventricular (LV) performance and systolic and diastolic wall stress were calculated from combined invasive and echocardiographic data. Plasma BNP was determined by the rapid point-of-care bedside analyzer (Biosite Triage, Biosite Diagnostics Inc., San Diego, California). Results: A significant relationship was observed between plasma BNP and pulmonary capillary wedge pressure (p < 0.001), fractional shortening (p = 0.001), and aortic valve area (p = 0.006). Furthermore, a significant correlation was noted between BNP and LV mass index (p = 0.005) as well as between BNP and markers of diastolic load such as LV end-diastolic wall stress (p = 0.011), indexed LV end-diastolic volume (p < 0.001), and isovolumic relaxation time (p = 0.02). Preoperative BNP levels were elevated in patients with AS compared with patients without AS. Plasma BNP was higher in AS patients with impaired versus normal preload reserve (297 ± 56 pg/ml vs. 168 ± 44 pg/ml; p = 0.017) and in AS patients with clinical deterioration after valve replacement compared with those without (399 ± 82 pg/ml vs. 124 ± 41 pg/ml; p = 0.011). Conclusions: In patients with AS, BNP appears to be regulated not only by systolic but also by diastolic load. This supports the hypothesis that myocardial stretch modulates BNP production in human pressure overload hypertrophy/failure. [Copyright &y& Elsevier]

Objectives: The hemodynamic effects of cardiac inducible nitric oxide synthase (iNOS) and of iNOS-mediated peroxynitrite in patients with left ventricular (LV) dysfunction are unclear. The present study investigates the incidence and functional significance of iNOS expression and nitrotyrosine formation in patients with heart failure.Methods: LV endomyocardial biopsies obtained from 24 patients with heart failure due to idiopathic dilated cardiomyopathy (ejection fraction [EF] <45% and left ventricular end-diastolic volume index [LVEDVI] >102 ml/m2) were analyzed for iNOS and nitrotyrosine. LV contractile performance was assessed by left ventricular ejection fraction (LVEF) and stroke work normalized for end-diastolic pressure (SW/EDP). LV filling pattern was assessed by Doppler E/A wave ratio, deceleration time (DT) of early LV filling and indexed LV end-diastolic volume normalized for EDP as a marker of diastolic distensibility.Results: iNOS immunostaining correlated significantly with nitrotyrosine formation (r = 0.86, p < 0.001). In the whole study group, patients expressing iNOS (n = 13) showed larger LV end-diastolic (173 ± 16 vs 128 ± 9 ml/m2, p = 0.031) and end-systolic volume indices (110 ± 16 vs 61 ± 9 ml/m2, p = 0.018) and similar LVEDP (18 ± 2 vs 21 ± 2 mm Hg, p = 0.227). In patients with advanced heart failure and reduced pre-load reserve (LVEDP > 16 mm Hg, n = 18), iNOS protein and nitrotyrosine formation correlated positively with LVSW/EDP (r = 0.65, p = 0.03 and r = 0.64, p = 0.04, respectively), DT (r = 0.96, p < 0.01 and r = 0.88, p < 0.01, respectively) and inversely with E/A (r = -0.82, p < 0.01 and r = -0.88, p < 0.01, respectively). In addition, nitrotyrosine formation correlated positively with LVEDVI/EDP (r = 0.64, p = 0.02). Advanced iNOS-positive heart failure patients had a higher LVEDVI/EDP compared with iNOS-negative patients (5.30 ± 0.64 vs 3.13 ± 0.34 ml/mm Hg · m2, p = 0.02).Conclusions: In heart failure, iNOS protein expression is associated with nitrotyrosine formation. Although iNOS-positive patients are generally characterized by larger LV volume and depressed function, the preserved NO generation appears to be associated with higher cardiac work due to the preserved Frank-Starling relationship in end-stage heart failure. [Copyright &y& Elsevier]

Objectives: The study investigated the expression and relationship of deoxyribonucleic acid (DNA) repair enzymes with hemodynamic and nitric oxide (NO)-mediated stress in the failing myocardium.Background: The role of apoptosis in human heart failure is controversial. Experimental studies suggested that NO-mediated stress modulates apoptosis of the cardiac myocytes. Of note, DNA repair enzymes such as redox factor/apurinic/apyridimine endonuclease Ref-1 protein, proliferative cell nuclear antigen (PCNA), the poly (ADP-ribose) polymerase (PARP), and DNA-protein kinase (DNA-PK) determine the cell fate after the DNA damage.Methods: Left ventricular (LV) endomyocardial biopsies from 23 patients with dilated cardiomyopathy were analyzed by immunohistochemistry.Results: Terminal deoxynucleotidyltransferase-mediated biotin-dUTP nick-end labeling (TUNEL) or cleaved caspase-3 and cleaved PARP could not be detected. The number of Ref-1-positive myocytes tended to be higher in patients with LV ejection fraction (EF) < or =35% versus LV EF >35% (21.23 +/- 4.8% vs. 13.8 +/- 5.8%, p = 0.1). The PCNA (7.1 +/- 2.8% vs. 0.9 +/- 0.6%, p = 0.05) and DNA-PK expressions (39.5 +/- 5.4% vs. 8.6 +/- 5.5%, p < 0.01) were higher in patients with LVEF < or =35% vs. LVEF >35%. The PCNA, Ref-1, and DNA-PK expression correlated with the LV end-systolic wall stress (r = 0.61, p < 0.01; r = 0.52, p < 0.01; and r = 0.73, p < 0.001, respectively). In addition, the PCNA and DNA-PK expression correlated with inducible NO synthase (r = 0.41, p = 0.05, and r = 0.53, p < 0.01, respectively).Conclusion: In this study, apoptosis could not be detected in the failing myocardium owing to idiopathic dilated cardiomyopathy. In contrast, failing myocardium was characterized by active DNA repair that was associated with elevated LV wall stress and activation of the inducible NO synthase. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to evaluate the oxygen uptake efficiency slope (OUES) as a predictor of peak oxygen consumption (Vo 2) in aged patients with coronary artery disease (CAD) and to compare its predictive value to that of ventilatory anaerobic threshold (VAT). Methods: A total of 160 aged (>60 years) patients with stable CAD performed a maximal cardiopulmonary exercise test. The equations were computed by using data of 85 randomly selected patients and were validated in the remaining 75 patients. Bland-Altman (BA) analysis was used to assess the agreement between measured and predicted peak Vo 2. Results: In the first 85 patients, peak Vo 2 correlated best with VAT and OUES per kilogram (P < .001). The linear regression to predict peak Vo 2 for OUES per kilogram was peak Vo 2 = 4.591 + 0.64 × OUES/kg (SEE = 2.61 mL kg−1 min−1). The BA 95% limits of agreement were −29% and +30% of the predicted value. For VAT, the linear regression to predict peak Vo 2 was peak Vo 2 = 2.995 + 1.251 × VAT (SEE = 2.26 mL kg−1 min−1). The BA 95% limits of agreement were −23% and +33% of the predicted value. Cross-tabulation analysis in 3 subgroups with different exercise capacities showed significant relationship between predicted and measured peak Vo 2 (all P < .001). OUES per kilogram showed the best measure of agreement with measured peak Vo 2, resulting in high sensitivity and specificity scores. Conclusion: OUES is not able to acceptably predict peak Vo 2 in aged patients with CAD but is at least as performant as VAT in categorizing patients into subgroups with different exercise capacities. Therefore, the objectively measurable OUES is the preferred submaximal predictor of functional capacity in the assessment of aged patients with CAD. [Copyright &y& Elsevier]

B-type natriuretic peptide or brain natriuretic peptide (BNP) is a cardiac peptide hormone. The principal stimulus for BNP synthesis is myocyte stretch. BNP binds to the natriuretic peptide receptor-A causing increased intracellular cyclic guanosine monophosphate (cGMP) production and shows cardio- and renoprotective effects. However, high endogenous BNP levels are associated with a lack of effect in severe heart failure. Moreover, in experimental heart failure, the response to treatments targeting the natriuretic peptide system is attenuated. This article reviews potential mechanisms that may explain the 'BNP paradox' in heart failure with a focus on interspecies differences, on known and presumed specificities of canine BNP biology, and on experimental studies in dogs. Resistance to BNP is far from fully understood but may be due to post-translational modifications and alteration in proBNP processing, receptor downregulation and desensitization, blunted intraceIlular signalling and increased clearance of BNP1-32. Alternatively, resistance to BNP may be due to BNP1-32 shortening into additional truncated forms that are less biologically effective. Future improvement in understanding of BNP biology may provide the rationale for innovative therapeutic strategies to maximize cardiovascular and renal cGMP bioavailability. [ABSTRACT FROM AUTHOR]

The need for a quantitative and operator-independent assessment of coronary microvascular function is increasingly recognized. We propose the theoretical framework of microvascular resistance reserve (MRR) as an index specific for the microvasculature, independent of autoregulation and myocardial mass, and based on operator-independent measurements of absolute values of coronary flow and pressure. In its general form, MRR equals coronary flow reserve (CFR) divided by fractional flow reserve (FFR) corrected for driving pressures. In 30 arteries, pressure, temperature, and flow velocity measurements were obtained simultaneously at baseline (BL), during infusion of saline at 10 mL/min (rest) and 20 mL/min (hyperemia). A strong correlation was found between continuous thermodilution-derived MRR and Doppler MRR (r = 0.88; 95% confidence interval: 0.72-0.93; P < 0.001). MRR was independent from the epicardial resistance, the lower the FFR value, the greater the difference between MRR and CFR. Therefore, MRR is proposed as a specific, quantitative, and operator-independent metric to quantify coronary microvascular dysfunction. [ABSTRACT FROM AUTHOR]

Graft occlusion after coronary artery bypass graft surgery (CABG) has been associated with native coronary artery competitive flow. The present study aims to characterize the functional progression of coronary artery disease (CAD) in native vessels after CABG, and to assess the relationship between preoperative FFR as derived from angiography and graft occlusion. Multicenter study of consecutive patients undergoing CABG between 2013 and 2018, in whom a follow-up angiogram had been performed. Serial vessel-fractional flow reserve (vFFR) analyses were obtained in each major native coronary vessel before and after CABG, excluding post-anastomotic segments and graft conduits. In 73 patients, serial angiograms were suitable for vFFR analysis, including 118 grafted (86 arterial and 32 saphenous grafts) and 64 non-grafted vessels. The median time between CABG and follow-up angiography was 2.4 years [IQR 1.5, 3.3]. Functional CAD progression, by means of decline in vFFR, was observed in grafted but not in non-grafted vessels (delta vFFR in grafted vessels 0.10 [IQR 0.05, 0.18] vs. 0.01 [IQR -0.01, 0.03], in non-grafted vessels, p < 0.001). Preoperative vFFR predicted graft occlusion (AUC: 0.66, 95% CI 0.52 to 0.80, p = 0.031). In patients undergoing CABG, preoperative vFFR derived from conventional angiograms without use of pressure wire was able to predict graft occlusion. Graft occlusion was more frequent in vessels with high vFFR values. Grafted native coronary vessels exhibited accelerated functional CAD progression, whereas in non-grafted native coronaries the functional status remained unchanged. • In patients undergoing CABG, preoperative non-significant angiography-derived FFR (>0.80) predicted graft occlusion. • Grafted native coronary vessels exhibited accelerated functional CAD progression • In non-grafted native coronaries the functional status remained unchanged during a median follow-up of 2.4 years. [ABSTRACT FROM AUTHOR]