Outcomes Following Percutaneous Coronary Intervention in Patients With Multivessel Disease Who Were Recommended for But Declined Coronary Artery Bypass Graft Surgery.

BACKGROUND: Patients may prefer percutaneous coronary intervention (PCI) over coronary artery bypass graft (CABG) surgery, despite heart team recommendations. The outcomes in such patients have not been examined. We sought to examine the results of PCI in patients who were recommended for but declined CABG. METHODS AND RESULTS: Consecutive patients with stable ischemic heart disease and unprotected left main or 3-vessel disease or Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery score >22 who underwent PCI after heart team review between 2013 and 2020 were included. Patients were categorized into 3 groups according to heart team recommendations on the basis of appropriate use criteria: (1) PCI-recommended; (2) CABG-eligible but refused CABG (CABG-refusal); and (3) CABG-ineligible. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. The study included 3687 patients undergoing PCI (PCI-recommended, n=1718 [46.6%]), CABG-refusal (n=1595 [43.3%]), and CABG-ineligible (n=374 [10.1%]). Clinical and procedural risk increased across the 3 groups, with the highest comorbidity burden in CABG-ineligible patients. Composite events within 1 year after PCI occurred in 55 (4.1%), 91 (7.0%), and 41 (14.8%) of patients in the PCI-recommended, CABG-refusal, and CABG-ineligible groups, respectively. After multivariable adjustment, the risk of the primary composite outcome was significantly higher in the CABG-refusal (hazard ratio [HR], 1.67 [95% CI, 1.08-3.56]; P=0.02) and CABG-ineligible patients (HR, 3.26 [95% CI, 1.28-3.65]; P=0.004) groups compared with the reference PCI-recommended group, driven by increased death and stroke. CONCLUSIONS: Cardiovascular event rates after PCI were significantly higher in patients with multivessel disease who declined or were ineligible for CABG. Our findings provide real-world data to inform shared decision-making discussions.

Comprehensive Management of ANOCA, Part 1-Definition, Patient Population, and Diagnosis: JACC State-of-the-Art Review.

Angina with nonobstructive coronary arteries (ANOCA) is increasingly recognized and may affect nearly one-half of patients undergoing invasive coronary angiography for suspected ischemic heart disease. This working diagnosis encompasses coronary microvascular dysfunction, microvascular and epicardial spasm, myocardial bridging, and other occult coronary abnormalities. Patients with ANOCA often face a high burden of symptoms and may experience repeated presentations to multiple medical providers before receiving a diagnosis. Given the challenges of establishing a diagnosis, patients with ANOCA frequently experience invalidation and recidivism, possibly leading to anxiety and depression. Advances in scientific knowledge and diagnostic testing now allow for routine evaluation of ANOCA noninvasively and in the cardiac catheterization laboratory with coronary function testing (CFT). CFT includes diagnostic coronary angiography, assessment of coronary flow reserve and microcirculatory resistance, provocative testing for endothelial dysfunction and coronary vasospasm, and intravascular imaging for identification of myocardial bridging, with hemodynamic assessment as needed.

Comprehensive Management of ANOCA, Part 2-Program Development, Treatment, and Research Initiatives: JACC State-of-the-Art Review.

Centers specializing in coronary function testing are critical to ensure a systematic approach to the diagnosis and treatment of angina with nonobstructive coronary arteries (ANOCA). Management leveraging lifestyle, pharmacology, and device-based therapeutic options for ANOCA can improve angina burden and quality of life in affected patients. Multidisciplinary care teams that can tailor and titrate therapies based on individual patient needs are critical to the success of comprehensive programs. As coronary function testing for ANOCA is more widely adopted, collaborative research initiatives will be fundamental to improve ANOCA care. These efforts will require standardized symptom assessments and data collection, which will propel future large-scale clinical trials.

Ticagrelor vs Prasugrel in a Contemporary Real-World Cohort Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Potent P2Y12 agents such as ticagrelor and prasugrel are increasingly utilized across the clinical spectrum of patients undergoing percutaneous coronary intervention (PCI). There is a paucity of data supporting their use in a patient population inclusive of both acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients. OBJECTIVES: The authors compared the efficacy and safety of ticagrelor and prasugrel in a real-world contemporary PCI cohort. METHODS: Consecutive patients undergoing PCI between 2014 and 2019 discharged on either prasugrel or ticagrelor were included from the prospectively collected institutional PCI registry. Primary endpoint was the composite of death and myocardial infarction (MI), with secondary outcomes including rates of bleeding, stroke, and target vessel revascularization at 1 year. RESULTS: Overall, 3,858 patients were included in the study (ticagrelor: n = 2,771; prasugrel: n = 1,087), and a majority (48.4%) underwent PCI in the context of CCS. Patients prescribed ticagrelor were more likely to be female, have a history of cerebrovascular disease, and have ACS presentation, while those receiving prasugrel were more likely to be White with a higher prevalence of prior revascularization. No difference in the risk of death or MI was noted across the groups (ticagrelor vs prasugrel: 3.3% vs 3.1%; HR: 0.88; 95% CI: 0.54-1.43; P = 0.59). Rates of target vessel revascularization were significantly lower in the ticagrelor cohort (9.3% vs 14.0%; adjusted HR: 0.71; 95% CI: 0.55-0.91; P = 0.007) with no differences in stroke or bleeding. The results were consistent in patients with CCS (HR: 0.84; 95% CI: 0.46-1.54) and ACS (HR: 1.18; 95% CI: 0.46-1.54), without evidence of interaction (P = 0.37), and confirmed across multivariable adjustment and propensity score stratification analysis. CONCLUSIONS: In this contemporary patient population undergoing PCI, prasugrel and ticagrelor were associated with similar 1-year efficacy and safety.

Prevalence, correlates, and impact of coronary calcification on adverse events following PCI with newer-generation DES: Findings from a large multiethnic registry.

OBJECTIVES: We sought to determine the prevalence, predictors, and clinical impact of target lesion calcification in patients undergoing percutaneous coronary intervention (PCI) with newer generation drug-eluting stents (DES) and devices. BACKGROUND: Coronary calcification is independently associated with adverse outcomes following PCI. While newer DES and contemporary devices are considered safer and more efficacious, their influence on outcomes following PCI of heavily calcified lesions is unknown. METHODS: We performed a retrospective analysis of a large, multiethnic cohort of patients undergoing PCI with new generation DES at an academic center between 2009 and 2013. Coronary calcification was qualitatively assessed as none/mild, moderate, or severe. Independent demographic, clinical, and anatomic predictors of moderate/severe calcification were identified using logistic regression. Associations between coronary calcification and 1-year MACE (death, myocardial infarction, or target vessel revascularization) were examined using Cox modeling. RESULTS: Compared to patients with none/mild (n = 10,180; 82.0%), those with moderate (n = 1,271; 10.0%) or severe (n = 994; 8.0%) calcification were older, more often Caucasian, had more complex target lesions, and worse renal function. The strongest demographic, clinical, and anatomic correlates of moderate/severe calcification were age, Caucasian race, renal dysfunction, lesion length, and left main location. Unadjusted MACE rates among those with none/mild, moderate, and severe calcification were 8.3, 14.6, and 17.8%, respectively (P < 0.001). After multivariable adjustment, the hazard ratio (95% CI) for MACE associated with moderate or severe coronary calcification was 1.63. CONCLUSIONS: Target lesion calcification remains independently associated with adverse outcomes in patients treated with newer generation DES and modern devices.

Impact of Diabetes Mellitus on the Pharmacodynamic Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Acute Coronary Syndrome Patients Undergoing Ad Hoc Percutaneous Coronary Intervention.

BACKGROUND: Diabetes mellitus (DM) is associated with enhanced platelet reactivity and impaired response to oral antiplatelet therapy, including clopidogrel. This post hoc analysis investigated the pharmacodynamic effects of ticagrelor versus clopidogrel loading dose (LD) in troponin-negative acute coronary syndrome patients with or without DM undergoing percutaneous coronary intervention in the Ad Hoc PCI study. METHODS AND RESULTS: Patients randomized (1:1) to receive ticagrelor 180 mg LD or clopidogrel 600 mg LD were assessed by diabetic status. Platelet reactivity (P2Y12 reaction units [PRU] on VerifyNow® assay) was measured pre-LD, at 0.5, 2, and 8 hours post-LD, and at the end of the percutaneous coronary intervention. The primary endpoint was PRU levels 2 hours post-LD; secondary endpoints included rates of high on-treatment platelet reactivity (PRU≥208). Of 100 randomized patients, 51 received ticagrelor (DM, n=20; non-DM, n=31) and 49 clopidogrel (DM, n=16; non-DM, n=33). At 2 hours post-LD, mean (SD) PRU levels in DM patients were 130.1 (111.7) with ticagrelor versus 287.6 (71.9) with clopidogrel (mean [95%CI] difference -157.5 [-225.3, -89.8]; P<0.001); in non-DM patients, they were 75.3 (75.7) versus 243.0 (72.4) (mean difference -167.7 [-207.1, -128.3]; P<0.001). High on-treatment platelet reactivity rates at 2 hours post-LD were also significantly (P<0.001) reduced with ticagrelor versus clopidogrel in DM and non-DM patients. Between-treatment differences for PRU and high on-treatment platelet reactivity were not significant at earlier time points but were at 8 hours post-LD (P<0.001). CONCLUSIONS: Compared with clopidogrel, ticagrelor achieved faster, enhanced platelet inhibition and reduced high on-treatment platelet reactivity rates, in DM and non-DM patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603082.

Three-dimensional volumetric assessment of coronary artery calcification in patients with stable coronary artery disease by OCT.

AIMS: There is a lack of a reliable technique to quantify coronary artery calcification (CAC). Hence, we used optical coherence tomography (OCT) to quantitate three-dimensional CAC volume to examine its association with plaque characteristics. METHODS AND RESULTS: A total of 250 patients with stable angina undergoing OCT imaging before PCI were included. CAC volume was calculated from every frame of the culprit lesion and divided into tertiles (low, intermediate and high). Quantitative calcium characteristics were assessed in 107 patients who underwent both OCT and IVUS. Increase in CAC volume was associated with reduced lipid volume index, lipid length and number of lipid plaques. Diabetes and LDL cholesterol predicted less coronary calcification whereas age and prior MI predicted increased CAC after adjusting for all clinical factors. Lipid volume index (ρ=-0.001 [-0.003 to -0.00003]; p=0.04) and mean calcium depth (ρ=-0.02 [-0.02 to -0.01]; p=0.000) were inversely related to CAC volume after adjusting for all OCT characteristics, whereas cap thickness increased with increase in CAC volume (ρ=0.01 [0.002-0.03]; p=0.02) only in unadjusted analysis. Regression analysis demonstrated a significant correlation between calcium length (ρ=0.83; p<0.001) and calcium arc (ρ=0.86; p<0.001) measured by IVUS and OCT. CONCLUSIONS: Target lesions with high CAC volume are characterised by reduced plaque lipid content and calcium closer to the luminal border. Fibrous cap thickness increased with increase in calcium volume.

Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Patients With Low-Risk ACS Undergoing Ad Hoc PCI.

BACKGROUND: Many low-risk acute coronary syndrome (ACS) patients are not pre-treated with a P2Y12 receptor inhibitor, and percutaneous coronary interventions (PCIs) are often performed on an ad hoc basis in this population. Pharmacodynamic (PD) studies comparing ticagrelor versus clopidogrel in patients undergoing ad hoc PCI are lacking. OBJECTIVES: This study sought to assess PD effects of ticagrelor versus clopidogrel loading dose (LD) in the peri-procedural period among troponin-negative ACS patients undergoing ad hoc PCI. METHODS: This was a prospective, open-label, randomized, multicenter, parallel-group, phase IV PD study. One hundred P2Y12 inhibitor-naïve patients presenting with biomarker-negative ACS and undergoing ad hoc PCI, on a background of aspirin therapy, were randomized to receive either ticagrelor 180 mg LD or clopidogrel 600 mg LD. Platelet reactivity (P2Y12 reaction units [PRU]; VerifyNow assay) was measured at 5 time points: pre-LD, at 0.5, 2, and 8 h post-LD, and at end of PCI. The primary endpoint was PRU levels 2 h post-LD; secondary endpoints included PRU levels at all other time points and inhibition of platelet aggregation; an exploratory analysis evaluated rates of high on-treatment platelet reactivity (HPR) (PRU >208). RESULTS: At 2 h, PRU levels were significantly lower with ticagrelor versus clopidogrel (98.4 ± 95.4 vs. 257.5 ± 74.5; p < 0.001; primary endpoint). PRU levels diverged as early as 0.5 h post-LD, with significant differences observed by the end of PCI (mean 0.6 h post-LD) and maintained up to 8 h post-LD. HPR rates were also significantly reduced with ticagrelor compared with clopidogrel at the end of PCI (p = 0.030), and at 2 h (p < 0.001) and 8 h (p < 0.001) after LD. CONCLUSIONS: In low-risk ACS patients undergoing ad hoc PCI, ticagrelor LD provides more prompt and potent platelet inhibition, and lower HPR rates, compared with clopidogrel LD. (Ad Hoc Percutaneous Coronary Intervention Study in Acute Coronary Syndrome Patients: NCT01603082).

The relationship among extent of lipid-rich plaque, lesion characteristics, and plaque progression/regression in patients with coronary artery disease: a serial near-infrared spectroscopy and intravascular ultrasound study.

AIMS: To evaluate the relationship between lipid content and plaque morphometry as well as the process of lesion progression and regression in patients with significant coronary artery disease. METHODS AND RESULTS: The present study, using data from the YELLOW trial, was conducted in patients having significant coronary lesions (fractional flow reserve <0.8) who underwent serial intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) at baseline and after 7 weeks. For each coronary plaque (≥50% plaque burden that was ≥5 mm in length), we evaluated plaque characteristics and the extent of lipid-rich plaque [LRP, defined as the 4 mm long segment with the maximum lipid-core burden index (maxLCBI4 mm)] on NIRS. Among 66 patients (age 63.0 ± 10.1 years; 82% statin use at baseline), 94 plaques were identified. The extent of LRP at baseline was positively correlated with IVUS plaque burden (r = 0.317, P = 0.002). A large LRP (maxLCBI4 mm ≥500) was present only in plaques with a large plaque burden (≥70%). Multivariate analysis demonstrated that plaque burden was the best predictor of the extent of LRP (P < 0.001). In lesions with a large plaque burden and a large amount of LRP at baseline, a reduction in LRP was seen in all lesions in patients receiving intensive statin therapy (P = 0.004) without a significant change in plaque burden. CONCLUSIONS: Coronary lesions containing a large amount of LRP also had a large plaque burden. Short-term regression of LRP (without a change in plaque burden) was observed mainly in plaques with a large plaque burden and a large amount of LRP at baseline. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01567826.

High-efficiency SPECT MPI: comparison of automated quantification, visual interpretation, and coronary angiography.

BACKGROUND: Recently introduced high-efficiency (HE) SPECT cameras with solid-state CZT detectors have been shown to decrease imaging time and reduce radiation exposure to patients. An automated, computer-derived quantification of HE MPI has been shown to correlate well with coronary angiography on one HE SPECT camera system (D-SPECT), but has not been compared to visual interpretation on any of the HE SPECT platforms. METHODS: Patients undergoing a clinically indicated Tc-99m sestamibi HE SPECT (GE Discovery 530c with supine and prone imaging) study over a 1-year period followed by a coronary angiogram within 2 months were included. Only patients with a history of CABG surgery were excluded. Both MPI studies and coronary angiograms were reinterpreted by blinded readers. One hundred and twenty two very low (risk of CAD < 5%) or low (risk of CAD < 10%) likelihood subjects with normal myocardial perfusion were used to create normal reference limits. Computer-derived quantification of the total perfusion deficit at stress and rest was obtained with QPS software. The visual and automated MPI quantification were compared to coronary angiography (≥70% luminal stenosis) by receiver operating curve (ROC) analysis. RESULTS: Of the 3,111 patients who underwent HE SPECT over a 1-year period, 160 patients qualified for the correlation study (66% male, 52% with a history of CAD). The ROC area under the curve (AUC) was similar for both the automated and the visual interpretations using both supine only and combined supine and prone images (0.69-0.74). Using thresholds determined from sensitivity and specificity curves, the automated reads showed higher specificity (59%-67% vs 27%-60%) and lower sensitivity (71%-72% vs 79%-93%) than the visual reads. By including prone images sensitivity decreased slightly but specificity increased for both. By excluding patients with known CAD and cardiomyopathies, AUC and specificity increased for both techniques (0.72-0.82). The use of a difference score to evaluate ischemic burden resulted in lower sensitivities but higher specificities for both automated and visual quantification. There was good agreement between the visual interpretation and automated quantification in the entire cohort of 160 unselected consecutive patients (r = 0.70-0.81, P < .0001). CONCLUSIONS: Automated and visual quantification of high-efficiency SPECT MPI with the GE Discovery camera provides similar overall diagnostic accuracy when compared to coronary angiography. There was good correlation between the two methods of assessment. Combined supine and prone stress imaging provided the best diagnostic accuracy.

Reduced stress dose with rapid acquisition CZT SPECT MPI in a non-obese clinical population: comparison to coronary angiography.

BACKGROUND: Cadmium Zinc Telluride (CZT) SPECT camera technology has the potential to reduce patient's radiation exposure and shorten imaging time. This study evaluated the correlation of low stress tracer dose, rapid CZT SPECT myocardial perfusion imaging (MPI) to coronary angiography in a <200-lbs population to further validate its ability to achieve both goals while preserving diagnostic accuracy. METHODS: All patients who had a low-dose stress (≤15 mCi) Tc-99m sestamibi SPECT MPI study using a CZT camera (GE Discovery NM 530c) with 3- to 5-minute image acquisition over a 2-year period followed by a coronary angiogram within 2 months were included. Patients with a history of coronary revascularization, left ventricular dysfunction, and LBBB or paced rhythms were excluded. Both MPI studies and coronary angiograms were interpreted by blinded readers and coronary artery disease (CAD) was defined as ≥70% stenosis. RESULTS: A total of 71 patients were included with a mean age of 64 years, 55% male, and a BMI of 25.4 kg/m(2) with an average stress dose of 13.3 mCi. Exercise stress was performed in 54% of patients and vasodilator pharmacologic stress in 46%. Sensitivity was 89%, specificity was 66%, and accuracy was 78% for detecting obstructive CAD. CONCLUSIONS: In this group of non-obese patients undergoing low stress dose imaging, high-efficiency CZT SPECT imaging demonstrated a high sensitivity, specificity, and accuracy for detecting obstructive epicardial CAD with a greatly reduced imaging time.

Comparison of high efficiency CZT SPECT MPI to coronary angiography.

BACKGROUND: The recently introduced cadmium zinc telluride (CZT) SPECT cameras have the potential to reduce radiation exposure to patients and shorten imaging time. So far, there has been only one small study comparing the results of high efficiency CZT SPECT myocardial perfusion imaging (MPI) to invasive coronary angiography. METHODS: All patients who had either a Tc-99m sestamibi or Tl-201 SPECT MPI study using a CZT camera (GE Discovery NM 530c) over a 1-year period followed by a coronary angiogram within 2 months were included. Only patients with a history of CABG surgery were excluded. Standard stress protocols were employed. Rest images were acquired for 5 min and stress supine and prone images for 3 min each. Both MPI studies and coronary angiograms were interpreted by blinded readers. A standard 17-segment model was employed for MPI interpretation, and coronary angiograms were interpreted for the presence of obstructive epicardial coronary artery disease (CAD) defined as ≥70% luminal narrowing. Correlation was based on the ability to diagnose obstructive epicardial CAD. RESULTS: Of the 3,111 patients who underwent SPECT imaging using the CZT camera during this time period, 230 patients qualified for the correlation study (mean age 64.2 ± 11.0 years old, 69% male, and 49% had a history of intracoronary stenting). Tc-99m was used in 76% vs Tl-201 in 24% of the studies. Exercise stress was performed in 60% of patients and vasodilator pharmacologic stress in 40%. Sensitivity was 95%, normalcy rate was 97%, and accuracy was 69% for detecting obstructive CAD. CONCLUSIONS: In this so far largest correlation study between coronary angiography and high efficiency CZT SPECT imaging, a high sensitivity and accuracy for detecting obstructive epicardial CAD was found for this new SPECT camera technology.

Antiplatelet drug 'resistance'. Part 2: laboratory resistance to antiplatelet drugs-fact or artifact?

Many patients experience recurrent ischemic events despite optimal antiplatelet therapy. This has generated much interest in finding a laboratory test of platelet function to identify such patients, who have been termed 'nonresponders' or antiplatelet 'resistant'. Laboratory tests of platelet function have identified 'resistance' in 5-60% of patients taking aspirin and 4-30% of those taking clopidogrel. However, these tests of 'resistance' have not correlated closely with subsequent recurrent events, and have not reliably identified nonresponders to antiplatelet therapy. Here, we identify and discuss three major limitations common to all these tests. Firstly, they are performed on citrate-anticoagulated blood, secondly, blood is stored for a variable period of time, and thirdly, the assessment of thrombotic status on the basis of platelet response to only one or two agonists ignores the complexity of the mechanism of platelet thrombus formation in vivo. In this Review we discuss the significance of these important limitations, and the applicability of such in vitro platelet function tests to the prediction of in vivo events. We conclude that such tests are so unphysiological that they cannot reliably predict the true thrombotic status of patients. Identification of 'resistance' on the basis of these tests lacks sensitivity and specificity for identifying thrombotic risk, and is likely to be artifactual.

Antiplatelet drug 'resistance'. Part 1: mechanisms and clinical measurements.

Antiplatelet drug therapy has become one of the cornerstones of treatment for patients with cardiovascular disease. Large clinical trials have shown that antiplatelet medications have important clinical benefits and prevent adverse outcomes in patients with coronary artery disease. Recurrent adverse cardiovascular events still occur in a substantial proportion of patients on standard dual antiplatelet therapy, however, which has been attributed to nonresponsiveness to this treatment. Both pharmacological and pharmacokinetic mechanisms are involved in variability in responsiveness to antiplatelet agents, and include drug bioavailability, medication noncompliance, drug-drug interactions, cytochrome P450 activity, and genetic polymorphisms. Numerous observational studies have consistently shown an association between antiplatelet drug nonresponsiveness and adverse clinical outcomes. However, these studies are limited by varying antiplatelet drug dosing regimens, heterogeneous laboratory assessments for ex vivo platelet function, and wide interindividual variation in platelet responses. Only within the last 2 years have randomized clinical trials indicated that increased dosing with antiplatelet drugs could reduce adverse clinical outcomes. Nonetheless, large clinical trials with standardized laboratory methods and well-defined protocols are needed that will definitively determine the association between antiplatelet drug nonresponsiveness and clinical events, and establish therapeutic strategies to overcome blunted antiplatelet effects.

Growth hormone regulation of glomerular AT1 angiotensin receptors in adult uninephrectomized male rats.

Sex differences exist in the mechanisms initiating early compensatory renal growth after unilateral nephrectomy (UNX); remnant kidney growth is growth hormone (GH) independent in adult female rats and GH dependent in adult male rats. The present study determined whether sex differences also exist in angiotensin type 1 receptor (AT1R) regulation during early remnant kidney (REM) growth after UNX, and if so, whether GH modulates AT1R expression after UNX in the male rat. Scatchard analysis of radioligand binding in glomeruli demonstrated that 48 h post-UNX, AT1R density (Bmax) was significantly decreased by 20% in female REM compared with control kidneys. In contrast, male REM glomerular Bmax was significantly increased by 28% compared with control kidneys. Furthermore, GH-suppressed male rats displayed attenuated REM growth, which was associated with a 35% decrease in AT1R Bmax. Losartan treatment also decreased REM AT1R Bmax by 55%. The activity of mRNA binding proteins that bind to the 5' leader sequence of the AT1R was regulated by UNX and GH treatment in an inverse manner to AT1R expression. These findings suggest that in rats 1) there are sex differences in the regulation of glomerular AT1R expression after UNX; 2) the increase in AT1R binding sites in the male REM is regulated by GH and mediates early remnant kidney growth; and 3) AT1R 5' leader sequence mRNA binding proteins play a role in UNX and GH regulation of glomerular AT1Rs in both males and females.