Sitara Khan

T1 Mapping in Discrimination of Hypertrophic Phenotypes: Hypertensive Heart Disease and Hypertrophic Cardiomyopathy Findings From the International T1 Multicenter Cardiovascular Magnetic Resonance Study

Background— The differential diagnosis of left ventricular (LV) hypertrophy remains challenging in clinical practice, in particular, between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness because of systemic hypertension. Diffuse myocardial disease is a characteristic feature in HCM, and an early manifestation of sarcomere–gene mutations in subexpressed family members (G+P− subjects). This study aimed to investigate whether detecting diffuse myocardial disease by T1 mapping can discriminate between HCM versus hypertensive heart disease as well as to detect genetically driven interstitial changes in the G+P− subjects. Methods and Results— Patients with diagnoses of HCM or hypertension (HCM, n=95; hypertension, n=69) and G+P− subjects (n=23) underwent a clinical cardiovascular magnetic resonance protocol (3 tesla) for cardiac volumes, function, and scar imaging. T1 mapping was performed before and >20 minutes after administration of 0.2 mmol/kg of gadobutrol. Native T1 and extracellular volume fraction were significantly higher in HCM compared with patients with hypertension ( P 15 mm ( P 2 SD above the mean of the normal range. Native T1 was an independent discriminator between HCM and hypertension, over and above extracellular volume fraction, LV wall thickness and indexed LV mass. Native T1 was also useful in separating G+P− subjects from controls. Conclusions— Native T1 may be applied to discriminate between HCM and hypertensive heart disease and detect early changes in G+P− subjects.Background—The differential diagnosis of left ventricular (LV) hypertrophy remains challenging in clinical practice, in particular, between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness because of systemic hypertension. Diffuse myocardial disease is a characteristic feature in HCM, and an early manifestation of sarcomere–gene mutations in subexpressed family members (G+P− subjects). This study aimed to investigate whether detecting diffuse myocardial disease by T1 mapping can discriminate between HCM versus hypertensive heart disease as well as to detect genetically driven interstitial changes in the G+P− subjects. Methods and Results—Patients with diagnoses of HCM or hypertension (HCM, n=95; hypertension, n=69) and G+P− subjects (n=23) underwent a clinical cardiovascular magnetic resonance protocol (3 tesla) for cardiac volumes, function, and scar imaging. T1 mapping was performed before and >20 minutes after administration of 0.2 mmol/kg of gadobutrol. Native T1 and extracellular volume fraction were significantly higher in HCM compared with patients with hypertension (P<0.0001), including in subgroup comparisons of HCM subjects without evidence of late gadolinium enhancement, as well as of hypertensive patients LV wall thickness of >15 mm (P<0.0001). Compared with controls, native T1 was significantly higher in G+P− subjects (P<0.0001) and 65% of G+P− subjects had a native T1 value >2 SD above the mean of the normal range. Native T1 was an independent discriminator between HCM and hypertension, over and above extracellular volume fraction, LV wall thickness and indexed LV mass. Native T1 was also useful in separating G+P− subjects from controls. Conclusions—Native T1 may be applied to discriminate between HCM and hypertensive heart disease and detect early changes in G+P− subjects.

Blood Pressure in Healthy Humans Is Regulated by Neuronal NO Synthase.

NO is physiologically generated by endothelial and neuronal NO synthase (nNOS) isoforms. Although nNOS was first identified in brain, it is expressed in other tissues, including perivascular nerves, cardiac and skeletal muscle. Increasing experimental evidence suggests that nNOS has important effects on cardiovascular function, but its composite effects on systemic hemodynamics in humans are unknown. We undertook the first human study to assess the physiological effects of systemic nNOS inhibition on basal hemodynamics. Seventeen healthy normotensive men aged 24±4 years received acute intravenous infusions of an nNOS-selective inhibitor, S-methyl-L-thiocitrulline, and placebo on separate occasions. An initial dose-escalation study showed that S-methyl-L-thiocitrulline (0.1–3.0 µmol/kg) induced dose-dependent changes in systemic hemodynamics. The highest dose of S-methyl-L-thiocitrulline (3.0 µmol/kg over 10 minutes) significantly increased systemic vascular resistance (+42±6%) and diastolic blood pressure (67±1 to 77±3 mm Hg) when compared with placebo (both P<0.01). There were significant decreases in heart rate (60±4 to 51±3 bpm; P<0.01) and left ventricular stroke volume (59±6 to 51±6 mL; P<0.01) but ejection fraction was unaltered. S-methyl-L-thiocitrulline had no effect on radial artery flow-mediated dilatation, an index of endothelial NOS activity. These results suggest that nNOS-derived NO has an important role in the physiological regulation of basal systemic vascular resistance and blood pressure in healthy humans.

Impaired Neuronal Nitric Oxide Synthase–Mediated Vasodilator Responses to Mental Stress in Essential Hypertension

Neuronal NO synthase (nNOS) regulates blood flow in resistance vasculature at rest and during mental stress. To investigate whether nNOS signaling is dysfunctional in essential hypertension, forearm blood flow responses to mental stress were examined in 88 subjects: 48 with essential hypertension (42±14 years; blood pressure, 141±17/85±15 mm Hg; mean±SD) and 40 normotensive controls (38±14 years; 117±13/74±9 mm Hg). A subsample of 34 subjects (17 hypertensive) participated in a single blind 2-phase crossover study, in which placebo or sildenafil 50 mg PO was administered before an intrabrachial artery infusion of the selective nNOS inhibitor S-methyl-L-thiocitrulline (SMTC, 0.05, 0.1, and 0.2 &mgr;mol/min) at rest and during mental stress. In a further subsample (n=21) with an impaired blood flow response to mental stress, responses were measured in the presence and absence of the &agr;-adrenergic antagonist phentolamine. The blood flow response to mental stress was impaired in hypertensive compared with normotensive subjects (37±7% versus 70±8% increase over baseline; P<0.001). SMTC blunted responses to mental stress in normotensive but not in hypertensive subjects (reduction of 40±11% versus 3.0±14%, respectively, P=0.01, between groups). Sildenafil reduced the blood flow response to stress in normotensive subjects from 89±14% to 43±14% (P<0.03) but had no significant effect in hypertensive subjects. Phentolamine augmented impaired blood flow responses to mental stress from 39±8% to 67±13% (P<0.02). Essential hypertension is associated with impaired mental stress–induced nNOS-mediated vasodilator responses; this may relate to increased sympathetic outflow in hypertension. nNOS dysfunction may impair vascular homeostasis in essential hypertension and contribute to stress-induced cardiovascular events.

The human coronary vasodilatory response to acute mental stress is mediated by neuronal nitric oxide synthase.

Acute mental stress induces vasodilation of the coronary microvasculature. Here, we show that this response involves neuronal nitric oxide synthase in the human coronary circulation.

Physiological Reduction in Left Ventricular Contractile Function in Healthy Postpartum Women: Potential Overlap with Peripartum Cardiomyopathy.

Aims Peripartum cardiomyopathy is a potentially life-threatening cause of heart failure, commoner in Afro-Caribbean than Caucasian women. Its diagnosis can be challenging due to physiological changes in cardiac function that also occur in healthy women during the early postpartum period. This study aimed to (i) establish the overlap between normal cardiac physiology in the immediate postpartum period and pathological changes in peripartum cardiomyopathy ii) identify any ethnicity-specific changes in cardiac function and cardiac biomarkers in healthy postpartum women. Methods and Results We conducted a cross-sectional study of 58 healthy postpartum women within 48 hours of delivery and 18 matched non-pregnant controls. Participants underwent cardiac assessment by echocardiography and strain analysis, including 3D echocardiography in 40 postpartum women. Results were compared with 12 retrospectively studied peripartum cardiomyopathy patients. Healthy postpartum women had significantly higher left ventricular volumes and mass, and lower ejection fraction and global longitudinal strain than non-pregnant controls. These parameters were significantly more impaired in peripartum cardiomyopathy patients but with overlapping ranges of values. Healthy postpartum women had higher levels of adrenomedullin, placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt1) compared to controls. The postpartum state, adrenomedullin, sFlt1 and the sFlt1:PlGF ratio were independent predictors of LV remodelling and function in healthy postpartum women. Conclusion Healthy postpartum women demonstrate several echocardiographic indicators of left ventricular remodelling and reduced function, which are associated with altered levels of angiogenic and cardiac biomarkers.

106 Echocardiographic Evaluation Of Post-partum Ventricular Remodelling – Implications For The Detection Of Cardiac Disease

Background Peripartum cardiomyopathy (PPCM) is a potentially life-threatening cause of heart failure that often presents soon after delivery. Diagnosis of the condition may be difficult due to the physiological changes in maternal cardiac function that also occur during the early postpartum period. Aims To a) define the normal echocardiographic pattern of cardiac remodelling and changes in cardiac biomarkers in the immediate postpartum period and b) establish the overlap between normal postpartum physiology and pathological changes in PPCM. Methods 58 healthy postpartum (PP) women (age 31.1 ± 5.6 years) and 19 healthy matched non-pregnant controls (age 31.8 ± 4.8 years) underwent an echocardiogram that included 2D strain analysis and 3D evaluation of the LV. Cardiac biomarkers were collectedin 37 women. Postpartum participants were studied within 48 h of delivery. A retrospective analysis of 12 patients diagnosed with PPCM, who had undergone 3D echocardiography at the time of diagnosis, was also performed. Data are presented as mean±SEM. Results Compared to controls, healthy PP women had higher LV volumes, mass and sphericity index (Table 1). These parameters were all significantly higher in patients with PPCM (Figure 1). 3D ejection fraction (EF) and global longitudinal strain was reduced in healthy PP women compared to normal, the range of values overlapping with PPCM patients (Figure 2). Diastolic dysfunction was present in healthy PP women, as reflected by an increased E/E’ lateral ratio, and a trend towards an increased E/E’ septal ratio. In PPCM patients, both E/E’ lateral and E/E’ septal ratios were increased. Healthy PP women had higher levels of adrenomedullin, soluble fms-like tyrosine kinase-1 (sFLT-1), and high sensitivity C-reactive protein compared to controls (Table 2). Levels of N-terminal pro-brain natriuretic peptide were unchanged between controls and healthy PP women. sFLT-1 correlated inversely with 3D EF (r2 = 0.13, p = 0.03). Conclusions In this first study to use 3D echocardiography for the characterisation of postpartum physiology, the LV showed geometric changes of eccentric hypertrophy, which have previously been described in pregnancy. Echocardiographic markers of systolic and diastolic function showed a small but significant impairment. There were also elevations in some serum biomarkers and there was an inverse correlation between the anti-angiogenic marker sFLT-1 and EF. Although patients with PPCM had substantially worse systolic and diastolic dysfunction than healthy postpartum women, the evidence of cardiac remodelling and changes in biomarkers in the latter group indicates that particular care is needed to confidently diagnose mild PPCM is the early postpartum period. Abstract 106 Table 1 Control Healthy PP PPCM p value n (AC/Cauc) 19 (10/9) 58 (28/30) 12 (7/5) LVEDV (ml) 83.7 ± 3.3 98.2 ± 4.0 137.2 ± 9.9 <0.02 LVESV (ml) 29.5 ± 2.0 40.5 ±2.0 86.7 ± 8.0 <0.001 LV mass (g) 70.6 ± 3.9 103.2 ± 3.8 135.4 ±5.8 <0.001 Sphericity index 0.29 ± 0.02 0.39 ± 0.02 0.48 ± 0.02 <0.01 3D EF (%) 65.0 ± 1.8 58.5 ± 1.1 37.6 ± 2.6 <0.01 GLS (%) -20.3 ± 0.50 -18.0 ± 0.59 -10.1 ± 1.6 <0.03 E/E’ lateral 6.3 ± 0.58 11.6 ± 0.88 10.8 ± 2.1 <0.001 E/E’ septal 8.1 ± 0.48 9.9 ± 0.53 17.1 ± 3.6 0.06 Abstract 106 Table 2 Control Healthy PP p value Nt pro-BNP (pg/ml) 37.7 ± 3.2 81.3 ± 18 NS Adrenomedullin (pg/ml) 0.41 ± 0.02 0.52 ± 0.02 <0.01 sFLT-1 (ng/L) 102 ± 11.4 1371 ± 128 <0.001 ox-LDL (ng/L) 57.7 ± 24.8 15.2 ± 3.6 <0.02 hs-CRP 1.3 ± 0.3 52.9 ± 7.4 <0.001 Abstract 106 Figure 1 Abstract 106 Figure 2

T1 Mapping in Discrimination of Hypertrophic Phenotypes: Hypertensive Heart Disease and Hypertrophic CardiomyopathyCLINICAL PERSPECTIVE

Background— The differential diagnosis of left ventricular (LV) hypertrophy remains challenging in clinical practice, in particular, between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness because of systemic hypertension. Diffuse myocardial disease is a characteristic feature in HCM, and an early manifestation of sarcomere–gene mutations in subexpressed family members (G+P− subjects). This study aimed to investigate whether detecting diffuse myocardial disease by T1 mapping can discriminate between HCM versus hypertensive heart disease as well as to detect genetically driven interstitial changes in the G+P− subjects. Methods and Results— Patients with diagnoses of HCM or hypertension (HCM, n=95; hypertension, n=69) and G+P− subjects (n=23) underwent a clinical cardiovascular magnetic resonance protocol (3 tesla) for cardiac volumes, function, and scar imaging. T1 mapping was performed before and >20 minutes after administration of 0.2 mmol/kg of gadobutrol. Native T1 and extracellular volume fraction were significantly higher in HCM compared with patients with hypertension ( P 15 mm ( P 2 SD above the mean of the normal range. Native T1 was an independent discriminator between HCM and hypertension, over and above extracellular volume fraction, LV wall thickness and indexed LV mass. Native T1 was also useful in separating G+P− subjects from controls. Conclusions— Native T1 may be applied to discriminate between HCM and hypertensive heart disease and detect early changes in G+P− subjects.Background—The differential diagnosis of left ventricular (LV) hypertrophy remains challenging in clinical practice, in particular, between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness because of systemic hypertension. Diffuse myocardial disease is a characteristic feature in HCM, and an early manifestation of sarcomere–gene mutations in subexpressed family members (G+P− subjects). This study aimed to investigate whether detecting diffuse myocardial disease by T1 mapping can discriminate between HCM versus hypertensive heart disease as well as to detect genetically driven interstitial changes in the G+P− subjects. Methods and Results—Patients with diagnoses of HCM or hypertension (HCM, n=95; hypertension, n=69) and G+P− subjects (n=23) underwent a clinical cardiovascular magnetic resonance protocol (3 tesla) for cardiac volumes, function, and scar imaging. T1 mapping was performed before and >20 minutes after administration of 0.2 mmol/kg of gadobutrol. Native T1 and extracellular volume fraction were significantly higher in HCM compared with patients with hypertension (P<0.0001), including in subgroup comparisons of HCM subjects without evidence of late gadolinium enhancement, as well as of hypertensive patients LV wall thickness of >15 mm (P<0.0001). Compared with controls, native T1 was significantly higher in G+P− subjects (P<0.0001) and 65% of G+P− subjects had a native T1 value >2 SD above the mean of the normal range. Native T1 was an independent discriminator between HCM and hypertension, over and above extracellular volume fraction, LV wall thickness and indexed LV mass. Native T1 was also useful in separating G+P− subjects from controls. Conclusions—Native T1 may be applied to discriminate between HCM and hypertensive heart disease and detect early changes in G+P− subjects.

T1 Mapping in Discrimination of Hypertrophic Phenotypes

Background— The differential diagnosis of left ventricular (LV) hypertrophy remains challenging in clinical practice, in particular, between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness because of systemic hypertension. Diffuse myocardial disease is a characteristic feature in HCM, and an early manifestation of sarcomere–gene mutations in subexpressed family members (G+P− subjects). This study aimed to investigate whether detecting diffuse myocardial disease by T1 mapping can discriminate between HCM versus hypertensive heart disease as well as to detect genetically driven interstitial changes in the G+P− subjects. Methods and Results— Patients with diagnoses of HCM or hypertension (HCM, n=95; hypertension, n=69) and G+P− subjects (n=23) underwent a clinical cardiovascular magnetic resonance protocol (3 tesla) for cardiac volumes, function, and scar imaging. T1 mapping was performed before and >20 minutes after administration of 0.2 mmol/kg of gadobutrol. Native T1 and extracellular volume fraction were significantly higher in HCM compared with patients with hypertension ( P 15 mm ( P 2 SD above the mean of the normal range. Native T1 was an independent discriminator between HCM and hypertension, over and above extracellular volume fraction, LV wall thickness and indexed LV mass. Native T1 was also useful in separating G+P− subjects from controls. Conclusions— Native T1 may be applied to discriminate between HCM and hypertensive heart disease and detect early changes in G+P− subjects.Background—The differential diagnosis of left ventricular (LV) hypertrophy remains challenging in clinical practice, in particular, between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness because of systemic hypertension. Diffuse myocardial disease is a characteristic feature in HCM, and an early manifestation of sarcomere–gene mutations in subexpressed family members (G+P− subjects). This study aimed to investigate whether detecting diffuse myocardial disease by T1 mapping can discriminate between HCM versus hypertensive heart disease as well as to detect genetically driven interstitial changes in the G+P− subjects. Methods and Results—Patients with diagnoses of HCM or hypertension (HCM, n=95; hypertension, n=69) and G+P− subjects (n=23) underwent a clinical cardiovascular magnetic resonance protocol (3 tesla) for cardiac volumes, function, and scar imaging. T1 mapping was performed before and >20 minutes after administration of 0.2 mmol/kg of gadobutrol. Native T1 and extracellular volume fraction were significantly higher in HCM compared with patients with hypertension (P<0.0001), including in subgroup comparisons of HCM subjects without evidence of late gadolinium enhancement, as well as of hypertensive patients LV wall thickness of >15 mm (P<0.0001). Compared with controls, native T1 was significantly higher in G+P− subjects (P<0.0001) and 65% of G+P− subjects had a native T1 value >2 SD above the mean of the normal range. Native T1 was an independent discriminator between HCM and hypertension, over and above extracellular volume fraction, LV wall thickness and indexed LV mass. Native T1 was also useful in separating G+P− subjects from controls. Conclusions—Native T1 may be applied to discriminate between HCM and hypertensive heart disease and detect early changes in G+P− subjects.