Martin M. LeWinter

Pharmacologic and Hemodynamic Influences on the Rate of Isovolumic Left Ventricular Relaxation in the Normal Conscious Dog

We studied the effects of acute pharmacologic and hemodynamic interventions on isovolumic left ventricular relaxation in 19 conscious dogs using micromanometer tip catheters. Isoproterenol (11 studies) augmented peak rate of rise of left ventricular pressure [(+) dP/dt] by 1,275+/-227 (SE) mm Hg/s (P < 0.001) and dP/dt at an isopressure point of 35 mm Hg during isovolumic relaxation [(-) dP/dt(35)] by 435+/-80 mm Hg/s (P < 0.001). Peak (-) dP/dt decreased by 467+/-89 mm Hg/s (P < 0.002). The time constant, T, derived from the logarithmic fall of pressure during isovolumic relaxation, shortened from 20+/-2.8 to 14.9+/-1.8 ms (P < 0.003). Calcium (11 studies) increased peak (+) dP/dt and (-) dP/dt(35) (both P < 0.0001); peak (-) dP/dt was unchanged. T shortened from 20.4+/-1.8 to 17.3+/-1.5 ms (P < 0.002). Volume (13 studies) did not affect either dP/dt or T. Phenylephrine (13 studies) augmented peak (-) dP/dt, but reduced (-) dP/dt(35) (both P < 0.01); T lengthened from 22.1+/-1.5 to 32.5+/-1.5 ms (P < 0.01). In 15 studies, rapid atrial pacing increased peak (+) dP/dt and (-) dP/dt(35) (both P < 0.01). In the first post-pacing beat, peak (-) dP/dt and (-) dP/dt(35) decreased (both P < 0.01), although peak (+) dP/dt increased further. T paralleled values of (-) dP/dt(35). In five dogs, beta adrenergic blockade had no significant effect on any variable after calcium, volume, or phenylephrine infusion or during or after atrial pacing when the pre-and post-propranolol states were compared. We conclude that positive inotropic interventions augment both left ventricular contraction and relaxation. The changes in isovolumic relaxation are independent of alterations in sympathetic tone produced by beta-adrenergic blockade. Peak (-) dP/dt may not be a valid measure of left ventricular relaxation rate during acute alterations in inotropic state or afterload.

Right ventricular ejection fraction in patients with acute anterior and inferior myocardial infarction assessed by radionuclide angiography.

SUMMARYWe measured right and left ventricular ejection fraction (EF) from high frequency time-activity curves obtained during the initial passage of an intravenous bolus of 99mTc (Sn) pyrophosphate. In 22 normal controls right ventricular EF averaged 0.52 ± 0.04 (SD). In 24 acute anterior or lateral infarction patients right ventricular EF was normal (0.56 ± 0.10), while left ventricular EF was reduced (0.45 ± 0.10, P < 0.001 vs controls). In 19 acute inferior infarction patients left ventricular EF also was depressed (0.51 ± 0.09, P < 0.001 vs controls). Among 7 of 19 inferior infarc- tion patients with right ventricular infarction by scintigraphy, right ventricular EF was reduced (0.39 ± 0.05; P < 0.001 vs normals; P < 0.01 vs inferior infarction patients without right ventricular involvement). In the latter group right ventricular EF averaged 0.51 ± 0.10 (NS vs normals). We conclude 1) a single injection of 19mTc (Sn) pyrophosphate can identify right and left ventricular dysfunction and infarct location in acute myocardial infarction, 2) right ventricular EF is well-preserved except when inferior infarction involves the right ventricle.

Prognosis after extension of myocardial infarct: the role of Q wave or non-Q wave infarction.

We examined whether or not subsets of patients with extension of myocardial infarct were at high risk for early and late mortality. Some data suggest increased risk in patients with non-Q wave infarcts and we hypothesized that infarct extension in this group might be associated with a poorer prognosis than that for patients with extension of Q wave infarcts. A total of 1253 patients with acute myocardial infarction who were included in our data base were followed prospectively. The patients were classified according to electrocardiographic results into the following groups: those with non-Q wave (n = 277) infarcts and those with Q-anterior (n = 462) and Q-inferior (n = 497) infarcts. Extension was diagnosed by two of the following criteria: (1) recurrent chest pain 24 hr or more after admission to the hospital, (2) new persistent electrocardiographic changes, and (3) elevation or reappearance of creatine kinase. By these criteria 85 (6%) patients had extension (8% of non-Q wave infarcts, 6% of Q-anterior infarcts, and 6% of Q-inferior infarcts). Hospital mortality in patients with extension was 15% in those with Q wave infarcts vs 43% in those with non-Q wave infarcts (p less than .01). Nine hundred and fifty-two patients were followed for 1 year. In 24% of those who did not survive 1 year there was extension of infarct; only 6% of survivors had extension (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Altered Crossbridge Kinetics in the αMHC403/+ Mouse Model of Familial Hypertrophic Cardiomyopathy

A mutation in the cardiac beta-myosin heavy chain, Arg403Gln (R403Q), causes a severe form of familial hypertrophic cardiomyopathy (FHC) in humans. We used small-amplitude (0.25%) length-perturbation analysis to examine the mechanical properties of skinned left ventricular papillary muscle strips from mouse hearts bearing the R403Q mutation in the alpha-myosin heavy chain (alphaMHC403/+). Myofibrillar disarray with variable penetrance occurred in the left ventricular free wall of the alphaMHC403/+ hearts. In resting strips (pCa 8), dynamic stiffness was approximately 40% greater than in wild-type strips, consistent with elevated diastolic stiffness reported for murine hearts with FHC. At pCa 6 (submaximal activation), strip isometric tension was approximately 3 times higher than for wild-type strips, whereas at pCa 5 (maximal activation), tension was marginally lower. At submaximal calcium activation the characteristic frequencies of the work-producing (b) and work-absorbing (c) steps of the crossbridge were less in alphaMHC403/+ strips than in wild-type strips (b=11+/-1 versus 15+/-1 Hz; c= 58+/-3 versus 66+/-3 Hz; 27 degrees C). At maximal calcium activation, strip oscillatory power was reduced (0. 53+/-0.25 versus 1.03+/-0.18 mW/mm3; 27 degrees C), which is partly attributable to the reduced frequency b, at which crossbridge work is maximum. The results are consistent with the hypothesis that the R403Q mutation reduces the strong binding affinity of myosin for actin. Myosin heads may accumulate in a preforce state that promotes cooperative activation of the thin filament at submaximal calcium but blunts maximal tension and oscillatory power output at maximal calcium. The calcium-dependent effect of the mutation (whether facilitating or debilitating), together with a variable degree of fibrosis and myofibrillar disorder, may contribute to the diversity of clinical symptoms observed in murine FHC.

Prediction of late mortality after myocardial infarction from variables measured at different times during hospitalization

The long-term prognostic importance of sets of variables from different times in the hospital course after acute myocardial infarction was examined in 818 patients discharged from the hospital. Cardiac mortality during the first year after discharge was 11.1%. For the end point death within 1 year after admission, discriminant function analysis identified 5 important factors from the history and the first 24 hours of hospitalization: maximal level of blood urea nitrogen, previous myocardial infarction, age, displaced left ventricular apex (abnormal apex) on physical examination, and sinus bradycardia (negative correlation). When data from the entire hospitalization were included, extension of infarction and maximal heart rate were also selected. When variables obtained at discharge were included, only the presence of S3 gallop and abnormal apex were selected. In subgroups of patients, neither the left ventricular ejection fraction nor the presence of complex ventricular arrhythmias during a 24-hour ambulatory monitoring were independent predictors. Correct prediction was similar for each analysis, with 55 to 60% of the deaths and 79 to 81% of survivors correctly identified. The high-risk group consisted of 25% of the patients with 28 to 30% predictive value for death in the first year. In conclusion, outcome up to 1 year after acute myocardial infarction can be predicted early after admission. Addition of more information later during the hospitalization and at discharge did not improve correct prediction and may be redundant for prognostic evaluation.

Relationship between myocardial fiber direction and segment shortening in the midwall of the canine left ventricle.

Myocardial fiber orientation undergoes an orderly transition from the epicardium to the endocardium in the left ventricle, with circumferential fibers predominating in the middle one-third of the heart wall. How fibers lying at different depths in the myocardium, running in different directions, interact to produce local deformation is not known. To define the relationship between the orientation of uniaxial myocardial fibers and local wall motion, we placed three sets of ultrasonic dimension gauges in the middle one-third of the apex-to-base distance of the left ventricle of nine dogs. One pair was placed in line and two intentionally out of line with the presumed local fiber direction. The relative angle between the gauge and the local myofibers was determined by the use of postmortem radiography and histological techniques. Our results show that in the midwall of the left ventricle, myocardial segment shortening is maximal in the direction of local fibers; the shortening measured by gauges placed out of line with the local fiber axis by more than 30° was significantly less than the actual in-line fiber shortening which occurred. This suggests that functional tethering between midwall fibers and endocardial or epicardial fibers does not play a major role in the pattern of midwall deformation. We also documented that an external reference line can be used to predict midwall myofiber direction. Using this line as a guide, ultrasonic dimension gauges could be placed within an average of 12° (range: 0.5 to 18.5°) from the local fiber axis.

Diastolic viscous properties of the intact canine left ventricle.

The diastolic viscous properties of the intact heart were studied in seven conscious dogs and in four right heart bypass preparations. The passive elastic properties were first determined by fitting a linear relation between the natural logarithm (hi) of the left ventricular pressure and the diameter or between In of the diastolic wall stress and the strain (r - 0.93-0.99). When the velocity of lengthening was less than 1 diam/sec, the pressure and stress data fell within the 95% confidence interval of the static elastic curve, both at low and high strain. At velocities of lengthening greater than 1 diam/sec, the pressure and stress values always deviated from the passive elastic relationship, but the magnitude of this deviation was not linearly related to the velocity of lengthening. When pressure and stress data at high velocities of lengthening were compared, the pressure or stress deviation from the passive elastic curve was always greater at high diameter than at low diameter. Moreover, the pressure and stress data at the time of minimum left ventricular pressure after systole showed greater deviation from the passive curve than expected from the diameter and the velocity of lengthening alone (+8 mm Hg in conscious dogs, P < 0.002; +2.4 mm Hg in open-chest dogs, P < 0.05), suggesting incomplete ventricular relaxation at that time. We conclude that the viscous properties of the left ventricle, like those of isolated cardiac muscle, are not linear but increase with length. These observations, together with the influence of incomplete ventricular relaxation in early diastole, preclude the determination of diastolic properties from only one diastolic cycle. Ore Res 45: 410-419, 1979

Titin is a major human disease gene

Titin is a giant multi-functional sarcomeric filament that provides passive stiffness to cardiac myocytes. At its N terminus, titin is embedded in the Z-disk of the sarcomere. The rest of the molecule is divided between an elastic I-band region, a thick filament-binding A-band region, and the M-band region where the C terminus is embedded (Figure 1A, bottom).1 The extensible I-band region of titin functions as a molecular spring that develops passive force during diastole when sarcomeres are stretched.2 This force is important for centering the A-band in the sarcomere3 and, together with the extracellular matrix, for defining diastolic stiffness.2 Other regions of titin (Z-disk, A-band, and M-band) are involved in numerous cellular processes including force-dependent signaling.4 Here we discuss recently discovered post-transcriptional and post-translational modifications of titin and address their roles in acquired cardiac disease, including dilated cardiomyopathy (DCM) and heart failure with preserved ejection fraction (HFpEF, often termed diastolic heart failure; for the purposes of this study we restrict the term HFpEF to HF patients with left ventricular EF > 0.50 in the absence of hypertrophic cardiomyopathy or valvular, infiltrative, or pericardial disease). The review also focuses on recent work that reveals mutations in the titin gene as a major source of familial cardiomyopathies, including mutations in the spring region of titin linked to arrhythmogenic right ventricular dysplasia5 and mutations in the A-band region of titin responsible for ≈30% of DCM cases.6 These findings have given rise to the emerging view that titin gene is a major disease gene. Figure 1. Schematic of titin in the sarcomere ( A ) and mechanisms for modifying titin-based passive tension ( B and C ). A , Bottom: Single titin molecules (shown in blue and yellow) span from Z-disk (N terminus) to M-band (C terminus). Middle: Composition of extensible I-band …

Metabolic Syndrome, Inflammation, and Incident Heart Failure in the Elderly The Cardiovascular Health Study

Background—Inflammation markers and metabolic syndrome (MetS) are associated with risk of congestive heart failure (CHF). We evaluated whether combining inflammation markers and MetS provided additive information for incident CHF and if incorporating inflammation markers to the MetS definition added prognostic information. Methods and Results—We studied 4017 men and women ≥65 years old, without baseline CHF or diabetes, participating in the Cardiovascular Health Study, an observational study with 12.2 years follow-up and 966 cases of incident CHF. Baseline “C-reactive protein (CRP)-MetS” or “interleukin (IL)-6–MetS” were defined as presence of 3 out of 6 components, with elevated CRP (≥3 mg/L) or IL-6 (≥2.21 pg/mL) as a sixth component added to ATPIII criteria. Cox models adjusted for CHF risk factors and incident coronary disease were used to calculate hazard ratios for CHF. MetS and elevated inflammation markers were independently associated with CHF risk (hazard ratios, 95% CI: 1.32, 1.16 to 1.51 for MetS; 1.53, 1.34 to 1.75 for CRP; 1.37, 1.19 to 1.55 for IL-6). There was a 20% relative excess risk attributed to the combination of MetS and CRP (95% CI, −44% to 88%). CRP-MetS and IL-6–MetS definitions reclassified 18% and 13%, respectively of participants as MetS. Both CRP-MetS and IL-6–MetS increased risk of CHF by 60% compared with those without MetS. Conclusion—MetS and inflammation markers provided additive information on CHF risk in this elderly cohort. Inflammation-incorporated MetS definitions identified more participants with the same risk level as ATPIII MetS. Considering inflammation markers and MetS together may be useful in clinical and research settings.

Efficacy of a new oral agent (tocainide) in the acute treatment of refractory ventricular arrhythmias

To assess the efficacy of tocainide, a new oral analog of lidocaine, 30 patients with ventricular arrhythmias refractory to quinidine, procainamide and propranolol were treated with this agent. The dose of tocainide ranged from 400 to 800 mg every 8 hours. Peak tocainide blood levels 1 to 4 hours after administration ranged from 5.0 to 15.0 microgram/ml (mean 10.3). The suppression of ventricular premature beats by 75 percent or more was arbitrarily used as a measure of drug efficacy. In 13 patients who met this criterion, ventricular premature complexes, assessed with 24 hour ambulatory tape monitoring, decreased by an average of 88 percent. In 8 of 11 patients, repeated symptomatic bouts of ventricular tachycardia were completely suppressed. Considering both the response of ventricular premature complexes and the abolition of ventricular tachycardia, 18 patients (60 percent) responded to tocainide. Twenty-one patients (70 percent) had initial gastrointestinal and central nervous system side effects; most of these were transient or responded to a reduction in dose. In two patients disorientation and a skin rash required withdrawal of tocainide. These adverse effects did not appear to be due to the interaction of tocainide with other antiarrhythmic agents. It is concluded that tocainide is an effective oral agent for the therapy of potentially lethal ventricular arrhythmias refractory to other medication.